Immunosuppressive Therapy Group Research Articles

Efficacy of prednisone combined with mycophenolate mofetil for immunoglobulin A nephropathy with moderate-to-severe renal dysfunction.

Immunoglobulin A nephropathy (IgAN) is a common form of chronic glomerulonephritis. Currently, IgAN is one of the main causes of chronic renal failure in China; its prognosis varies greatly between patients, with renal function at the time of diagnosis and prognosis being strongly correlated. Mycophenolate mofetil (MMF) is a drug with a good immunomodulatory effect and is commonly used clinically. However, its effects in IgAN have not yet been clearly demonstrated. Therefore, herein, we retrospectively compared the effectiveness and safety of prednisone alone or combined with MMF for the treatment of primary IgAN with moderate-to-severe renal impairment. To evaluate the effectiveness and safety of prednisone and MMF in treating IgAN with moderate-to-severe renal dysfunction. Between January 2011 and December 2020, 200 patients with moderate-to-severe IgAN were included in this study, all of whom were admitted to Wuxi People's Hospital affiliated with Nanjing Medical University. All patients underwent a renal puncture biopsy, which revealed primary IgAN with a glomerular filtration rate (GFR) of 30-60 mL/min. The patients were divided into a glucocorticoid therapy group (GTG) and an immunosuppressive therapy group (ITG) according to the different treatment regimens, with 100 patients in each group. Based on general treatments, such as angiotensin-converting enzyme inhibitors/ angiotensin receptor blockers, patients in the GTG were administered prednisone 0.5-0.8 mg/ (kg·d-1) for 4-8 wk, which was reduced by 5 mg every two weeks until the maintenance(30 mg/d) dose was reached and maintained for 12 mo. In the ITG, MMF was administered at 1.0 g/d for 6-12 mo, followed by a maintenance dosage of 0.5 g/d for 12 mo. Age, sex, blood pressure, 24-h urinary egg white measurement, serum creatinine (Scr), blood uric acid, blood albumin, blood potassium (K), hemoglobin, GFR, alanine aminotransferase, total cholesterol (T-CHO), fasting blood glucose, and body mass index were recorded. The 24-h urinary protein, Scr, and GFR levels were recorded 3, 6, 9, and 12 mo after treatment. Follow-up data were also collected. No discernible differences existed between the two groups in terms of age, sex, blood pressure, creatinine, 24-h urinary protein level, GFR, or other biochemical indicators at the time of enrollment. Both regimens significantly reduced the 24-h urinary protein quantitation and stabilized renal function. Nine months after treatment, the 24-h urinary protein and Scr of the ITG decreased more significantly than those of the GTG. By the 12th month of treatment, the 24-h urinary protein and Scr in both groups continued to decrease compared to those by the 9th month. In addition, the overall response rate in the ITG was significantly higher than that in the GTG. The occurrence of side effects did not vary significantly between the two regimens; however, endpoint events were significantly more common in the GTG than in the ITG. The follow-up time for the GTG was noticeably lower than that for the ITG. Prednisone combined with MMF was effective for the treatment of IgAN with moderate-to-severe renal dysfunction.

Overall Survival and Erythroid Response in Patients with Low-Risk Myelodysplastic Neoplasms after First-Line Treatment in a Low-Middle Income Country

Introduction Myelodysplastic neoplasms/syndromes (MDS) are a heterogeneous group of clonal disorders characterized by ineffective hematopoiesis and an increased risk of transformation to acute myeloid leukemia (AML). Current standard risk stratification model, the Revised International Prognostic Scoring System (IPSS-R), classifies patients into lower (≤3.5 points) or higher risk MDS. Lower-risk MDS (LR-MDS) treatment is based on the prevailing cytopenia and intends to improve symptomatic burden and minimize transfusion dependency. Anemia is present in 80-90% of patients with MDS. Throughout most of the course of the disease, patients with MDS have a hemoglobin < 10 g/dL, which leads to a decreased quality of life. Also, 50% of patients with MDS will eventually need red blood cell transfusions. Current options for the active treatment of anemia in LR-MDS are limited and vary among countries. Although erythropoiesis stimulating agents (ESAs) are considered standard of care in the absence of del5q, immunosuppressive therapy (IST) and androgens are still used in low income countries. The present study aims to evaluate whether erythroid responses and overall survival differ in patients with LR-MDS, based on their first-line treatment. Methods This is a retrospective study in patients with LR-MDS at Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, a tertiary care center in Mexico City. Eligible patients were diagnosed between January 2002 and December 2022 according to World Health Organization (WHO) 2016 criteria. Response was assessed according to International Working Group (IWG) 2018 criteria. We defined erythroid response (HI-E) as the sum of the responses achieved within different transfusion burden categories. First line therapy included ESAs, IST (cyclosporine ± eltrombopag), and androgens (mesterolone, danazol). These were compared through bivariate analysis, Kaplan-Meier curves and log-rank test. Results Until December 2022, 109 LR-MDS patients were considered for inclusion. Among them, 29 patients were lost to follow-up, and 25 patients were solely observed without any further therapy. Also, 7 patients who received other therapies were excluded. Ultimately, 48 patients were included in this analysis, 56.3% (n=27) were female, mean age was 62.8 (±15.9) years. Based on WHO 2016 classification, MDS with uni- and multilineage dysplasia was present in 58.3% (n=28) of the patients, while 29.2% (n=14) had hypoplastic MDS. Anemia was present in 89.6% (n=43) of the patients. When evaluating transfusion burden, 37.5% (n=18) of patients were non-transfusion dependent (NTD), 31.3% (n=15) low-transfusion burden (LTB), and another 31.3% (n=15) high-transfusion burden (HTB). ESAs and IST were the most frequently used frontline therapies, each accounting for 41.7% (n=20) of the patients; the remaining 16% (n= 8) received androgens. When comparing baseline characteristics between treatment arms, we found lower hemoglobin values and a greater proportion of severe anemia in ESA-treated patients (p= 0.039, p= 0.036), however, no differences in transfusion burden was observed (p= 0.212). Erythroid response rates were 25% (n=5), 20% (n=4) and 62.5% (n=5) among those treated with ESAs, IST and androgens, respectively (p= 0.071). When assessing HI-E by transfusion burden, no differences were observed between treatment arms except in HTB patients (p= 0.023). Neither time to response, nor duration of response were significantly different between treatment groups ( Table 1). Importantly, 3 of the 4 responders in the IST group received cyclosporine monotherapy, also 50% were hypoplastic MDS. After a median follow up of 47 months (IQR:22.5-85.5), the median overall survival(OS) for the entire cohort was not reached. The 3-year-OS rates for IST, ESA and androgens were 94%, 54% and 50%, respectively (p= 0.018) ( Figure 1). Conclusions In spite of the bias and limitations in the retrospective nature of this study, IST seems to be a valid option in frontline therapy for LR-MDS, since HI-E rates are similar to those observed with ESAs. Additionally, IST group showed a better OS. Results obtained with androgens merit further study and should be interpreted with caution because of the sample size.

