Clinical Relapse Rate Research Articles

Histologic Inflammation can Predict Future Clinical Relapse in Ulcerative Colitis Patients in Endoscopic Remission.

In ulcerative colitis (UC), endoscopic improvement, defined as a Mayo Endoscopic Score (MES) of 0 or 1, is a target of treatment. The aim of our study was to evaluate the risk of clinical relapse between patients with an MES of 0 or 1 and determine if histologic activity using the Robarts Histopathologic Index (RHI) was predictive of clinical relapse. UC patients with an MES score of 0 or 1, no prior colectomy, and at least 1 year of outpatient follow-up after colonoscopy were included. Demographic, clinical characteristics, and clinical relapse were retrospectively collected. Biopsy specimens were read by a gastrointestinal pathologist. Primary outcome was defined as a composite of relapse requiring change in medical therapy, new steroid use, UC-related hospitalization, and/or colectomy. Four hundred and forty-five UC patients were identified. Ninety-five percent of patients with MES 0 were in histologic remission by the RHI whereas only 35% of patients with MES 1 were in histologic remission. Twenty-six percent of patients experienced a clinical relapse; patients with MES 1 or RHI > 3 were significantly more likely to relapse (P < .01) compared to patients with MES 0 or RHI ≤ 3. When patients were stratified into 4 groups (MES 0, RHI ≤ 3; MES 0, RHI > 3; MES 1, RHI ≤ 3; MES 1, RHI > 3) and adjusted for age and sex, RHI > 3 was predictive of relapse (P = .008). UC patients with endoscopic improvement have a high rate of clinical relapse over time. Histologic activity is a predictor of clinical relapse.

Natalizumab Treatment Induces Proinflammatory CD4 T Cells Preferentially in the Integrin β7+ Compartment.

Natalizumab, a monoclonal humanized antibody targeting integrin α4, inhibits the transmigration of lymphocytes into the CNS by preventing the interaction of integrin α4β1 with V-CAM expressed on brain vascular endothelial cells. Although natalizumab treatment reduces the clinical relapse rate in patients with relapsing-remitting MS, its discontinuation after reactivation of the JC virus is associated with a rebound of the disease in 20% of patients. The mechanisms of this rebound are not elucidated, but natalizumab increases the frequencies of circulating CD4 T cells expressing proinflammatory cytokines as well as the proportion of circulating Th17/Th1 cells (Th1-like Th17 cells). Gut-derived memory CD4 T cells are a population of growing interest in the pathogenesis of MS, but whether and how their properties are affected by natalizumab is not known. Here, we studied the phenotype and cytokine expression profile of circulating gut-derived memory CD4 T cells in patients with relapsing-remitting MS under natalizumab. We identified gut-derived memory CD4 T cells by their expression of integrin β7 and compared their properties and those of integrin β7- memory CD4 T cells across healthy donors and patients with relapsing-remitting MS treated or not with natalizumab. We also compared the capacity of integrin β7- and integrin β7+ CD4 T-cell subsets to transmigrate in vitro across a model of blood-brain barrier. The proportions of proinflammatory Th17/Th1 cells as well as of IL-17A+IFNγ+ and IL-17A+GM-CSF+ cells were higher in memory CD4 T cells expressing integrin β7 in patients receiving natalizumab compared with healthy donors and patients with relapsing-remitting MS not receiving natalizumab. By contrast, integrin β7 negative memory CD4 T cells only presented a modest increased in their proportion of Th17/Th1 cells under natalizumab. We further observed that integrin β7+ Th17/Th1 cells migrated as efficiently as integrin β7- Th17/Th1 across a monolayer of brain microvascular endothelial cells. Our study shows that circulating integrin β7+ memory CD4 T cells of patients with relapsing-remitting MS under natalizumab are enriched in proinflammatory cells supporting the hypothesis that integrin β7+ memory CD4 T cells could play a pathogenic role in the disease rebound observed at natalizumab discontinuation.

Treatment of Pediatric Pemphigus Foliaceus.

