Combination therapy of ursodeoxycholic acid and glucocorticoid and (or) immunosuppressant in patients with primary biliary cholangitis: A meta-analysis

Background/objectives:Primary biliary cholangitis (PBC) is a chronic inflammatory autoimmune cholestasis liver disease. There were many studies comparing a combination of glucocorticoids and/or immunosuppressants to a single UDCA therapy in PBC patients, while the literature demonstrated divergent finds. To evaluate the effectiveness of ursodeoxycholic acid (UDCA) combined with glucocorticoids and (or) immunosuppressants on biochemistry, immunology, histology, clinical symptoms, and adverse reactions of PBC from the perspective of evidence-based medicine.Materials and methods:PubMed, web of science, the Cochrane Library, EMBASE databases were searched to collect clinical randomized trials and self-control studies of UDCA combined with glucocorticoids and (or) immunosuppressants and UDCA monotherapy in the treatment of PBC. The retrieval time is from the establishment of the database to August 2020. Two reviewers independently screened literature, extracted data and evaluated the bias of included studies. Revman 5.3 software was used for meta-analysis.Results:Six studies including 201 patients were included. The meta-analysis found that the combination therapy can improve some biochemical indexes, immunological indexes, and clinical symptoms of patients with PBC. However, combination therapy has no significant improvement in other biochemical indicators which respond to liver and bile duct damage, such as ALT, GGT, and ALB. Besides, the improvement of liver histology is limited, and the incidence of adverse events is higher.Conclusion:Overall, the combination therapy showed no improvement in key biochemical parameters and limited improvement in liver pathology. Besides, the side effects were more serious. Therefore, in the current treatment regimen, it is not recommended for PBC patients.     

Effect of the Anti‐C1s Humanized Antibody TNT009 and Its Parental Mouse Variant TNT003 on HLA Antibody–Induced Complement Activation—A Preclinical In Vitro Study

The classic pathway (CP) of complement is believed to significantly contribute to alloantibody‐mediated transplant injury, and targeted complement inhibition is currently considered to be a promising approach for preventing rejection. Here, we investigated the mode of action and efficacy of the humanized anti‐C1s monoclonal antibody TNT009 and its parental mouse variant, TNT003, in preclinical in vitro models of HLA antibody–triggered CP activation. In flow cytometric assays, we measured the attachment of C1 subcomponents and C4/C3 split products (C4b/d, C3b/d) to HLA antigen–coated flow beads or HLA‐mismatched aortic endothelial cells and splenic lymphocytes. Anti‐C1s antibodies profoundly inhibited C3 activation at concentrations >20 μg/mL, in both solid phase and cellular assays. While C4 activation was also prevented, this was not the case for C1 subcomponent attachment. Analysis of serum samples obtained from 68 sensitized transplant candidates revealed that the potency of inhibition was related to the extent of baseline CP activation. This study demonstrates that anti‐C1s antibodies TNT009 and TNT003 are highly effective in blocking HLA antibody–triggered complement activation downstream of C1. Our results provide the foundation for clinical studies designed to investigate the potential of TNT009 in the treatment or prevention of complement‐mediated tissue injury in sensitized transplant recipients.     

Cutaneous Toxicities From Transplantation‐Related Medications

Despite the abundance of information on cutaneous malignancies associated with solid organ transplantation in the transplant literature, there is limited information regarding nonmalignant skin changes after transplantation. There are numerous skin toxicities secondary to immunosuppressive and other transplant‐related medications that can vary in presentation, severity, and prognosis. To limit associated morbidity and mortality, solid organ transplant recipient care providers should effectively identify and manage cutaneous manifestations secondary to drug toxicity. Toxicities from the following transplant‐related medications will be discussed: antithymocyte globulins, systemic steroids, cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil, mammalian target of rapamycin inhibitors sirolimus and everolimus, basiliximab and daclizumab, belatacept, and voriconazole.     

Determining the effect of immunosuppressant adherence on graft failure risk among renal transplant recipients

The objective was to use the United States Renal Data System (USRDS) to quantify the relationship between immunosuppressant therapy (IST) adherence and risk of graft failure among adult renal transplant recipients (RTRs). A secondary objective was to examine the relationship among select patient characteristics and IST adherence. The study sample included adult RTRs who: received primary transplant between January 1, 1999 and December 31, 2005; experienced graft survival for at least 12 months post‐transplant and had at least 12 months of data in the USRDS; utilized Medicare coverage for IST; and were prescribed cyclosporine or tacrolimus. IST adherence was measured by medication possession ratio (MPR). Pearson chi‐square tests were used to examine associations between patient characteristics and MPR quartiles. Cox proportional hazards regression was used to assess relationships among time to graft failure, MPR, and patient characteristics. Thirty‐one thousand nine hundred and thirteen RTRs met inclusion criteria. Older age, female gender, white race, deceased donors, and tacrolimus were associated with greater adherence (p < 0.001). Cox proportional hazard modeling indicated greater adherence, white race, and having a living donor were significantly associated with longer graft survival (p < 0.05). Future prospective studies should further examine the clinical significance of IST nonadherence as it relates to graft failure.     