Comparison of Hematopoietic Stem Cell Transplantation and Repeated Immunosuppressive Therapy As Second-Line Treatment for Relapsed/Refractory Severe Aplastic Anemia

The optimal treatment for patients with severe aplastic anemia (SAA) who fail or have relapse after an initial course of immunosuppressive therapy (IST) has not been established. We conducted a retrospective study to compare the effectiveness of allogeneic hematopoietic stem cell transplantation (allo-HSCT) (n = 36) with repeated IST (n = 33) as salvage therapy for relapsed/refractory SAA between 2007 and 2022. In the repeated IST group, patients were treated with antithymocyte globulin (ATG) (n = 16) or high-dose cyclophosphamide (HD-CTX) (n = 17). The overall response rate was 42.4% at 6 months, and 60.6% at 12 months. In the HSCT group, 6 were matched sibling donor (MSD), 7 were matched unrelated donor (MUD), and 23 were haploidentical donor (HID). All patients achieved neutrophil engraftment and no primary graft failure was observed. The rate of platelet engraftment was 88.9%, with a median time of 16 days. The cumulative incidences of grade II-IV, III-IV acute GVHD was 36.1% ± 0.7%, 13.9% ± 0.3% at day +100, and chronic GVHD was 36.2% ± 0.7% at 5 years. Compared with IST, HSCT recipients showed much higher hematologic recovery rate at 3-, 6- and 12-months post treatment (63.9%, 83.3% and 86.1%, respectively, P < 0.001). The estimated 5-year overall survival (OS) (79.8% ± 6.8% vs. 80.0% ± 7.3%, p = 0.957) were similar; however, the estimated 5-year failure-free survival (FFS) was significantly better in the HSCT group (79.8% ± 6.8% vs. 55.2% ± 9.2%, p = 0.049). In multivariate analysis, age ≤ 35 years at salvage HSCT was the only favorable factor for OS and FFS ( p = 0.019, 95% CI 0.019-0.706). These results suggest that HSCT and repeated IST are both effective for refractory/relapsed SAA in the salvage setting. Considering the superior FFS in the HSCT cohort, especially in younger patients (age ≤ 35 years), we recommend HSCT instead of a second IST for these patients.

Comparison of anti-thymocyte globulin-based immunosuppressive therapy and allogeneic hematopoietic stem cell transplantation in patients with transfusion-dependent non-severe aplastic anaemia: a retrospective study from a single centre

Objectives The selection and timing of anti-thymocyte globulin (ATG)-based immunosuppressive therapy (IST) or allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with transfusion-dependent non-severe aplastic anemia (TD-NSAA) pose significant clinical challenges. This study aims to compare the efficacy and long-term outcomes of the two treatments in TD-NSAA. Methods Patients who underwent ATG-based IST or allo-HSCT between July 2011 and December 2019 were reviewed. We gathered their clinical information, treatment response, survival data, and subsequently analysed the associated risk factors. Results A total of 97 TD-NSAA patients were reviewed, and 55 patients who underwent either ATG-based IST (n = 27) or allo-HSCT (n = 28) were enrolled. We observed a significant disparity in the 12-month overall response rate (ORR) (48.1% in IST vs 78.6% in HSCT, p < 0.05), but not in five-year overall survival (OS) and event-free survival (EFS). Multivariate Cox regression analysis identified the transfusion of ≥78.75 units of red blood cells (RBCs) as the sole independent risk factor for OS (HR: 17.04, p = 0.039) in the IST group. For the HSCT group, disease duration (DD) ≥20 months and transfusion of ≥78.75 units of RBCs predicted an adverse EFS. Frontline IST exhibited superior 12-month ORR (68.8% vs 18.2%, p = 0.018) and five-year EFS when compared to non-frontline. Patients with a DD ranging from 6 to 20 months displayed a better EFS (p = 0.016) in HSCT group than those in the ATG-based IST group. Conclusions Prior treatment history, disease duration, and serum ferritin levels should be carefully weighed when making the choice between ATG-based IST and allo-HSCT for TD-NSAA.

Efficacy of Selective Laser Trabeculoplasty in Patients on Systemic Immunosuppressive Therapy.

When comparing patients on systemic immunosuppressive therapy to those without, there was no difference in intraocular pressure (IOP) early after SLT; however, at 1 year following SLT, IOP was higher in the immunosuppression group compared with controls. To determine whether patients taking systemic immunosuppressive medications have a different IOP-lowering response to selective laser trabeculoplasty (SLT) compared with a control group of patients. All patients who underwent SLT at Mayo Clinic 2017-2021 were identified. Patients on systemic immunosuppressive medications at the time of SLT were compared with control patients not receiving systemic immunosuppressive medications. The primary endpoints of this study were the percentage IOP reduction at 1 to 2, 3 to 6, and 12 months. Additional analyses included the percentage of patients who did not require additional therapy at each time point. There were 108 eyes of 72 patients that underwent SLT in the immunosuppressed group and 1997 eyes of 1417 patients in the control group. There was no significant difference in age-adjusted change in IOP between groups at the first postoperative visit 1 to 2 months following SLT (-18.8±20.7% vs. -16.0±16.5%, P =0.256) or 3-6 months following SLT (-15.2±21.6% vs. -18.3±23.2%, P =0.062). However, at 12 months following SLT, the IOP reduction in the immunosuppressive therapy group was significantly less compared with the control group (-15.1±21.2% vs. -20.3±22.9%, P =0.045). There was no difference between groups in the number of additional treatments during the study intervals. Patients in the systemic immunosuppressive therapy group showed equivalent early IOP-lowering after SLT compared with a control group, but the treatment response was diminished at 1 year. Further studies investigating IOP regulation after SLT in immunosuppressed patients are needed.