Pemphigus foliaceus (PF) is an autoimmune blistering disease limited to the superficial skin without mucosal involvement. It is clinically, histologically, and immunopathologically distinct from pemphigus vulgaris (PV). As data on pediatric PF is often merged with data on both pediatric and adult PV patients, isolating clinical outcomes in pediatric PF is not always possible. Therefore, the authors of this review analyzed clinical outcomes following therapy in pediatric PF patients only. A search of databases resulted in 33 pediatric patients with PF. In total, 19 (57.6%) patients were treated with conventional immunosuppressive therapies (CISTs), which consisted of systemic corticosteroids and multiple immunosuppressive agents (ISAs). Further, 14 (42.4%) patients were treated with biologic agents, predominantly rituximab (RTX). The mean age of those treated with biologics was 12.8 years (range = 0.88-18 years) compared to 8.9 years (range = 0.92-15 years) of those treated with CIST (p = 0.01). Treatment with biologics was initiated significantly longer after the diagnosis of PF when compared to patients treated with CIST (p = 0.003). RTX was used in all patients who received biologic therapy. Two (6%) patients also received intravenous immunoglobulin. When clinical outcomes were compared between CIST and biologic therapy, rates of clinical remission, partial remission, and relapse, were not statistically significantly different between groups. When RTX was used, rates of relapse and adverse events were higher in those treated with the lymphoma protocol (375 mg/m2once weekly for four weeks) compared to those treated with the rheumatoid arthritis protocol (two doses of 1,000 mg two weeks apart) (p < 0.0001). The incidence of adverse events was statistically significantly higher in patients treated with CIST when compared to RTX (p = 0.003). These included both physical and psychological changes. The infection rate after treatment with RTX was 7.1%. These outcomes occurred during a follow-up of 12.5 months (range = 1-36 months) in the CIST group and 20.5 months (range = 6-67 months) in the biologic therapy group. The difference in the follow-up period was not statistically significant. The literature suggests that biologics are superior to CIST in treating pemphigus patients.The results of this review suggest similar responses to therapy in pediatric PF patients treated with biologics compared to CIST. This may have been due to a limited duration of follow-up and a lack of detailed treatment outcomes in pediatric PF patients. The data in this review strongly suggests that specific treatment protocols need to be developed and implemented for pediatric PF patients. These patients are at a critical phase in life where PF therapy can influence or affect physical growth, hormonal changes, psychosocial development, and essential education.

Comparison of Efficacy and Safety of Oral Use of Terbinafine and Itraconazole for the treatment of Tinea paedis: A Randomized Controlled Parallel Group Open Labeled Trial with Clinico-Mycological Correlation

Treatment of tinea paedis is very crucial with the different antifungal drugs. The purpose of the present study was to compare the efficacy and safety of oral use of terbinafine and itraconazole for the treatment of tinea paedis. This study was a double-blind, randomized, single-center clinical trial. The patients were randomly allocated to receive a daily dose of terbinafine 500 mg daily for 4 weeks (Group I) or 200 mg of itraconazole for 4 weeks daily (Group II). The primary efficacy criterion was mycological cure, defined as negative results on microscopy and culture at the end of follow-up and no requirement of second intervention treatment. Secondary efficacy criteria included clinical cure without second intervention treatment and mycological and clinical relapse rates. A total of 50 patients were included in this study, it was observed that majority patients were age belonged to 31-40 years in both groups. Regarding gender distribution of the study patients, it was observed that male were predominant in both groups, which was 20(80.0%) in group A and 19(76.0%) in group B. All hyperkeratotic patients were shown 100.0% cases of clinical response. However, interdigital lesion were recovered in 7(100.0%) cases in group A and 6(85.7%) cases in group B. In conclusion, tinea paedis is significantly improved by both drugs, without significant difference after 8 weeks follow-up. CBMJ 2023 July: vol. 12 no. 02 P: 150-156

Long-term comparisons of the durability of 6 months versus 12 months antiviral therapy for hepatitis B after chemotherapy cessation

BackgroundProphylaxis antiviral therapy is recommended for patients with hepatitis B receiving chemotherapy but the ideal treatment duration after chemotherapy cessation needs more evidence for clarification. AimsThis study aimed to compare the relapse rate of short finite intervals of 6 months and 12 months of -nucleos(t)ide analogue (NA) therapy in patients stratified by low hepatitis B virus (HBV)-DNA of < 2000 IU/ml or high HBV DNA of ≥ 2000 IU/ml. MethodsPatients started tenofovir or entecavir treatment 1 week before chemotherapy and were assigned to different treatment duration groups randomly after stratified by HBV DNA pretreatment: (1) HBV DNA of < 2000 IU/ml at 6-month or 12-month duration; (2)HBV DNA of ≥ 2000 IU/ml at 6-month or 12-month duration. Virological relapse (VR) was defined as HBV DNA of > 2000 IU/ml, and clinical relapse (CR) was defined as HBV DNA of > 2000 IU/ml and alanine aminotransferase of > 80 IU/L during the follow-up period. The primary endpoint was to compare the durability between groups 1 year after antiviral therapy cessation. The secondary endpoint was VR and CR rate at long-term follow-up after antiviral therapy cessation. ResultsThis study enrolled 61 patients, and 5 patients were lost to follow-up or tumor recurrence. VR and CR rates were 46.4% and 14.3% at 1-year and 55.3% and 16.1%, at long-term follow-up, respectively. VR and CR rates demonstrated no difference between the groups. Pretreatment HBV DNA at ≥ 2000 IU/ml and end-of-treatment hepatitis B surface antigen (HBsAg) at ≥ 500 IU/ml were the predictor of VR (hazard ratio [HR]: 2.98; p = 0.010 and HR: 2.38; p = 0.037). ConclusionsProlongation from 6 months to 12 months of NA consolidation after chemotherapy cessation did not affect the VR or CR of HBV. High pretreatment HBV DNA and end-of-treatment HBsAg levels could predict VR after antiviral therapy cessation for chemotherapy.