Biological activities of 3,4,5‐trihydroxypiperidines and their N‐ and O‐derivatives

3,4,5‐Trihydroxypiperidines belong to the family of 1,5‐dideoxy‐1,5‐iminosugar natural products and are structural analogues of pentose monosaccharides in the pyranose form. The biological activities of these apparently structurally simple molecules and their N‐ and O‐alkylated and ‐arylated derivatives are no less remarkable than their C‐6 hydroxymethyl counterparts of the hexoses (such as 1‐deoxynojirimycin, DNJ). Their biological profiles indicate that the hydroxymethyl branch is crucial to neither potency nor selectivity, with O‐alkylation demonstrated to produce exquisite selectivity extending beyond glycosidase inhibition, to immunosuppressant and antibacterial activities.     

Three-year outcomes from the CRADLE study in de novo pediatric kidney transplant recipients receiving everolimus with reduced tacrolimus and early steroid withdrawal

CRADLE was a 36-month multicenter study in pediatric (≥1 to <18 years) kidney transplant recipients randomized at 4 to 6 weeks posttransplant to receive everolimus + reduced-exposure tacrolimus (EVR + rTAC; n = 52) with corticosteroid withdrawal at 6-month posttransplant or continue mycophenolate mofetil + standard-exposure TAC (MMF + sTAC; n = 54) with corticosteroids. The incidence of composite efficacy failure (biopsy-proven acute rejection [BPAR], graft loss, or death) at month 36 was 9.8% vs 9.6% (difference: 0.2%; 80% confidence interval: −7.3 to 7.7) for EVR + rTAC and MMF + sTAC, respectively, which was driven by BPARs. Graft loss was low (2.1% vs 3.8%) with no deaths. Mean estimated glomerular filtration rate at month 36 was comparable between groups (68.1 vs 67.3 mL/min/1.73 m²). Mean changes (z-score) in height (0.72 vs 0.39; P = .158) and weight (0.61 vs 0.82; P = .453) from randomization to month 36 were comparable, whereas growth in prepubertal patients on EVR + rTAC was better (P = .050) vs MMF + sTAC. The overall incidence of adverse events (AEs) and serious AEs was comparable between groups. Rejection was the leading AE for study drug discontinuation in the EVR + rTAC group. In conclusion, though AE-related study drug discontinuation was higher, an EVR + rTAC regimen represents an alternative treatment option that enables withdrawal of steroids as well as reduction of CNIs for pediatric kidney transplant recipients. ClinicalTrials.gov: NCT01544491.     

Effects of mTOR inhibitor–related proteinuria on progression of cardiac allograft vasculopathy and outcomes among heart transplant recipients

We have previously described the use of sirolimus (SRL) as primary immunosuppression following heart transplantation (HT). The advantages of this approach include attenuation of cardiac allograft vasculopathy (CAV), improvement in glomerular filtration rate (GFR), and reduced malignancy. However, in some patients SRL may cause significant proteinuria. We sought to investigate the prognostic value of proteinuria after conversion to SRL. CAV progression and adverse clinical events were studied. CAV progression was assessed by measuring the Δ change in plaque volume (PV) and plaque index (PI) per year using coronary intravascular ultrasound. Proteinuria was defined as Δ urine protein ≥300 mg/24 h at 1 year after conversion to SRL. Overall, 137 patients were analyzed (26% with proteinuria). Patients with proteinuria had significantly lower GFR (P = .005) but similar GFR during follow-up. Delta PV (P < .001) and Δ PI (P = .001) were significantly higher among patients with proteinuria after adjustment for baseline characteristics. Multivariate Cox regression analysis showed higher all-cause mortality (hazard ratio 3.8; P = .01) with proteinuria but similar risk of CAV-related events (P = .61). Our results indicate that proteinuria is a marker of baseline renal dysfunction, and that HT recipients who develop proteinuria after conversion to SRL have less attenuation of CAV progression and higher mortality risk.     

Complement inhibition for prevention of antibody-mediated rejection in immunologically high-risk heart allograft recipients

Allosensitization represents a major barrier to heart transplantation (HTx). We assessed the efficacy and safety of complement inhibition at transplant in highly sensitized heart transplant recipients. We performed a single-center, single-arm, open-label trial (NCT02013037). Patients with panel reactive antibodies (PRA) ≥70% and pre–formed donor-specific antibodies (DSA) were eligible. In addition to standard of care, patients received nine infusions of eculizumab during the first 2 months posttransplant. The primary composite endpoint was antibody-mediated rejection (AMR) ≥pAMR2 and/or left ventricular dysfunction during the first year. Secondary endpoints included hemodynamic compromise, allograft rejection, and patient survival. Twenty patients were included. Median cPRA and mean fluorescence intensity of immunodominant DSA were 95% (90%–97%) and 6250 (5000–10 000), respectively. Retrospective B cell and T cell flow crossmatches were positive in 14 and 11 patients, respectively. The primary endpoint occurred in four patients (20%). Survival at 1 year was 90% with no deaths resulting from AMR. In a prespecified analysis comparing treated patients to matched control patients, we observed a dramatic reduction in the risk of biopsy-proven AMR in patients treated with eculizumab (HR = 0.36, 95% CI = 0.14–0.95, p = .032). Our findings support the prophylactic use of complement inhibition for heart transplantation at high immunological risk. ClinincalTrials.gov, NCT02013037.