Efficacy subgroup analyses from the phase 3 CHAMPION-NMOSD trial in adults with anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (S5.003)

<h3>Objective:</h3> This prespecified analysis of the CHAMPION-NMOSD global, open-label, multicenter, phase 3, externally controlled study aimed to evaluate the efficacy of ravulizumab in clinically relevant patient subgroups. <h3>Background:</h3> CHAMPION-NMOSD (NCT04201262) is a study of ravulizumab in adults with anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder. Ravulizumab binds to the same complement component 5 epitope as eculizumab; however, its longer elimination half-life extends the dosing interval (every 8 versus 2 weeks). <h3>Design/Methods:</h3> Patients (≥18 years) received a weight-based intravenous loading dose of ravulizumab (2400–3000 mg) on day 1, followed by maintenance doses (3000–3600 mg) on day 15 and once every 8 weeks thereafter. Concurrent placebo treatment was precluded owing to the availability of eculizumab and other treatments; the placebo arm from PREVENT (NCT01892345) was the external comparator. Prespecified efficacy subgroup analyses of time to first adjudicated on-trial relapse (primary endpoint) were conducted and safety outcomes were analyzed across subgroups. <h3>Results:</h3> At baseline, 30/58 ravulizumab-treated patients were receiving monotherapy and 28/58 concomitant immunosuppressive therapy (IST): steroids (n=12), azathioprine (n=7), mycophenolate mofetil (n=6) or other (n=3). No ravulizumab-treated patient experienced a positively adjudicated on-trial relapse. Based on time to first adjudicated on-trial relapse, ravulizumab was superior to placebo in preventing on-trial relapse in monotherapy (HR, 0.021; 95% CI: 0–0.176; relapse risk reduction [RRR], 97.9%; <i>p</i>&lt;0.0001) and IST groups (HR, 0.031; 95% CI: 0–0.234; RRR, 96.9%; <i>p</i>&lt;0.0001). Significant differences versus placebo were seen in patients who had previously received rituximab (n=20; RRR, 93.7%; <i>p</i>=0.0078) or not (n=38; RRR, 98.1%; <i>p</i>&lt;0.0001). Ravulizumab was superior to placebo in prespecified subgroups by age, sex, race and geographic region. Overall safety profile was consistent with that of ravulizumab across other approved indications. <h3>Conclusions:</h3> The robust effect of ravulizumab on RRR was observed across all prespecified subgroups, including ravulizumab monotherapy, concomitant IST use, age, sex, geographic region, and prior rituximab use. <b>Disclosure:</b> Dr. Levy has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Mitsubishi Pharma. Dr. Levy has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB Pharma. Dr. Levy has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi. Dr. Levy has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. Dr. Levy has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Horizon. Dr. Levy has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech. Dr. Levy has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. Dr. Levy has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Various law firms. The institution of Dr. Levy has received research support from National Institutes Health. Dr. Pittock has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genentech, Inc.. Dr. Pittock has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sage Therapeutics, Inc.. The institution of Dr. Pittock has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Astellas. Dr. Pittock has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Prime Therapeutics. Dr. Pittock has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB. Dr. Pittock has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche/Genentech. The institution of Dr. Pittock has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. The institution of Dr. Pittock has received personal compensation in the range of $500-$4,999 for serving as a Consultant for MedImmune/Viela Bio. Dr. Pittock has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Arialys Therapeutics. The institution of Dr. Pittock has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche/Genentech. Dr. Pittock has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB, Inc. Dr. Pittock has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Hoffman/LaRoche AG. Dr. Pittock has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genetech. Dr. Pittock has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for F. Hofman/LaRoche. The institution of Dr. Pittock has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. The institution of Dr. Pittock has received research support from Grifols. The institution of Dr. Pittock has received research support from NIH. The institution of Dr. Pittock has received research support from Viela Bio/MedImmune/Horizon. The institution of Dr. Pittock has received research support from Alexion Pharmaceuticals. The institution of Dr. Pittock has received research support from F. Hoffman/LaRoche/Genentech. The institution of Dr. Pittock has received research support from NovelMed. The institution of Dr. Pittock has received research support from AstaZeneca. Dr. Pittock has received intellectual property interests from a discovery or technology relating to health care. Dr. Pittock has received intellectual property interests from a discovery or technology relating to health care. Michael Barnett has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sydney Neuroimaging Analysis Centre. An immediate family member of Michael Barnett has received stock or an ownership interest from RxMx. The institution of Michael Barnett has received research support from Genzyme Sanofi. The institution of Michael Barnett has received research support from Biogen. The institution of Michael Barnett has received research support from Novartis. Dr. Bennett has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Horizon Therapeutics. Dr. Bennett has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Alexion. Dr. Bennett has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genentech. Dr. Bennett has received personal compensation in the range of $500-$4,999 for serving as a Consultant for TG Therapeutics. Dr. Bennett has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Reistone Bio. Dr. Bennett has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Roche. Dr. Bennett has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Antigenomycs. Dr. Bennett has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Chugai. Dr. Bennett has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Mitsubishi Tanabe. Dr. Bennett has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for EMD Serono. Dr. Bennett has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for MedEdicus. Dr. Bennett has received personal compensation in the range of $500-$4,999 for serving as a Consultant for ImCyse. Dr. Bennett has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Clene Nanomedicine. Dr. Bennett has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Bennett has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Alexion. Dr. Bennett has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Podoll. Dr. Bennett has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Patterson. The institution of Dr. Bennett has received research support from Novartis. The institution of Dr. Bennett has received research support from Alexion. Dr. Bennett has received intellectual property interests from a discovery or technology relating to health care. Dr. Bennett has received publishing royalties from a publication relating to health care. Achim Berthele has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Achim Berthele has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Bayer. Achim Berthele has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Celgene. Achim Berthele has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck. Achim Berthele has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Achim Berthele has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. Achim Berthele has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Achim Berthele has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen. Achim Berthele has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Alexion.Jerome De Seze has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pharma. Jerome De Seze has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pharma. Jerome De Seze has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pharma. Jerome De Seze has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pharma. Jerome De Seze has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pharma. Jerome De Seze has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pharma. Jerome De Seze has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pharma. Jerome De Seze has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pharma. Dr. Nakashima has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. Dr. Nakashima has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Nakashima has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Nakashima has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Chugai. Dr. Nakashima has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Alexion. Dr. Nakashima has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Biogen. Dr. Nakashima has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Novartis. Dr. Nakashima has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Chugai. The institution of Dr. Nakashima has received research support from LSI Medience. Celia Oreja Guevara has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for merck. Celia Oreja Guevara has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for roche. Celia Oreja Guevara has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for sanofi. Celia Oreja Guevara has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for novartis. Celia Oreja Guevara has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for alexion. Dr. Palace has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Merck Serono, Medimmune, Argenx, Janssen, Mitsubushi, UCB, Roche, Novartis, Amplo, Alexion, Chugai, Sanofi. Dr. Palace has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Argenx, Sanofi. Dr. Palace has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Roche, UCB, Alexion, Chugai. Dr. Palace has stock in Astra Zenica. The institution of Dr. Palace has received research support from Roche, AMPLO, Alexion, UCB,.Meddimune, . Dr. Palace has received intellectual property interests from a discovery or technology relating to health care. The institution of Dr. Paul has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Mitsubishi Tanabe PC (MTPC). The institution of Dr. Paul has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Aarhus University. Dr. Paul has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. Dr. Paul has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Paul has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi Genzyme. Dr. Paul has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB Pharma. Dr. Paul has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for CELGENE. Dr. Paul has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bayer. Dr. Paul has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Dr. Paul has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for ACRELION. Dr. Paul has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Viela Bio. Dr. Paul has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Alexion. Dr. Paul has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Dr. Paul has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Pfizter. Dr. Paul has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck Serono. The institution of Dr. Paul has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer. Carlo Pozzilli has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Carlo Pozzilli has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Carlo Pozzilli has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck. Carlo Pozzilli has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Alexion. Kerstin Allen has received personal compensation for serving as an employee of Alexion Pharmaceuticals. Kerstin Allen has stock in AstraZeneca. Kerstin Allen has stock in Alexion Pharmaceuticals. Dr. Mashhoon has received personal compensation for serving as an employee of Alexion, AstraZeneca Rare Disease . Dr. Mashhoon has stock in AstraZeneca. Dr. Yountz has received personal compensation for serving as an employee of Alexion, AstraZeneca Rare Disease. Dr. Yountz has stock in AstraZeneca. Dr. Kim has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Aprilbio, HanAll BioPharma, Viela Bio. Dr. Kim has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Alexion, Biogen, Celltrion, Eisai, Merck Serono, Novartis, Sanofi Genzyme, Teva-Handok. Dr. Kim has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Multiple Sclerosis Journal, Journal of Clinical Neurology.

