Significant Difference In Clinical Response Research Articles

Management of immune thrombotic thrombocytopenic purpura without therapeutic plasma exchange

AbstractImmune thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening autoimmune disorder caused by ADAMTS13 deficiency. Caplacizumab, an anti–von Willebrand factor nanobody, is approved for iTTP treatment, reducing the need for therapeutic plasma exchange (TPE) and improving platelet count recovery and survival. We conducted a retrospective study on 42 acute iTTP cases in Austria and Germany, treated with a modified regimen aimed at avoiding TPE if platelet count increased after the first caplacizumab dose. Baseline characteristics and patient outcomes were compared with a control group of 59 patients with iTTP receiving frontline treatment with TPE, caplacizumab, and immunosuppression. The main outcome was the time to platelet count normalization. Secondary outcomes included clinical response, exacerbation, refractory iTTP, iTTP-related deaths, and the time to platelet count doubling. The median time to platelet count normalization was similar between the 2 cohorts (3 and 4 days; P = .31). There were no significant differences in clinical response, exacerbations, refractoriness, iTTP-related deaths, or time to platelet count doubling, reflecting the short-term treatment response. Four patients did not respond to the first caplacizumab dose, and TPE was subsequently initiated. Cytomegalovirus infection, HIV/hepatitis B coinfection, an ovarian teratoma with associated antiplatelet antibodies, and multiple platelet transfusions before the correct diagnosis may have impeded the immediate treatment response in these patients. In conclusion, caplacizumab and immunosuppression alone, without TPE, rapidly controlled thrombotic microangiopathy and achieved a sustained clinical response in iTTP. Our study provides a basis for TPE-free iTTP management in experienced centers via shared decision-making between patients and treating physicians.

#1491 Management of immune thrombotic thrombocytopenic purpura without therapeutic plasma exchange

Abstract Background and Aims Immune thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening autoimmune disorder caused by ADAMTS13 deficiency. The anti-VWF nanobody Caplacizumab is approved for iTTP treatment, reducing the need for therapeutic plasma exchange (TPE) and improving platelet recovery and survival. This study evaluates the treatment of acute iTTP with caplacizumab and immunosuppression, but without TPE, in comparison to the conventional management with TPE, caplacizumab and immunosuppression. Method All patients in this study were identified from the Austrian Thrombotic Microangiopathy Registry (ATMAR) and the German REACT-2020 TTP registry (ClinicalTrials.gov identifier: NCT04985318). A total of 42 acute iTTP episodes in 41 patients were managed with a treatment regimen aimed at avoiding first-line TPE if the platelet count increased after the first dose of 10 mg caplacizumab, and the patient's condition and organ function remained stable (TPE-free cohort). This treatment modification was implemented based on shared decision making. An extensive efficacy and safety analysis of this approach was performed, in comparison with a control group of 59 iTTP patients, receiving frontline caplacizumab treatment with TPE and immunosuppression (TPE cohort). The main outcome was time to platelet count normalization. Secondary outcomes included clinical response, exacerbation, refractoriness, and iTTP-related deaths. Results The primary outcome parameter, time to platelet count normalization, was not significantly different between TPE-free and TPE-based management (Kaplan-Meier estimator and log-rank test, Table 1 and Fig. 1). The median time to platelet count normalization was 3 days in the TPE-free cohort and 4 days in the TPE cohort. There were no significant differences in clinical response, exacerbations, refractoriness, or iTTP-related deaths. For evaluation of the short-term treatment response, both cohorts were assessed for the time to platelet count doubling. The median time to platelet count doubling was 1 day in both cohorts. Four patients in the TPE-free cohort did not immediately respond to the first caplacizumab injection and subsequently underwent TPE, after a maximum monitoring period of 40 hours. In these patients, TPE was initiated at a median of 1.5 days after the first caplacizumab dose, and TPE was performed for a median of 4.5 days. This delayed platelet response could be attributed to concomitant diseases and factors, e.g. active HIV and hepatitis B virus coinfection, active CMV infection, concomitant antiplatelet antibodies in association with an ovarian teratoma, and multiple platelet transfusions before the correct diagnosis. During overall follow-up, complications were observed in 11 patients (26.2%) in the TPE-free group and 16 patients (27.1%) in the TPE group, excluding complications of iTTP that were evaluated as outcome parameters. Serious complications occurred in 4 patients (6.8%) from the TPE cohort while on TPE, including severe systemic anaphylactic reactions with severe hypotension, generalized seizure and supraventricular tachycardia. Bleeding complications were reported without a significant difference between groups. Conclusion For the first time since the introduction of TPE in the early 1990s, the results of our study systematically challenge the absolute need for TPE and suggest a paradigm shift in acute iTTP management. In detail, our treatment approach was successfully implemented in 38 of 42 acute iTTP episodes (90.5%). We observed no significant difference in the time to platelet count normalization between patients with iTTP treated with and without TPE. The analysis of key secondary outcomes did not reveal significant differences in the proportion of patients who achieved a clinical response or experienced exacerbations, refractoriness, or TTP-related deaths. In conclusion, Caplacizumab and immunosuppression, without TPE, rapidly controlled microvascular thrombosis and achieved a sustained clinical response in iTTP.