Histological Disease Activity as Predictor of Clinical Relapse, Hospitalization, and Surgery in Inflammatory Bowel Disease: Systematic Review and Meta-Analysis.

The clinical impact of histological remission on short- and long-term clinical outcomes in patients with inflammatory bowel disease (IBD) is not well established. We assessed risk of clinical relapse, hospitalization, and need for surgery in patients achieving histological remission in comparison with active histological disease. A systematic review was conducted using MEDLINE, Scopus, Cochrane CENTRAL, EMBASE, and conference abstracts from inception to November 2022. Our main outcome was the rate of clinical relapse in patients with IBD who reached histological remission vs patients with active histological disease. Secondary outcomes were clinical complications of IBD such as hospitalization and need for surgery. The endpoints were investigated at 2 time points, 6 to 12 months (short term) and >12 months (long term). Short-term outcome analysis showed that the risk of clinical relapse was significantly higher in ulcerative colitis patients with active histological disease in comparison with patients at histological remission (risk ratio [RR], 2.41; 95% confidence interval [CI], 1.69-3.44; P < .01). The risk of hospitalization in ulcerative colitis patients was not significant among the 2 groups (RR, 4.22; 95% CI, 0.91-19.62; P = .07). Long-term outcome analysis demonstrated that the risk of clinical relapse (RR, 2.07; 95% CI, 1.55-2.76; P < .01), need for surgery (RR, 3.14; 95% CI, 1.53-6.45; P < .01), and hospitalization (RR, 2.52; 95% CI, 1.59-4.00; P < .01) was significantly higher in patients with active histological disease. Histological remission in IBD represents an important therapeutic goal that is not yet routinely pursued in clinical practice. In our study, patients who achieved histological remission have more favorable outcomes than those with active histological disease in ulcerative colitis.

Higher rate of HBsAg loss after discontinuation of tenofovir than entecavir in patients with chronic hepatitis B.

To compare the rates of hepatitis B surface antigen (HBsAg) loss after discontinuation of entecavir versus tenofovir disoproxil fumarate (TDF) in patients with chronic hepatitis B (CHB) without cirrhosis. A total of 891 patients who received entecavir (n = 556) or TDF (n = 335) followed up post-treatment for at least 12 months were retrospectively assessed. A total of 677 patients who had continued entecavir or TDF therapy for at least 4 years were enrolled as the continued group. Patients who discontinued TDF had higher rates of virological and clinical relapse and retreatment than patients who discontinued entecavir in both the HBeAg-positive and HBeAg-negative subgroups. In the entire discontinued cohort, the cumulative rates of HBsAg loss at 7 years were 22.6% and 35.4% in the entecavir and TDF groups respectively. Patients who discontinued TDF had significantly higher rates of HBsAg loss than patients who discontinued entecavir therapy in all (p = 0.019) and propensity score-matched (p = 0.015) patients, especially among the subgroups who achieved a sustained response (p < 0.001). Cox regression analysis revealed that TDF, longer treatment duration and lower HBsAg levels at end of treatment were independently associated with HBsAg loss in the entire discontinued group. The incidence of HBsAg loss was significantly higher in the discontinued group than in the continued group after propensity score matching (p < 0.001), including HBeAg-positive and HBeAg-negative patients. Patients who discontinued TDF had significantly higher rates of HBsAg loss than patients who discontinued entecavir, especially among the subgroups without HBV relapse after cessation of therapy.

HBV relapse rates in patients who discontinue tenofovir disoproxil fumarate with or without switching to tenofovir alafenamide.