Incidence of cytomegalovirus DNAemia in pediatric kidney, liver, and heart transplant recipients: Efficacy and risk factors associated with failure of weight‐based dosed valganciclovir prophylaxis

Cytomegalovirus (CMV) is associated with morbidity and mortality in solid organ transplant recipients (SOTR). Valganciclovir (VGC) is extensively used for prophylaxis. Optimal dosing in children, risk factors for failure, and the impact of dose adjustments on CMV DNAemia is not well established. This retrospective cohort study of pediatric SOTR transplanted between 2010-2018 evaluated the epidemiology of CMV DNAemia and used Cox-regression to assess the risk factors for CMV DNAemia within one-year following SOTR. In 393 pediatric SOTR (heart [96, 24.4%], kidney [180, 45.6%], liver [117, 29.8%]; median age 9.5 ± 0.3 years), overall CMV DNAemia incidence was 6.6/10 000 days (95%CI 5.1/10 000-7.9/10 000) and varied by organ groups: heart 8.2/10 000 days (95%CI 4.9/10 000-11.4/10 000), kidney 5.8/10 000 days (95%CI 3.9/10 000-7.8/10 000), liver 6.2/10 000 days (95%CI 3.7/10 000-8.7/10 000). CMV DNAemia was detected in 75 of 275 (27.2%) patients who received prophylaxis (40 cases occurred during prophylaxis and 35 occurred after completion of prophylaxis). The median VGC dose given according to institutional weight-based algorithm was approximately 1.5-fold lower than the manufacturer-recommended dose. This discordance was more prominent at younger age groups (3.2-fold lower in <2-year-old [100 mg versus 325 mg], 2.5-fold lower in <6-year-old [200 mg versus 447 mg]). Dose reduction due to adverse events was an independent risk factor for breakthrough CMV DNAemia (hazard ratio 2.2, 95%CI 1.2-3.8) among patients with similar age, CMV risk stratification, starting VGC dose, immunosuppressive therapy, and organ group. CMV events occurred while on VGC prophylaxis. Weight-based VGC may prevent supratherapeutic VGC exposure especially in younger children. Dose reduction of VGC prophylaxis for adverse event management places patients at an increased risk for CMV DNAemia suggesting other agents with fewer adverse effects should be considered and need to be studied in children.

Efficacy of combined immunosuppression with or without eltrombopag in children with newly diagnosed aplastic anemia.

We compared the efficacy and safety of eltrombopag (ELTR) combined with immunosuppressive therapy (IST) and IST alone in treatment-naïve children with severe (SAA)and very severe (vSAA) aplastic anemia. Ninety-eight pediatric patients were randomized to receive horse antithymocyte globulin (hATG) and cyclosporin A (CsA) with (n=49) or without (n= 49) ELTR. The primary endpoint was the overall response rate (ORR) at 4months. After 4 months, nonresponders were crossed over to the alternative group. In all patients, the ORR in ELTR+ IST and IST groups was similar (65% vs 53%; P= .218); however, the complete response (CR) rate was significantly higher in the ELTR+ IST group (31% vs 12%; P=.027). In severity subgroups, the ORR was 89% vs 57% (P= .028) in favor of IST+ ELTR in SAA, but it did not differ in patients with vSAA (52% vs 50%; P= .902). At 6 months after the crossover, 61% of initial ELTR(-) patients achieved a response compared with 17% of initial ELTR(+) patients (P= .016). No significant difference in ELTR+ IST and IST groups was observed in the 3-year overall survival (OS) (89% vs 91%; P= .673) or the 3-year event-free survival (EFS) (53% vs 41%; P=.326). There was no unexpected toxicity related to ELTR. Adding ELTR to standard IST was well tolerated and increased the CR rate. The greatest benefit from ELTR combined with IST was observed in patients with SAA but not in those with vSAA. The second course of IST resulted in a high ORR in initial ELTR(-) patients who added ELTR and had limited efficacy among patients who received ELTR upfront. This trial was registered at Clinicaltrials.gov as #NCT03413306.

Comparison of Hematopoietic Stem Cell Transplantation and Immunosuppressive Therapy for Patients with Severe Hepatitis-Associated Aplastic Anemia