High-Loading-Dose Colistin with Nebulized Administration for Carbapenem-Resistant Acinetobacter baumannii Pneumonia in Critically Ill Patients: A Retrospective Cohort Study.

Carbapenem-resistant Acinetobacter baumannii (CRAB) infections pose a serious threat, with high morbidity and mortality rates. This retrospective cohort study, conducted at Nakornping Hospital between January 2015 and October 2022, aimed to evaluate the efficacy and safety of a high loading dose (LD) of colistin combined with nebulized colistin in critically ill patients with CRAB pneumonia. Of the 261 patients included, 95 received LD colistin, and 166 received LD colistin with nebulized colistin. Multivariate Cox regression analysis, adjusted for baseline covariates using inverse probability weighting, showed no significant difference in 30-day survival between patients who received LD colistin and those who received LD colistin with nebulized colistin (adjusted hazard ratio [aHR]: 1.17, 95% confidence interval [CI]: 0.80-1.72, p = 0.418). Likewise, there were no significant differences in clinical response (aHR: 0.93, 95% CI: 0.66-1.31, p = 0.688), microbiological response (aHR: 1.21, 95% CI: 0.85-1.73, p = 0.279), or nephrotoxicity (aHR: 1.14, 95% CI: 0.79-1.64, p = 0.492) between the two treatment groups. No significant adverse events related to nebulized colistin were reported. These findings suggest that the addition of nebulized colistin may not offer additional benefits in terms of 30-day survival, clinical or microbiological response, or nephrotoxicity in these patients.

A RANDOMIZED, PLACEBO-CONTROLLED TRIAL OF PSYLLIUM FIBER AND FECAL MICROBIOTA TRANSPLANTATION FOR MILD TO MODERATE ULCERATIVE COLITIS

Abstract BACKGROUND Emerging clinical data shows potential for fecal microbiota transplantation (FMT) in treating ulcerative colitis (UC), though factors affecting clinical response remain poorly defined. Pre-clinical data suggest the role of dietary fiber in enhancing microbial metabolites to mitigate colitis severity. This study aimed to evaluate the role of the prebiotic psyllium in improving the clinical outcomes of FMT for mild to moderate UC, with the long-term goal of enhancing FMT as a therapeutic strategy for UC. METHODS In a randomized, placebo-controlled clinical trial, 32 participants were screened, and 27 adults with mild to moderate UC were enrolled. Baseline fiber intake was assessed through a food frequency questionnaire. Subjects were randomly assigned to receive FMT alone, FMT with daily fiber (10g of psyllium), or a placebo with or without fiber. The primary endpoint was clinical response by Mayo score at week 8. Secondary endpoints included clinical response by partial Mayo (pMayo) score, endoscopic sub-score, and clinical remission. At week 8, participants underwent crossover treatment with clinical evaluation at week 12. The study ended early due to the manufacturer discontinuing fecal microbiota preparation supply. RESULTS Analysis of primary and secondary endpoints in "FMT alone" and "FMT with fiber" groups revealed no statistically significant differences in clinical response (55.56% alone, N=9 vs. 22.22% fiber, N=9, p=0.1686). Participants with low and high dietary fiber consumption had similar response rates, regardless of supplemental fiber. Consequently, we combined the "FMT" and "no FMT" groups, which showed a significantly higher proportion of subjects achieving clinical response in the FMT group as defined by the partial Mayo score (50.00% FMT group (N=18) and 11.1% in the no FMT group (N=9), p=0.0485). A similar trend was observed for clinical response as defined by the total Mayo score and endoscopic sub-score, where the FMT group outperformed the placebo (38.89% FMT, N=18, vs. 11.11% placebo, N=9, p=0.1362). Among the 9 subjects who received FMT at week 0 and exhibited clinical response defined by pMayo, 77.8% (n=7) maintained their response at week 12. Additionally, 2 patients who initially had no response at week 8 achieved a clinical response by week 12. CONCLUSION The results demonstrate a robust effect of single-dose FMT via colonoscopy in a mild to moderate UC cohort. Given the low cohort size, our results lack the statistical power to reveal the clinical impact of fiber supplementation in FMT. Notably, a substantial proportion of initially responsive FMT recipients maintained their clinical response at week 12, indicating the potential for sustained benefits. Microbiome and metabolomic analyses are currently underway to assess the functional impact of dietary fiber in shaping the effectiveness of FMT for UC.

