Efficacy and safety of Iguratimod as an add-on therapy for refractory lupus nephritis: A preliminary investigational study.

Objectives: IGU (IGU), a novel immunomodulatory agent for rheumatoid arthritis, has been shown to be effective and safe as monotherapy in a small population with refractory lupus nephritis (LN). The aim of this prospective study was to evaluate the efficacy and safety of IGU as an add-on therapy in patients with refractory LN in the context of clinical practice. Methods: This is a single-arm observational study. We have enrolled LN patients since 2019 at Renji Hospital. All participants should have recurrent or refractory LN with at least one immunosuppressant (IS) and have a baseline urine protein/creatinine ratio (UPCR) >1.0. After enrollment, we added IGU (25 mg twice daily) to one of their previous immunosuppressants (IS) without increasing the dose of steroids. The primary outcome was the complete renal response (CRR) in the 6th month. UPCR decrease of over 50% was defined as partial response (PR). Extended follow-up was performed after the initial 6 months. Results: We enrolled 26 eligible participants. 11/26 patients had chronic kidney disease (CKD) stage 2/3 at the baseline. The IS combined with IGU included mycophenolate mofetil, tacrolimus, and cyclosporin A. No IS change was allowed. 80.7% of patients had baseline steroids less than 0.5mg/kg daily and there was no steroids escalation during the IGU treatment. The CRR rate was 42.3% (11/26) at month 6. With a median follow-up of 52 weeks (range: 23-116 weeks), the CRR rate at the last visit was 50% (13/26) and 73.1% (19/26) of patients had UPCR decrease of over 50%. Six patients withdrew, three for no response and three for renal flare after initial CRR. One patient had an estimated glomerular filtration rate worsening of over 20% and was classified as renal flare. Three mild to moderate adverse events were recorded. Conclusions: Our investigation merits further investigation in IGU as a potentially tolerable component of combination therapy for refractory LN.

Omics-based integrated analysis identified IKZF2 as a biomarker associated with lupus nephritis.

Lupus nephritis (LN) is a crucial complication of systemic lupus erythematosus (SLE). IKZF2 was identified as a lupus susceptibility locus, while its exact molecular function in LN is unknown. We aimed to explore the relationship between IKZF2 and LN based on multi-omics data. In our study, we carried out a meta-analysis of publicly available data, including not only tubulointerstitium, but also glomerulus tissue samples from LN patients and controls. Based on the common differentially expressed genes (co-DEGs) and previous researches, we selected IKZF2 for further analysis. Then, we analyzed potential molecular mechanisms of co-DEGs and IKZF2 in LN. To explore the possible targets of IKZF2, protein-protein interaction network (PPI) network and ceRNA network of IKZF2 were also constructed. Moreover, we performed immune infiltration analysis and evaluated clinical value of IKZF2. A total of 26 co-DEGs were observed in the integration of the above DEGs coming from the four sets of data, of which IKZF2 was selected for further analysis. Functional enrichment analysis from IKZF2 and related PPI network confirmed the tight relationship between IKZF2 and the immune reaction. Moreover, immune filtration analysis revealed the significant correlation between IKZF2 and naïve B cell, NK cell activation, NK cell rest and other immune cells. Receiver operating characteristic (ROC) analysis showed that the areas under the ROC curves were 0.721, 0.80, 0.682, and 0.859 for IKZF2 in four datasets, which demonstrated the clinical value of IKZF2. Our study revealed that IKZF2 may play an essential role in the molecular function and development of LN, and might be a potential biomarker for distinguishing LN patients and healthy ones.

Intra-abdominal infection in acute pancreatitis in eastern China: microbiological features and a prediction model.

BACKGROUND: This study aimed to investigate the microbiol distribution of intra-abdominal infection in patients with acute pancreatitis, and to develop a reliable prediction model to guide the use of antibiotics. METHODS: Inpatient with acute pancreatitis between January 2015 and June 2020 were enrolled in the study. Participants were divided into the intra-abdominal infection group and non-infection group. Isolated pathogens and antibiotic susceptibility were documented. Characteristics parameters, laboratory results, and outcomes were also compared. Least absolute shrinkage and selection operator (LASSO) regression model was used to select the risk factors associated with intra-abdominal infection in patients with acute pancreatitis. Logistic regression analysis, random forest model, and artificial neural network were also used to validate the performance of the selected predictors in intra-abdominal infection prediction. A novel nomogram based on selected predictors was established to provide individualized risk of developing intra-abdominal infection in patients with acute pancreatitis. RESULTS: A total amount of 711 participants were enrolled in the study, and of these, 182 (25.6%) had intra-abdominal infection. Of the 247 isolated pathogens, 45 (18.2%) were multidrug-resistant bacteria, and antibiotic susceptibility was lower than that of China Antimicrobial Surveillance Network 2020. The LASSO method identified 5 independent predictors [intra-abdominal pressure (IAP), acute physiology and chronic health evaluation II (APACHE II), computed tomography severity index (CTSI), the severity of pancreatitis, and intensive care unit (ICU) admission] of intra-abdominal infection, which were validated by three different models. The area under the curve was >0.95 for all 5 predictors. A clinically useful nomogram based on these predictors was successfully established. CONCLUSIONS: Multidrug-resistant bacteria were quite common in intra-abdominal infection. IAP, APACHE II, CTSI, the severity of pancreatitis, and ICU admission were identified as risk factors and the new nomogram based on these could help clinicians estimate the risk of intra-abdominal infection and optimize antimicrobial prescription for acute pancreatitis patients.