Background：Hepatitis-associated aplastic anemia (HAAA) is known as a rare variant of acquired aplastic anemia, characterized by a syndrome of bone marrow failure following the development of hepatitis. Immunosuppressive therapy (IST) or hematopoietic stem cell transplantation (HSCT) could provide lifesaving opportunities for severe HAAA patients. However, to date, no cohort has characterized treatment outcome and long-term survival between those patients receiving IST and HSCT. In this study, we aim to retrospectively evaluate the outcome of these two therapies for severe HAAA in China. Methods: Patients consecutively diagnosed as severe HAAA between August 2008 and Jan 2021 were enrolled in this study. The definition of severe HAAA is that severe aplastic anemia developed within three months after documented hepatitis. The enrollments were patients who received HSCT or IST as a first-line treatment. Patients with HSCT were conditioned as described previously with cyclophosphamide (Cy, 120-150 mg/kg, divided doses on days -6 to -2), and rabbit ATG (Thymoglobulin®, Genzyme, Cambridge, MA) (2.5mg/kg once i.v. daily on days -6 to -2) or p-ALG (Anti-lymphocyte Immunoglobulin®, Wuhan Institute of Biological Products Co., Ltd., China) (20mg/kg once i.v. daily on days -6 to -2), Fludarabine 150 mg/m2 i.v.in divided doses on days -6 to -2, with or without Busulfan (Bu, 0.8 mg/kg four times i.v. daily on days -7 and -6). IST consisted of both rabbit ATG (rATG) (3~3.75mg/kg once i.v. daily on 5 days), porcine antilymphocyte globulin (pALG)(20mg/kg once i.v. daily on 5 days), combined with a six-month course of cyclosporine (3mg per kilogram per day orally, with adjustment of the dose to maintain a blood level between 200 and 400 ng per milliliter). Probabilities of overall survival (OS), failure-free survival (FFS), and treatment-related-mortality (TRM) were calculated by Kaplan-Meier method. Results and Discussion: This study retrospectively included 94 consecutive HAAA patients, including 68 patients underwent HSCT and 26 patients receiving IST. The IST and HSCT groups were similar with respect to age and gender ratio. The median follow up were 1752 (±153.62, 95%CI 1450.90~2053.10) days, and 2648 (±321.41, 95%CI 2018.05-3277.96) days among alive patients in the IST and HSCT group, respectively. In HSCT group, all patients achieved neutrophil engraftment. No primary or secondary graft failures (GF) was documented. Compared with patients receiving alternative donor HSCT (n=11), patients in matched sibling donor HSCT (MSD-HSCT) group (n=15) had a significant lower cumulative incidence of acute graft versus host disease (aGVHD) (20±10.33% vs 56.4±15.47%, p=0.048), and lower incidence of cytomegalovirus (CMV) reactivation group (72.73% vs 13.33%, p=0.004). No clinical significance of chronic graft versus host disease (cGVHD) incidence group (43.4±18.85% vs 50±35.4%, p=0.78) and bacterial/fungus infection (26.67% vs 36.36%, p=0.683) was found between MSD-HSCT group and alternative donor-HSCT. Attributable causes of death were pneumonias and severe infection in patients receiving HSCT. In IST group, the hematology response rate to treatment evaluated at 3m, 6m and 12m was 27.68%, 52.94%, and 60.23%, respectively. There were thirteen patients were non-evaluable, including six patients transferred to perform HSCT, two patients were diagnosed MDS/AML transformation and one patient relapsed. The 5-year overall survival (OS) and failure-free survival (FFS) rate was 85.5±4.44% (95% CI, 0.772, 0.946) and 69.6± 5.35% (95% CI, 0.599,0.809) of all enrolled HAAA patients, respectively (Figure 1). For patients receiving different therapy, the 5-year OS rates were 92.86 ± 6.88% in MSD-HSCT group, 72.7± 13.43% in alternative donor-HSCT, and 84.1 ± 7.28% in the IST group (P = 0.56). Otherwise, the 5-year estimated FFS rate was 56.0± 11.51% in the IST group, compared with 92.86 ± 6.88% in the MSD-HSCT group and 72.7± 13.43% in alternative donor-HSCT group (P = 0.10). The cumulative incidence of treatment-related-mortality (TRM) of MSD-HSCT, alternative-HSCT and IST was 7.1±6.9% (95% CI, 80.30-100), 27.3±13.4% (95% CI, 50.60-100), 14±5.54% % (95% CI, 7.58-97.6) (p=0.22), respectively. Even there was no difference between the HSCT and IST groups in OS, MSD-HSCT group still showed superior FFS. Patients receiving alternative donor HSCT, and IST showed comparable OS and FFS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Comparison of ATG-Based Immunosuppressive Treatment and Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Transfusion-Dependent Non-Severe Aplastic Anemia: A Single Center, Retrospective Analysis

Transfusion-dependent non-severe aplastic anemia (TD-NSAA) refers to aplastic anemia (AA) that is dependent on blood transfusion but does not fulfilling the criteria for severe AA (SAA). It has been clear that allogeneic hematopoietic stem cell transplantation (HSCT) and anti-thymocyte globulin (ATG)-based immunosuppressive therapy (IST) is the front line for the treatment of SAA, but there is no consensus on the treatment timing and strategy for TD-NSAA. The natural history observation reported that the progress-free survival (PFS) of TD-NSAA at 60 months after diagnosis is around 62%, but decreased significantly to 22% at 120 months. In China, the practical guideline recommends cyclosporine-based IST with or without hematopoietic stimulating regimes (such as androgens) as initial treatment, and further treated as SAA if no response was observed after 6 months management. As reported, the hematopoietic response of ATG-based IST was much better than CsA-based IST (75% Vs. 55.8%, 6-month) for TD-NSAA, however, the relapse and clonal expansion are still the unavoidable events. For HSCT, the long-term PFS is much better than IST for SAA, but the complications (including graft versus host disease, various infection, etc.), transplantation related mortality, as well as donor availability still limited its application. At present, there is limited data compared the efficiency of HSCT and IST for TD-NSAA. With the development of haplo-identical transplantation in China, most TD-NSAA own a donor, and we also performed HSCT for those young patients after informed consent. Herein, we respectively compared the efficiency of ATG-based IST and HSCT for TD-NSAA, and also analyzed the risk factors that contribute to the overall survival (OS) as well as event free survival (EFS). During Jul 2011 to Dec 2019, 97 TD-NSAA patients were diagnosed in our cohort, among them, 5 only received supportive treatment, 30 received CsA-based IST with or without androgen, and the other 62 patients received HSCT or ATG-based IST therapy. We further analyzed the efficiency and prognosis of 55 patients aged 16-60 years old who received HSCT or ATG-based IST therapy. Among them, 27 (49.09%) patients received ATG-based IST, and the others performed HSCT (including 14 from sibling donor, 7 from haplo-identical donor and 7 from unrelated donor) (the baseline information showed in Table1). Results showed that the 12-month overall response rate (ORR) of ATG-based IST and HSCT were 48.1% (with 18.52% CR) and 78.57% (with 60.71% CR), respectively (P=0.04, Fig A). The median time of achieving transfusion-free was 94(35-205) and 24(11-139) days, respectively in ATG-based IST and HSCT group (P<0.001, Fig B). The 5-year OS and EFS rates were 54.9±13.3% and 34.5±12.1% in ATG-based IST group respectively, and 70.0±9.0% and 62.6±9.6% in HSCT group, while no statistically differences was observed (Fig C and D). To explore the possible influencing factors of 5-year OS and EFS, we performed COX regression analysis based on age, disease duration, baseline absolute neutrophil count (ANC), hemoglobin (HB), platelet count (PLT), serum ferritin (SF), lymphocyte percentage, and CD4/CD8 ratio. Univariate analysis showed that disease duration, baseline HB, SF, and ANC may affect OS and EFS of patients in ATG-based IST group (Table 2), and multivariate analysis showed that SF≧1000ng/ml was an independent risk factor for OS in ATG-based IST group. While in the HSCT group, patients with disease duration≧20 months had a higher risk of events (Table 3). The subgroup analysis showed that in HSCT group, patients with disease duration of 6 to 20 months had a lower risk of events (HR=0.196, 95%CI: 0.046-0.832); the HR of the group <6 months and ≥20 months were not statistically significant (Fig E). TD-NSAA patients with disease duration between 6 months and 20 months had a higher EFS rate in HSCT group than that in ATG-based IST group (Fig F). The subgroup analysis of mortality was not statistically significant (Fig G). To conclusion, TD-NSAA patients should be actively treated, patients with shorter disease duration and no iron overload may achieve a better response. The 12-month ORR in the HSCT group was higher than that in the IST group, but there was no significant difference in OS rate and EFS rate, even there is a great difference tendency. For TD-NSAA patients with a disease duration between 6 to 20 months, HSCT has a higher EFS rate than IST, which may be a better choice. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The effect of immunosuppressive therapy on the development of ventilator-associated pneumonia in patients with COVID-19