P1064 Upadacitinib is safe and effective in Ulcerative Colitis patients with prior exposure to Tofacitinib

Abstract Background Upadacitinib is a novel selective Janus Kinase (JAK) inhibitor which has recently been approved for use in ulcerative colitis. Clinical trials have rigorous criteria and excluded patients with prior exposure to JAK inhibitors. Given limited real-world effectiveness data we examined outcomes of patients treated with upadacitinib for ulcerative colitis in a real-world population, with a focus on prior tofacitinib exposure. Methods This retrospective, multi-centre study recruited patients commencing upadacitinib for moderate-to-severe ulcerative colitis from September 2022 until March 2023 from 13 Inflammatory Bowel Disease centres across Australia. Clinical, biochemical, endoscopic and intestinal ultrasound outcomes were recorded at baseline, week 8 and week 16. The primary outcome was a comparison between clinical remission using PRO2 definitions (STRIDE II guidelines) in those with prior Tofacitinib exposure compared with Tofacitinib-naïve. Secondary endpoints included clinical response, corticosteroid free clinical remission (CFCR), biochemical response and transmural remission assessed by intestinal ultrasound (IUS). Adverse events in both cohorts were also recorded. Results 152 patients were identified and included (Table 1) – 42 tofacitinib-exposed and 110 tofacitinib-naïve. Complete clinical data was available for all patients at baseline, week 8, and week 16. For the overall cohort, the rate of clinical remission was 20% (30/152) at baseline, 78% (119/152) at week 8 and 85% (129/152) at week 16. In patients with prior tofacitinib exposure, the rate of clinical remission was 23% (10/42) at baseline, 72% (30/42) at week 8 and 86% (36/42) at week 16. In tofacitinib-naïve patients, the rate of clinical remission was 19% (21/110) at baseline, 78% (86/110) at week 8 and 84% (92/110) at week 16 (Figure 1). There was no statistically significant difference in rate of clinical remission at baseline (p=0.23), week 8 (p=0.13) or week 16 (p=0.67). There was no statistically significant difference in clinical response, CFCR, biochemical response or transmural remission by IUS between the cohorts. Adverse events were seen in 40 (26%) patients over the course of 16 weeks follow-up. Most common were acne (12%), rash (4%) and nasopharyngitis (4%). No venous thromboembolism, systemic infection or cardiovascular events were observed. These events were spread evenly among both groups (p=0.37). Conclusion This is the largest real-world study to show that upadacitinib is effective and safe for patients with moderate to severe ulcerative colitis and prior tofacitinib exposure.

Management of Immune Thrombotic Thrombocytopenic Purpura without Therapeutic Plasma Exchange: Analysis of Efficacy and Safety Data