The incidence and relapse pattern in patients stopping tenofovir alafenamide (TAF), a prodrug of tenofovir which is more concentrated in hepatocytes, is unknown. HBeAg-negative CHB patients stopping tenofovir disoproxil fumarate (TDF) (off-TDF) or who had switched to TAF more than 3 months before discontinuation (off-TAF) were recruited. The propensity score-matching method (PSM) was used, creating a ratio of 1:3 between the off-TAF versus the off-TDF groups to adjust for associated factors. After PSM, 180 off-TDF and 60 off-TAF patients were analyzed. The cumulative rates of virological and clinical relapse at 52 weeks were 75.1% and 58.5% respectively in the off-TDF group and 91.1% and 61.6% in the off-TAF group. Patients in the off-TAF group had significantly higher rates of virological relapse than those in the off-TDF group (p=0.021), but not clinical relapse (p=0.785). Multivariate cox regression analysis showed that off-TAF group was an independent factor for virological relapse, but not clinical relapse. Severity of clinical relapse and hepatic decompensation rate were comparable between off-TDF and off-TAF groups CONCLUSIONS: The off-TAF group had a higher virological relapse rate than the off-TDF group. The difference in clinical relapse pattern and severity was not clinically important between the two groups.

Circulating ether lipids in prostate cancer.

e17009 Background: Decreased circulating levels of ether lipids (glycerophospholipids with an ether-linked fatty alcohol, e.g. plasmalogens) have been observed in obesity, diabetes and cardiovascular disease. In vitro and in vivo studies suggest that ether lipids are anti-inflammatory and protective against obesity. A recent landmark study revealed that ether lipids can kill cancer cells through ferroptosis. However, the role of ether lipids in prostate cancer has not been thoroughly investigated despite the known association of dysregulated lipid metabolism with poorer clinical outcomes. The aim of this study was to assess the relationship between the circulating profiles of ether lipids and clinical outcomes in localised and metastatic prostate cancer. Methods: The profiles of ~150 ether lipids (8 lipid classes) in plasma lipidomic data from localised prostate cancer (389 men in Australia) and metastatic castration-resistant prostate cancer (mCRPC)(2 cohorts –147 men in USA, 128 men in Australia) were analysed for associations with disease progression or overall survival (OS). Open-access genomic data of mCRPC tumours (108 men, CbioPortal) were analysed for aberrations in genes associated with ether lipid metabolism in relation to clinical outcome. Results: Previously in these study cohorts, we had identified men with poorer prognosis based on their plasma lipidome and our validated sphingolipid signature. These men with poorer prognosis have lower plasma levels of ether lipids than those with better prognosis (t-test p &lt; 0.05, localised disease – 110 ether lipids, mCRPC – 54 ether lipids). Decreased plasma levels of up to 46 ether lipid species were associated with higher rates of clinical relapse in localised disease (hazard ratio (HR) range 0.37-0.73, p-value range 0.006-0.049), shorter radiological progression-free survival in mCRPC (HR range 0.35-0.73, p-value range 0.00009-0.049), and shorter OS in mCRPC (HR range 0.33-0.79, p-value range 0.000004-0.0497). Chromosomal loss of tumour GNPAT, an essential gene in ether lipid synthesis, was associated with shorter OS in mCRPC (HR = 1.36, 95% CI 1.02-1.81, p = 0.03). Conclusions: Lower circulating levels of ether lipids were associated with worse prognosis in localised and metastatic prostate cancer, suggesting that these lipids are protective against disease progression. Further research is required to understand the role of ether lipids in disease progression, and to determine if modulation of ether lipid levels through supplementation is beneficial.

Chronic Hepatitis B Relapse Rates after Cessation of Tenofovir Alafenamide and Entecavir Therapy