Aim: It remains unclear whether immunosuppressive treatments such as corticosteroids and IL-6 receptor blockers have an effect on the development of ventilator-associated pneumonia (VAP). The aim of this study was to investigate the effect of immunosuppressive therapy on the development of VAP in critically ill patients with COVID-19.&#x0D; Material and Method: Two hundred thirty five patients with critically ill patients with COVID-19, who were treated in the intensive care unit (ICU) and received mechanical ventilator support, were evaluated retrospectively. VAP development, secondary infections, microorganisms isolated, and resistance patterns were compared between the groups that received and did not receive immunosuppressive therapy, and also the groups that did not receive immunosuppressive therapy, received only corticosteroid, received only tocilizumab, and received corticosteroid plus tocilizumab were compared in the subgroup analysis.&#x0D; Results: In the immunosuppressive treatment group, VAP development (40.2% vs. 21.2%; p=0.001), secondary infection development (48.4% vs. 29.2%; p=0.003), at least one drug resistant bacteria growth (46.7% vs. 27.4%; p=0.001), extensively-drug resistant (XDR) microorganism growth (89.8% vs. 72.7%; p=0.033) were higher than the group that did not receive immunosuppressive treatment. VAP (53.3%; p=0.004), secondary infection (73.3%; p=0.0002), the growth of bacteria resistant to at least one drug (70%; p=0.0003) were highest in the corticosteroid plus tocilizumab group in the subgroup analysis. In addition, XDR (95.5% vs. 72.7%; p=0.032) and pan-drug resistant (PDR) microorganism growth (31.8% vs. 9.1% p=0.032) were higher in the corticosteroid plus tocilizumab group than the no immunosuppressive therapy group. There was no difference between the groups in terms of mortality (p&gt;0.05).&#x0D; Conclusion: Immunosuppressive therapy has been found to potentially enhance the risk of VAP and secondary infections in critically ill patients with COVID-19 pneumonia as well as the growth of bacteria resistant to at least one drug, the length of stay in hospital and ICUs. In addition, it has been evaluated that there may be an increase in the growth of XDR and PDR microorganisms when corticosteroid and tocilizumab are used together. Although there was no difference in mortality, using immunosuppressive therapy may require careful use of targeted antibiotics and longer-term antimicrobial therapy.

A real-word experience of eltrombopag plus rabbit antithymocyte immunoglobulin-based IST in Chinese patients with severe aplastic anemia.

Eltrombopag (EPAG), a thrombopoietin receptor agonist, was approved for the treatment of severe aplastic anemia (SAA) combined with immunosuppressive therapy (IST). However, the effects of real-life use of low doses of EPAG combined with rabbit antithymocyte globulin (ATG)-based IST in Asian patients with SAA are yet unknown. A total of 121 previously untreated Chinese patients with SAA were enrolled in a multicenter registry of the Chinese Eastern Collaboration Group of Anemia (2014-2020): 67 patients received IST alone and 54 patients received additional EPAG. Patients receiving IST plus EPAG had a higher overall response rate (ORR) at 1month (P = 0.002), 3months (P = 0.028), 6months (P = 0.006), and 12months (P = 0.031) compared to those receiving IST alone. EPAG was the favorable factor for response efficacy at 6months. The complete response rate in the EPAG plus IST group was 17% at 3months, 27% at 6months, and 32% at 12months, compared to 7% (P = 0.069), 14% (P = 0.11), and 33% (P = 0.92) for those treated with IST alone. The 2-year overall survival rate in EPAG plus IST and IST alone groups was 98% and 88%, respectively (P = 0.078). The rate of adverse events, including clonal evolution, infection, and transaminitis, was similar in the two cohorts. The addition of EPAG to IST was well-tolerated and associated with high rates of hematologic responses among the previously untreated Chinese patients with SAA.

A multicentre trial of intensive immunosuppressive therapy combined with umbilical cord blood for the treatment of severe aplastic anaemia

Immunosuppressive therapy (IST) is an effective treatment regimen for severe aplastic anaemia (SAA) patients without HLA-identical donors. This study further compared the outcomes between IST and IIST-UCB in SAA on the basis of research shown that IST combined with umbilical cord blood infusion (IIST-UCB) treated effectively. A total of 123 patients from 11 hospitals in China were enrolled. Sixty-nine patients in IIST-UCB group were treated with ATG + CsA + CTX combined with cord blood, while 54 patients in IST group with ATG + CsA. The overall remission rates (ORRs), complete remission (CR) rates and partial response (PR) rates of IIST-UCB group and IST group at 3 months were 69.67% vs 51.85% (P = .045), 21.74% vs 3.7% (P = .004) and 47.83% vs 48.15% (P = .972), respectively. After 6 months of treatment, they were 76.81% vs 57.41% (P = .022), 37.68% vs 11.11% (P = .001) and 39.13% vs 46.30% (P = .425), respectively. After 1 year of treatment, they were 85.51% vs 61.11% (P = .002), 59.42% vs 25.93% (P = .000) and 26.09% vs 35.19% (P = .275), respectively. The ORRs and CR rates of IIST-UCB group were both significantly higher than IST group after 3 months, 6 months and 1 year of treatment. The neutrophil granulocyte, platelet and haemoglobin recovery times of IIST-UCB group were significantly shorter than IST group. Compared with standard IST, IIST-UCB as an effective therapy for SAA patients without HLA-identical donors accelerated the haematopoietic reconstitution, resulting in higher early CR rates.

Effect of Cyclophosphamide and Glucocorticoid Therapy in IgA Nephropathy: A Single-Center Retrospective Analysis.