Comparison of iguratimod and conventional cyclophosphamide with sequential azathioprine as treatment of active lupus nephritis: study protocol for a multi-center, randomized, controlled clinical trial (iGeLU study).

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease that can involve multiple organs or systems. Lupus nephritis (LN) is associated with high mortality and morbidity. However, plenty of patients do not respond to present treatment or relapse. Iguratimod (IGU) is a new small molecular, anti-rheumatic drug and has shown the potential for drug repurposing from rheumatoid arthritis (RA) to LN treatment. It has been approved for treating RA in northeast Asia. Beyond expectation in a recent observational study, over 90% of thirteen refractory LN patients responded to iguratimod monotherapy in 24 weeks, with no steroids dose increasing or any other medication add-on during the entire follow-up. METHODS/DESIGN: This study is a multi-center, randomized, 52-week parallel positive drug-controlled study. The study was designed as a head-to-head comparison between the iguratimod and present first-line therapy on LN patients. A total of 120 patients (60 patients each group) is in the enrolling plan. All enrolled patients are assigned randomly into trial and control groups. The patients will be selected from six study sites in China and will all have biopsy-proven active lupus nephritis. In the first 24 weeks of the trial, IGU is compared with cyclophosphamide as an induction therapy, and in the second 24 weeks, IGU is compared with azathioprine as a maintenance therapy. The primary outcome is renal remission rate including both complete remission and partial remission at week 52, which will be analyzed using a non-inferiority hypothesis test. DISCUSSION: Most patients diagnosed with SLE will develop LN within 5 years and LN remains a major cause of morbidity and death for SLE patients. Although some medications are proven effective for the treatment of this condition, at least 20-35% LN patients have to suffer from relapse or ineffective treatment and medication intolerance is also frequent. This trial is designed to demonstrate whether iguratimod can be used as an alternative induction or maintenance therapy in subjects who have lupus nephritis. Data from this study will provide an evidence on whether or not iguratimod should be recommended to active LN patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT02936375 . Registered on October 18, 2016.

The Role of Pentraxin 3 in Aspergillosis: Reality and Prospects.

Pentraxin 3 (PTX3) is a soluble pattern recognition receptor (PRR), which is produced by several kinds of cells, such as neutrophils, dendritic cells, macrophages, and epithelial cells. PTX3 is known to play an important protective effect against Aspergillus. Genetic linkage in gene-targeted mice and human PTX3 plays a non-redundant role in the immune protection against specific pathogens, especially Aspergillus. Recent studies have shown that the polymorphism of PTX3 is associated with increased susceptibility to invasive aspergillosis (IA). In this review, we provide an overview of these studies that underline the potential of PTX3 in diagnosis and therapy of IA.

Iguratimod as an alternative induction therapy for refractory lupus nephritis: a preliminary investigational study.

OBJECTIVES: Iguratimod, a novel immunomodulatory agent for rheumatoid arthritis, has been shown to be effective against murine lupus. The aim of this study was to make a preliminary evaluation of the efficacy and safety of iguratimod as salvage therapy in patients with refractory lupus nephritis (LN). METHODS: We enrolled eligible patients with refractory LN, which we defined as having failed or relapsed on at least two immunosuppressant agents. After enrollment, we substituted iguratimod (25 mg twice daily) for their previous immunosuppressant agents without increasing the dose of steroids. The primary outcome was complete/partial remission (PR/CR) at week 24. Patients who achieved remission continued iguratimod as maintenance therapy over an extended follow-up. RESULTS: The study cohort comprised 14 patients with refractory LN, 10 of whom had recent treatment failure and 4 repeated relapses with inadequate initial responses. At enrollment, none of the patients had detectable evidence of extra-renal involvement. The median prednisone dosage was 10 mg/d (IQR 0-10 mg/day). Thirteen patients were eligible for response evaluation, with one patient missed. The renal response rate was 92.3% (12/13) at week 24, with 38.5% (5/13) achieving CR and 53.8% (7/13) achieving PR. We then continued to follow up the responding patients for up to 144 weeks. Twenty-five percent of the patients (3/12) had renal relapse after initial PR. The estimated glomerular filtration rate of all patients maintained stable during follow-up. One patient had a severe adverse reaction (anemia) but recovered fully after stopping iguratimod. CONCLUSIONS: Our study supports the potential of iguratimod for treatment of refractory LN. Iguratimod could be a promising candidate drug for this condition.