Chronic hepatitis B (CHB) relapse occurs after the cessation of nucleos(t)ide analogues (NUC) therapy due to the waning of viral suppression. Few studies have investigated the viral relapse rate and clinical relapse rate after tenofovir alafenamide (TAF) therapy. We compared the CHB relapse rate between TAF and entecavir therapy. We enrolled patients with chronic hepatitis B who underwent TAF or entecavir therapy. NUC therapy was terminated after HBeAg loss for 1 year in HBeAg-positive patients and after undetectable serum HBV DNA on three separate tests each >6 months apart in HBeAg-negative patients. After cessation of NUC therapy, we followed alanine aminotransferase (ALT) levels at 12, 24, and 48 weeks. Serum HBV DNA levels were checked if patients showed a two-fold elevation from the upper limit of normal ALT levels (41 IU/mL). Clinical relapse (CR) was defined as a two-fold elevation in ALT levels and HBV DNA levels > 2000 IU/mL. We then investigated the CR rate of HBV after cessation of TAF and entecavir therapy at 12, 24, and 48 weeks. Of the 117 patients enrolled, 78 were in the entecavir group and 39 were in the TAF group. At 12 weeks after cessation of NUC therapy, no patients had HBV CR in the entecavir group. However, three patients (CR cumulative rate 7.9%) had CR in the TAF group. At 24 weeks, the CR cumulative rate in the entecavir and TAF groups were 1.3% and 13.2%, respectively (p < 0.05). At 48 weeks, the CR cumulative rates were 9.2% and 24.2%, respectively (p = 0.055). Patients in the TAF group had a higher cumulative rate of CR than those in the entecavir group (log-rank p = 0.023). Furthermore, patients in the TAF group had earlier CR times than those in the entecavir group, especially in the first 24 weeks after cessation of therapies (p < 0.05). The cessation of TAF therapy had significantly earlier and higher CR rates than that of entecavir therapy. Close monitoring of liver function and HBV DNA levels may be necessary, especially within 24 weeks after cessation of TAF therapy.

Amplifying STING activation by bioinspired nanomedicine for targeted chemo- and immunotherapy of acute myeloid leukemia.

Chemotherapy resistance and the tumor immune microenvironment are dual reasons for the poor therapeutic efficacy of treating acute myeloid leukemia (AML), causing suboptimal clinical outcomes and high relapse rates. Activation of the stimulator of interferon genes (STING) pathway based on innate immunity can effectively improve antitumor immunity. However, traditional STING agonists are limited due to their easy degradation and difficult membrane transport. Here, a bioinspired nanomedicine synergizing chemo- and immunotherapy was developed by activating the STING pathway for targeted and systemic AML cell damage. We show that a leukemia cell membrane (LCM)-camouflaged hollow MnO2 nanocarrier (HM) with encapsulated doxorubicin (DOX) (denoted LHMD) could bind specifically to AML cells with a homologous targeting effect. Then, MnO2 was decomposed into Mn2+ in response to endosomal acid and glutathione (GSH), which improved the magnetic resonance imaging (MRI) signal for AML detection and activated the STING pathway. In mouse models, LHMD was confirmed to eradicate established AML and prevent the engraftment of AML cells. The percentages of T-helper 1 (Th1) and T-helper 17 (Th17) cells and the concentrations of type I interferon (IFN-Ⅰ) and proinflammatory cytokines increased, while the percentage of T-helper 2 (Th2) cells decreased, reflecting the anti-AML immune response induced by Mn2+ after treatment with LHMD. This nanotechnology-based therapeutic regimen may represent a generalizable strategy for generating an anti-leukemia immune response. STATEMENT OF SIGNIFICANCE: Relapse and chemotherapy refractoriness are main causes for the dismal prognosis of AML, making it urgent to develop more effective anti-AML therapies. This study proposes an innovative strategy to combat this issue by designing a biomimetic BM-targeted nanomedicine based on a MnO2 nano-carrier to rationally deliver chemotherapeutic agents and to trigger Mn2+ mediated STING pathway activation for potent immune- and chemotherapy against AML cells. Hence, the nanomedicine design addresses the challenges associated with AML therapy and proposes a promising strategy to improve the therapeutic efficacy against AML.

A nomogram incorporating ileal and anastomotic lesions separately to predict the long-term outcome of Crohn's disease after ileocolonic resection.