IgA nephropathy (IgAN) is the most common primary glomerulonephritis in adults, which causes ESKD in ≤45% of patients in the long term. The optimal therapeutic approach remains undetermined. In this study, we report the results of a single-center retrospective analysis of patients with IgAN. We retrospectively evaluated the therapeutic approach and outcome of all patients at our center with biopsy-proven IgAN between 2000 and 2020, focusing on the effect of intravenous cyclophosphamide therapy combined with glucocorticoids ("immunosuppressive therapy group"). The control group received standard supportive care. Patients in the immunosuppressive therapy group had worse kidney function before the initiation of therapy, as indicated by higher serum creatinine, more proteinuria, and a higher degree of hematuria than the control group; they also displayed a higher body mass index. The Oxford classification of IgA nephropathy (MEST-C score) suggested more inflammatory activity in the immunosuppressive therapy group, including more crescents and endocapillary hypercellularity. During the follow-up, proteinuria and hematuria decreased in both groups, and to a significantly greater extent in the immunosuppressive therapy group. Cyclophosphamide treatment significantly improved kidney function as determined by the fold-change of eGFR during the observation period. The number of infections and hospitalizations did not differ, but the incidence of diabetes was increased in the immunosuppressive therapy group. This study suggests immunosuppressive therapy with cyclophosphamide combined with glucocorticoids improves kidney function, proteinuria, and hematuria. The therapy was safe for infectious complications, but was associated with an increased incidence of diabetes, which might be attributable in part to the use of steroids in patients with a higher body mass index at baseline. Although immunosuppressive therapy in IgAN remains controversial, our findings suggest that at least some patients benefit from more aggressive therapy.

Cost of illness of oral lichen planus: a multicenter university hospital-based outpatient observational study.

ObjectivesTo estimate the economic costs of oral lichen planus (OLP) through a multicenter university hospital–based outpatient study conducted in Italy and Finland.Materials and methodsA multicenter retrospective study was conducted on patients affected by OLP to evaluate the economic cost of managing the disease. Direct costs concerning diagnostic procedures, therapeutic management, and follow-up visits were obtained from clinical records. Statistics was performed with IBM SPSS Statistics.ResultsOne hundred and eight patients with a confirmed diagnosis of OLP (81 women and 27 men), 58 Italians and 50 Finnish, were enrolled in this study. The mean annual cost was 1087.2 euros per patient. The mean annual cost was higher in Finnish than in Italian cohort (1558.7 euros vs. 680.7 euros—p < 0.05). Within the Italian cohort, the local immunosuppressive therapy group and atrophic and erosive OLP type had a higher cost (p < 0.05). Within the Finnish cohort, the local immunosuppressive therapy group had a higher cost (p < 0.05).ConclusionsOLP-related costs are very similar to other chronic oral disorders (i.e., periodontitis) with differences between investigated countries. Moreover, patients with more severe clinical features, who need immunosuppressive therapy, are facing more expensive costs.Clinical relevance.In this multicenter cost of illness study, we estimated the direct health care costs of OLP and we found that patients with more severe clinical features, who therefore need symptomatic therapy, are facing more expensive costs.

Eltrombopag Added to Immunosuppression in Severe Aplastic Anemia

BackgroundA single-group, phase 1–2 study indicated that eltrombopag improved the efficacy of standard immunosuppressive therapy that entailed horse antithymocyte globulin (ATG) plus cyclosporine in patients with severe aplastic anemia.MethodsIn this prospective, investigator-led, open-label, multicenter, randomized, phase 3 trial, we compared the efficacy and safety of horse ATG plus cyclosporine with or without eltrombopag as front-line therapy in previously untreated patients with severe aplastic anemia. The primary end point was a hematologic complete response at 3 months.ResultsPatients were assigned to receive immunosuppressive therapy (Group A, 101 patients) or immunosuppressive therapy plus eltrombopag (Group B, 96 patients). The percentage of patients who had a complete response at 3 months was 10% in Group A and 22% in Group B (odds ratio, 3.2; 95% confidence interval [CI], 1.3 to 7.8; P=0.01). At 6 months, the overall response rate (the percentage of patients who had a complete or partial response) was 41% in Group A and 68% in Group B. The median times to the first response were 8.8 months (Group A) and 3.0 months (Group B). The incidence of severe adverse events was similar in the two groups. With a median follow-up of 24 months, a karyotypic abnormality that was classified as myelodysplastic syndrome developed in 1 patient (Group A) and 2 patients (Group B); event-free survival was 34% and 46%, respectively. Somatic mutations were detected in 29% (Group A) and 31% (Group Β) of the patients at baseline; these percentages increased to 66% and 55%, respectively, at 6 months, without affecting the hematologic response and 2-year outcome.ConclusionsThe addition of eltrombopag to standard immunosuppressive therapy improved the rate, rapidity, and strength of hematologic response among previously untreated patients with severe aplastic anemia, without additional toxic effects. (Funded by Novartis and others; RACE ClinicalTrials.gov number, NCT02099747; EudraCT number, 2014-000363-40.)

Post-Transplantation Immunosuppression After TCRΑβ/CD19 Graft Depletion Does Not Improve HSCT Outcomes in Primary Immunodeficiency

We recently demonstrated that TCRαβ+/CD19+ graft depletion successfully prevents severe acute and chronic graft-versus-host disease (GVHD) in pediatric patients with primary immunodeficiencies (PID) receiving transplants from both matched unrelated and mismatched related donors. However, in all patients, short-term post-hematopoietic stem cell transplantation (HSCT) immunosuppressive therapy (IST) was used. There are limited data on TCRαβ+/CD19+ graft depletion with no post-HSCT IST implementation. In the current study 74 PID patients who underwent first HSCT from matched unrelated (n=51) or mismatched related donors (n=23) with TCRαβ+/CD19+ graft depletion were included. All received as a conditioning regimen a combination of treosulfan with fludarabine and either melphalan or thiotepa. In all, thymoglobulin 5 mg/kg (days −5, −4, −3) and rituximab at day −1 were used. In 48 patients, various approaches to short-term post-transplantation IST were used, and 26 patients received no post-HSCT IST. The rates of engraftment, acute and chronic GVHD, survival, and mortality were similar in those who received and did not receive IST, with a slightly higher incidence of graft rejection in patients not receiving IST: 19% in the non-IST group against 13% in the IST group (P = .41). The incidence of cytomegalovirus reactivation was 50% and 39% (P = .50) and Epstein-Barr virus reactivation 10% and 0 (P = .20) in the IST and non-IST groups, respectively. No grade 4 adverse events were seen in both groups, although in 19 of 40 (47.5%) patients receiving calcineurin inhibitors, the therapy was discontinued before day 45. More robust immune recovery with both T- and B-lymphocytes was observed in the non-IST group. To conclude, TCRαβ+/CD19+ in combination with particular serotherapy effectively prevents severe acute and chronic GVHD in PID. Regarding remaining risks of infectious complications and additional drug-related toxicity, there are no benefits to post-HSCT IST use in these patients.

Efficacy and Safety of Hematopoietic Stem Cell Transplantation Vs. Immunosuppressive Therapy in Patients with Hepatitis-Associated Aplastic Anemia: A Single-Center Cohort Study and Meta-Analysis

Hepatitis-associated aplastic anemia (HAAA) refers to aplastic anemia (AA) in which pancytopenia appears within 6 months after an acute attack of hepatitis. The incidence of HAAA in the Far East and West accounts for 4-10% and 2-5%, respectively, in all AA cases. HAAA frequently occurs in young men, with a median age of 19 (6-56) years, and the two-month mortality after the onset of HAAA can reach 78-88% if the disease was leaved untreated. To date, the underlying pathogenesis is not yet clarified, and no specific correlation has been established between HAAA and chemical toxicants, neither radiation. Based on available studies, the hyper-activation of T lymphocytes and abnormal humoral immunity were confirmed in HAAA, and a large number of infiltrated lymphocytes are also noted in liver at the early stage of the disease, which resulting in liver dysfunction. Some viruses, including hepatitis A, hepatitis B, hepatitis C, parvovirus B19, human herpesvirus (HHV), and Epstein-Barr virus were correlated to the development of HAAA. However, the clinical results of the serological tests for hepatitis-associated viruses of most patients are negative, i.e., serologically negative HAAA.The frontline treatments are agreed to be allogeneic hematopoietic stem cell transplantation (allo-HSCT) or immunosuppressive therapy (IST). Because of the relatively scattered clinical data, compared to other acquired AA, the basis of treatment decision-making is insufficient. Some studies speculated that both IST and HSCT are effective, while others believe that transplantation should be the first choice if suitable donors are available. Therefore, we conducted a retrospective study and meta-analysis for better understanding and choice of the treatment.Our retrospective cohort study enrolled 18 HAAA patients, including 12 males and 6 females. A total of 12 (66.7%) patients received IST treatment, in which 4(33.33%) achieved completed remission (CR), 1(8.33%) partial remission (PR), and 7(58.33%) no response (NR), with a total effective rate of 41.7%. 6 patients (33.3%) received HSCT treatment, in which, 2 achieved CR, 1 PR, and 3 NR, with an effective rate of 50% (Table 1). The one-year overall survival (OS) rate of the IST group was significantly higher than that of the HSCT group (P<0.05) (Figure A). In further, we also conducted a meta-analysis which encompassed 6 studies and encompassing 345 cases. The results showed that the pooled mortality of IST and HSCT on HAAA was RR=1.16(95% CI: 0.63-2.13) (Figure B) and the difference was not statistically significant; the pooled one-year overall survival rate was RR=0.95(95% CI: 0.84-1.08)(Figure C), and the difference was not statistically significant; the pooled effective rate was RR=0.68(95% CI: 0.49-0.95)(Figure D), indicating that the efficacy of HSCT group was significantly higher than that of IST. The subgroup analysis showed that the pooled RR of the group <16-years-old was 0.61(95% CI: 0.41-0.95); the pooled RR of the group >16-years-old was 0.86 (95% CI: 0.50-1.46)(Figure E). The effective rate of ATG/ALG combined with CSA was 51.35%, and that of CSA alone was 46.7%. Compared to the HSCT group, the efficacy of ATG/ALG + CSA group (RR=0.73, 95% CI: 0.51-1.04) was better than that of CSA alone (RR=0.59, 95% CI: 0.32-1.09) (Figure F). The result of comparing ATG/ALG + CSA with CSA showed that the pooled RR was 1.35(95% CI: 0.70, 2.59) (Figure G), and the difference was not significant. This phenomenon could be attributed to the small number of articles included and insufficient sample size after subgroup analysis according to the IST treatment. We speculated that ATG/ALG combined with CSA has advantages in the treatment of HAAA compared to CSA alone.In summary, HSCT is more effective than IST in the treatment of HAAA, especially for patients <16-years-old, who should receive HSCT at the earliest. ATG/ALG combined with CSA can also be an idea option of IST treatment, but not single CsA. For patients >16-years-old, there is no significant difference in the efficacy between the HSCT and ATG/ALG + CsA strategies. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Long-term outcomes of IgA nephropathy patients with less than 25% crescents and mild proteinuria.

Whether immunosuppressive therapy in IgA nephropathy (IgAN) patients with lessthan25% crescents (C1) and mild proteinuria can improve the renal outcome is still unclear. We recruited 140 IgAN patients with C1 and proteinuria < 1g/24h who received supportive care (n = 52) or steroid-based immunosuppressive therapy (n = 88) in Xijing Hospital from July 2008 to December 2016. The primary outcome was the rate of renal function decline. The median of proteinuria was 575.5mg/24h, the fraction of crescents was 7% (5%, 12%) and follow-up time was 69.1months. The rate of renal function decline [0.5 (- 1.5, 3.2) vs - 0.7 (- 3.5, 0.5) ml/min per 1.73 m2 per year; P = 0.01] was slower in steroid-based immunosuppressive therapy group than supportive care group. Multivariate linear regression analyses showed steroid-based immunosuppressive therapy significantly slowed down the rate of renal function decline (β = - 0.220, 95% CI - 3.804 to - 0.449, P = 0.013) after adjusting age, sex, MAP, proteinuria, eGFR, M1, E1, S1, T1-2, the fraction of crescents and RASB. In the matched cohort, the rate of renal function decline was also slower in steroid-based immunosuppressive therapy group. The incidence of adverse events was similar between the two groups. Steroid-based immunosuppressive therapy may slow down the rate of renal function decline of IgAN patients with C1 and proteinuria ≤ 1g/24h.

Kidney injury molecule-1 levels are associated with therapeutic outcomes and renal tubulointerstitial injury severity in idiopathic membranous nephropathy.

Kidney injury molecule-1 (KIM-1) has an important role in chronic kidney disease development. The present study aimed to retrospectively analyze patients with idiopathic membranous nephrology (IMN) with different therapeutic outcomes to investigate the association between KIM-1 levels and therapeutic outcomes. A total of 51 patients with IMN and 20 healthy controls were included. Patients were classified into three groups: Spontaneous remission, remission with immunosuppressive therapy (IST) and nonremission with IST. Clinical and biochemical variables were collected. Urinary KIM-1 levels were measured by ELISA and renal KIM-1 expression was evaluated by immunohistochemistry. Patients with IMN were characterized as having elevated urinary and renal KIM-1 levels compared with those in the controls. Significantly increased urinary and renal KIM-1 levels were observed in the nonremission with IST group compared with those in the spontaneous remission group, and the same trend was observed for the plasma anti-podocyte antigen phospholipase A2 receptor antibody levels. Patients with more severe tubular injury (T2 index) presented with significantly higher urinary and renal KIM-1 levels than those with the T0 index. Urinary and renal KIM-1 levels were positively correlated with blood urea nitrogen, serum creatinine, serum cystatin-C, urinary albumin/creatinine ratio, urinary β2-microglobulin and the renal interstitial fibrosis index, and they were negatively correlated with serum albumin. Furthermore, urinary KIM-1 levels were positively correlated with the renal KIM-1 levels. In conclusion, the measurement of urinary and renal KIM-1 levels may be helpful in guiding medication selection and predicting therapeutic outcomes for patients with IMN.