The Rutgeerts score (RS) is widely used to predict postoperative recurrence after ileocolonic resection for Crohn's disease (CD) based on the severity of lesions at the neoterminal ileum and anastomosis (RS i0-i4). However, the value of anastomotic ulcers remains controversial. Our aim was to establish a nomogram model incorporating ileal and anastomotic lesions separately to predict the long-term outcomes of CD after ileal or ileocolonic resection. A total of 136 patients with CD were included in this retrospective cohort study. Consecutive CD patients who underwent ileal or ileocolonic resections with postoperative ileocolonoscopy evaluation within 1 year after the surgery were included. The primary endpoint was postoperative clinical relapse (CR). An endoscopic classification separating ileal and anastomotic lesions was applied (Ix for neoterminal ileum lesions; Ax for anastomotic lesions). A nomogram was constructed to predict CR. The performance of the model was evaluated by the receiver-operating characteristic (ROC) curve and decision curve analysis (DCA). CR was observed in 47.1% (n = 64) of patients within a median follow-up of 26.9 (interquartile range, 11.4-55.2) months. The risk of CR was significantly higher in patients with an RS ⩾ i2 assessed by the first postoperative endoscopy compared with patients with an RS ⩽ i1 (p < 0.001). Moreover, the cumulative rate of CR was significantly higher in patients with ileal lesions (I1-4) compared with patients without (I0) (p < 0.001). Besides, patients with anastomotic lesions (A1-3) had significantly higher rates of CR than patients without (A0) (p = 0.002). A nomogram, incorporating scores of postoperative ileal or anastomotic lesions, sex, L2-subtype and perianal disease, was established. The DCA analysis indicated that the nomogram had a higher benefit for CR, especially at the timeframe of 24-60 months after index endoscopy, compared to the traditional RS score. A nomogram incorporating postoperative ileal and anastomotic lesions separately was developed to predict CR in CD patients, which may serve as a practical tool to identify high-risk patients who need timely postoperative intervention.

Impact of rhG-CSF on Clinical Efficacy and Immune Cell Subsets after Initial Induction Chemotherapy in AML.

The impact of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in acute myeloid leukemia (AML) is still controversial. The purpose of this study is to explore the impact of rhG-CSF administration on clinical efficacy and immune cell subsets after initial induction chemotherapy in AML. The clinical efficacy and immune cell subsets were compared in the newly diagnosed patients with AML according to whether rhG-CSF was used after initial induction chemotherapy. Next, rhG-CSF stimulation experi-ments on leukemia cell lines and primary leukemia blasts were performed in vitro. There was no statistical difference between control group and rhG-CSF therapy group in complete remission rate and relapse free survival. The duration of agranulocytosis was significantly shortened in rhG-CSF therapy group compared with control group. The percentage of circulating monocytic myeloid-derived suppressor cells (M-MDSCs) and regulatory T cells (Tregs) were significantly increased after the administration of rhG-CSF. Furthermore, it was found that rhG-CSF did not promote the proliferation of leukemia cell lines and primary leukemia blasts, but increased the proportion of M-MDSCs and Tregs in vitro. Administration of rhG-CSF after initial induction therapy of AML does not affect the clinical remission and relapse rate, but reduces the duration of agranulocytosis and increases the proportion of M-MDSCs and Tregs.

227. Impact of Asymptomatic Bacteriuria on Primary Efficacy Analyses in the Evaluation of Novel Antimicrobials for the Treatment of Patients with Urinary Tract Infection

Abstract Background Per FDA Guidance, the primary efficacy endpoint for trials evaluating antimicrobials for treatment of uncomplicated urinary tract infection (uUTI) and complicated urinary tract infection (cUTI) is a combined clinical/microbiologic outcome response. Overall success requires both resolution of UTI symptoms and demonstration that the causative uropathogen is reduced to &amp;lt; 103 CFU/mL at a fixed time point after randomization, regardless of whether the patient is symptomatic. In clinical practice, it is not standard of care to routinely screen for or treat asymptomatic bacteriuria (ASB), nor to obtain ‘proof of cure’ cultures. In the clinical trial setting, the impact of post-treatment asymptomatic bladder recolonization on the rates of microbiologic response, re-infection, or emergence of resistance is unknown. Methods Study IT001-301 and -302 are double blind, double-dummy, Phase 3 randomized trials comparing sulopenem to comparator for patients with pyuria, bacteriuria, and clinical signs/symptoms of uUTI and cUTI, respectively. In Study 301, 1671 ambulatory female adults with uUTI were randomized to oral sulopenem bid x 5d or oral ciprofloxacin bid x 3d. In Study 302, 1395 hospitalized adults with cUTI were randomized to sulopenem IV once daily x 5d followed by oral sulopenem bid or ertapenem IV once daily x 5d followed by either oral ciprofloxacin or amoxicillin-clavulanate bid, depending on baseline uropathogen susceptibility. The primary endpoint was overall (clinical + microbiologic) response in micro-MITT population at TOC visit (D12 in uUTI study and D21 in cUTI study). Results Figure 1 Conclusion Different classes of antibiotics appear to have a differential effect on the frequency of post-treatment ASB with quinolones having a lower rate relative to beta-lactams. The presence of ASB a week or more after completing UTI therapy was not associated with a higher rate of clinical relapse for UTI patients; treatment with ciprofloxacin was associated with the selection of resistant pathogens in the post-treatment flora. Inclusion of ASB in the primary endpoint for studies of UTI should be reconsidered as it implies that a post-treatment culture should be obtained to document resolution of infection, a practice inconsistent with available treatment recommendations. Disclosures Steven I. Aronin, MD, Iterum Therapeutics: Stocks/Bonds Michael Dunne, MD, Iterum Therapeutics: Advisor/Consultant|Iterum Therapeutics: Board Member|Iterum Therapeutics: Stocks/Bonds Sailaja Puttagunta, MD, Iterum Therapeutics: Stocks/Bonds.

Vitamin D Supplementation Practices among Multiple Sclerosis Patients and Professionals.

Vitamin D serum level increase is associated with a reduction in clinical relapse rate, gadolinium-enhancing lesions, new or enlarging T2 lesions and new active lesions in the MRI in MS patients. However, current RCTs assessing the vitamin D supplementation therapeutic effect in MS provide inconclusive results. Experts recommend vitamin D measurements and implementations among patients with MS. This article discusses an observational study, performed without any intervention to evaluate the vitamin D status and practices among MS patients and professionals in the clinical setting. A total of 139 patients with MS treated by disease-modifying therapy were recruited and fulfilled the standardized questionnaire assessing the vitamin D supplementation practices and vitamin D level influencing factors such as education, insolation, smoking, obesity and current treatment. The collected data were then compared to the patients' vitamin D serum levels available in medical records at the baseline and after 12 months of observation. Professionals' practices and recommendations were also assessed. A total of 74.1% patients confirmed vitamin D supplementation, and all patients were administered cholecalciferol, taken orally. However, only 43.69% of the patients achieved an optimal vitamin D concentration (30-50 ng/mL). The lack of a doctor's recommendation was the most frequent reason for the absence of vitamin D supplementation. The most often recommended vitamin D daily dose was 4000 IU. There was no adverse effect of supplementation observed. Vitamin D status in patients with MS is currently better than in the general population, but still, a significant percentage of patients do not implement vitamin D.

Combined baseline HBcrAg and end-of-treatment HBsAg predict HBV relapse after entecavir or tenofovir cessation.

For patients with chronic hepatitis B (CHB), the optimal stopping criteria for entecavir or tenofovir disoproxil fumarate treatment remain unclear. This study recruited CHB patients with levels of hepatitis B surface antigen (HBsAg) <100 IU/mL at the end of treatment (EOT) from Kaohsiung (n = 190) and Linkou (n = 188) Chang Gung Memorial Hospitals for use as development and validation groups, respectively. In the development group, 108 patients with HBsAg ≤40 IU/mL were used for analysis of predictors of HBV relapse and HBsAg loss. Multivariate analysis showed that age, nucleos(t)ide analogue (NA)-experienced status, baseline hepatitis B core-related antigen (HBcrAg) and HBsAg at EOT were associated independently with virological and clinical relapse. An HBsAg level of 20 IU/mL at EOT was the best cut-off value for minimizing HBV relapse. Patients with EOT HBsAg ≤20 IU/mL had lower virological and clinical relapse rates and higher HBsAg loss rates than those with EOT HBsAg 21-40 IU/mL and HBsAg 41-100 IU/mL in the development and validation groups. The virological and clinical relapse rates were very low (5-year rates: 6.5% and 0%, respectively) and HBsAg loss rate was very high (5-year rate: 81.7%) in patients with a combination of baseline HBcrAg ≤4 log U/mL and EOT HBsAg ≤20 IU/mL in the development group. A combination of baseline HBcrAg ≤4 log U/mL and EOT HBsAg level ≤20 IU/mL might reduce the risk of HBV relapse and increase HBsAg loss rate, and might be helpful for off-NA follow-up strategy.

Peroxisome proliferator-activated receptor-γ as the gatekeeper of tight junction in Clostridioides difficile infection.

Clostridioides difficile is a major causative pathogen of nosocomial antibiotic-associated diarrhea and severe colitis. Despite the use of vancomycin and fidaxomicin as standard drugs for the treatment of C. difficile infection (CDI), clinical relapse rates remain high. Therefore, new alternative therapeutics to treat CDI are urgently required. The nuclear receptor, peroxisome proliferator-activated receptor-γ (PPAR-γ), is mainly expressed in the adipose tissue and modulates lipid metabolism and insulin sensitization. Previous studies have shown that PPAR-γ is highly expressed in colonic tissues and regulates tight junction function in epithelial cells. However, the role of PPAR-γ in CDI pathogenesis remains unclear. In this study, we used a mouse model of CDI and found that both expression levels of PPAR-γ and the tight junction protein, occludin, were decreased in colonic tissues. Furthermore, to investigate the role of PPAR-γ in CDI, we used PPAR-γ defective mice and found that intestinal permeability and bacterial dissemination in these mice were significantly higher than those in wild-type mice during CDI. Administration of the PPAR-γ agonist, pioglitazone, to activate PPAR-γ activity improved the phenotypes of CDI, including bodyweight loss, inflammation, and intestinal integrity. Taken together, these results demonstrate that PPAR-γ is a potential therapeutic target in CDI, as it modulates colonic inflammation and integrity.

55 RISK FACTORS ASSOCIATED WITH RELAPSES IN PEDIATRIC LUMINAL CROHN'S DISEASE, A RETROSPECTIVE COHORT STUDY

Abstract Background Crohn's diseaseis an inflammatory bowel disease that has a high incidence in Northern countries. The relapse rate of Crohn's disease one year after diagnosis is around 40 to 50% for all treatment modalities combined. Few risk factors are associated with the risk of relapses of Crohn's disease in children. Objectives The aims of this retrospective cohort study were to describe the rate of relapses in children with Crohn's disease, its evolution over the past decade and to determine risk factors associated with relapse. Design/Methods Patients under 18 years old and diagnosed between 2009 and 2019 were included. Patients’ clinical, endoscopic, histological, and laboratory characteristics, as well as their treatments, were collected from their medical records and the prospective CHU Sainte-Justine inflammatory bowel disease registry. Survival analyses and Cox regression models were used to assess the impact of those risk factors on relapse. Results 639 patients were included. There was a decrease in the clinical relapse rate over the past decade: 70.9% of patients diagnosed between 2009 and 2014 experienced a relapse compared to 49.1% of patients diagnosed between 2015 and 2019 (p&amp;lt;0.0001). The following variables were associated with clinical relapse: female sex (adjusted hazard ratio (aHR)= 1.51, p=0.0009), high PCDAI (aHR= 1.02, p=0.04) and SES-CD (aHR= 1.03, p=0.03) scores at diagnosis, upper digestive tract involvement (aHR= 1.59, p=0.0003), exposure to oral 5-ASA (aHR= 1.91, p=0.0003), use of immunomodulatory agents compared to TNF-alpha inhibitors (methotrexate aHR= 1.91, p=0.0006; thiopurines aHR= 2.06, p&amp;lt;0.0001), presence of granulomas (aHR= 1.27, p=0.04) and increased eosinophils on intestinal biopsies (aHR= 1.34, p=0.02), high levels of C-reactive protein (aHR= 1.01, p&amp;lt;0.0001) and fecal calprotectin (aHR=1.09, p&amp;lt;0.0001) during clinical remission and low serum infliximab levels during maintenance (aHR for mean serum infliximab level under 7ug/mL = 2.48, p=0.005). Conclusion Relapse risk was significantly associated with baseline clinical, endoscopic, histological and laboratory data and treatment strategies. These results could help better select treatment options for pediatric Crohn's disease at induction and maintenance. Figure 1: Kaplan-Meier curve representing patients time to relapse according to the first maintenance treatment administered. Figure 2: Kaplan-Meier curve representing patients time to relapse according to the mean infliximab level in post-induction.

A Mysterious Case of Abdominal Pain

A Mysterious Case of Abdominal Pain

Disease recurrence in patients with Crohn’s disease after biologic therapy or surgery: a meta-analysis

BackgroundRelapse is a problem in patients with Crohn’s disease (CD) after medical therapy (including biologics) and after surgery to treat acute inflammation. It is unclear whether the recurrence rate over time is higher after surgical therapy than after continuous drug treatment.AimWe sought to compare clinical relapse rates and the need for re-interventions (resection or therapeutic endoscopic intervention) in patients with CD.MethodsA meta-analysis was performed according to PRISMA guidelines.ResultsThe need for re-intervention with medication or surgery due to surgical or clinical recurrence increased over time. The recurrence rates in patients after ileocecal resection were lower than the rates under biologic therapy. The odds ratio for clinical recurrence under biologics versus after surgical treatment was 2.50 (95% confidence interval [CI] 1.53–4.08, p-value < 0.001). The odds ratio for surgical recurrence under biologics versus after surgery was 3.60 (95% CI 1.06–12.3, p-value 0.041).ConclusionThese findings support surgical resection as a treatment option in patients with CD with limited disease.