Background: Immune thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening autoimmune disorder caused by ADAMTS13 deficiency. Caplacizumab, an anti-VWF nanobody, is approved for iTTP treatment, reducing the need for therapeutic plasma exchange (TPE) and improving platelet recovery and survival. Methods: We conducted a retrospective study on 42 acute iTTP cases in Austria and Germany, treated with a modified regimen aimed at avoiding TPE if platelet count increased post-first caplacizumab dose. An extensive efficacy and safety analysis of this approach was performed, in comparison with a control group of 59 patients with iTTP, receiving frontline caplacizumab treatment with TPE and immunosuppression (standard of care, SOC). The main outcome was time to platelet count normalization. Secondary outcomes included clinical response, exacerbation, refractory iTTP, and iTTP-related deaths. Retrospective safety assessments with evaluation of treatment emergent adverse events (TEAE) were performed in both cohorts. Results: The median time to platelet count normalization was similar between the two cohorts (3 and 4 days; P = 0.31, see Figure 1). There were no significant differences in clinical response, exacerbations, refractoriness, or iTTP-related deaths (see Table 1). Four patients did not respond to the first dose of caplacizumab, and TPE was initiated. Cytomegalovirus infection, HIV/hepatitis B co-infection, and ovarian teratoma may have hindered immediate treatment response. Platelet count doubling and median platelet count change after first caplacizumab dose were unaffected by TPE. The median time to LDH normalization was 11 days in the TPE-free cohort. During overall follow-up at least one adverse event (TEAE) was observed in 11 patients (26.2%) in the TPE-free group and 15 patients (25.4%) in the SOC group (excluding adverse events of iTTP that were evaluated as outcome parameters) (see Table 1). There was one TTP-related death reported in the SOC group (1.7%). The cause of death in this patient was cerebral ischemia due to multiple strokes. Serious adverse events associated with therapeutic plasma exchange were observed in 3 patients (5.1%) exclusively in the SOC cohort. These included (1) in-hospital cardiac arrest (IHCA), (2) generalized seizure and supraventricular tachycardia and (3) a transfusion reaction with hypotension, rigors, pruritus and exanthema. Bleeding complications were reported without a significant difference and mainly comprised gingival bleeding and epistaxis. Two patients in the TPE-free cohort (4.8%) experienced major bleeding events, namely subdural hematoma requiring surgical intervention and gastrointestinal bleeding with mass transfusion. Spontaneous subdural hematoma occurred in one patient after 20 days of caplacizumab treatment. Gastrointestinal bleeding from a colon diverticulum occurred in another patient after a clinical response and resulted in a significant drop in hemoglobin and thrombocytes. Gastrointestinal bleeding worsened with concomitant factor XIII deficiency, which was reconstituted intravenously in addition to mass transfusion. Conclusion: Caplacizumab and immunosuppression, without TPE, rapidly controlled microvascular thrombosis and achieved a sustained clinical response in iTTP. The efficacy was similar to the control group, which received SOC. Standard iTTP treatment with TPE may lead to a prolonged hospital stay, including admission to the ICU, multiple sessions of daily TPE with associated risks, and the associated costs of plasma, equipment, nursing care, and medical supervision. The number of patients experiencing critical adverse events was comparable between groups. Bearing all restrictions of a retrospective cohort in mind, we did not identify a critical safety signal for TPE-free iTTP-treatment. However, TPE itself resulted in three life-threatening adverse events in the SOC cohort, including an in-hospital cardiac arrest. In conclusion, omitting TPE appears to be a viable choice for acute iTTP management that may reduce treatment burden without compromising patient outcomes or safety.

Nb-UVB and PUVA therapy in treating early stages of Mycosis Fungoides: A single-center cross-sectional study.

Mycosis fungoides (MF) and Sezary Syndrome are the most common forms of cutaneous T-cell lymphoma. Early-stage MF is known to have an indolent behavior, and the EORTC guidelines recommend treating patients with skin-directed therapies, such as phototherapy, instead of systemic therapies. Phototherapy is a popular therapeutic option, with two commonly used light sources-PUVA and narrow band-nb UVB. PUVA is less commonly used due to its potential carcinogenic role, but it has systemic effects, while nb-UVB has mostly skin-limited effects. There is ongoing debate regarding the role of UVB light, and in 2021, the Cutaneous Lymphoma Italian Study Group reached a consensus on technical schedules for NB-UVB and PUVA for MF. This study aims to analyze and compare the efficacy of the two phototherapy options in treating early-MF patients. The study included patients diagnosed with stage IA/B MF in the last 10 years, who had at least 12 months of follow-up data and a minimum of 24 phototherapy sessions (PUVA or nb UVB) and treated with topical steroids apart from phototherapy. Results showed that the two phototherapy options were similarly effective in treating early MF, with no significant differences in clinical response, although PUVA was associated with more adverse effects. The study provides valuable insights into the use of phototherapy in early MF, and the results can be used to guide treatment decisions and improve patient outcomes.

Dose-adjusted EPOCH-R vs. R-CHOP in frontline management of Waldeyer's ring diffuse large B-cell lymphoma: a retrospective study from a single institution.

To compare the efficacy and safety of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus rituximab (DA-EPOCH-R) with standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in Waldeyer's ring diffuse large B-cell lymphoma (WR-DLBCL) at a single institution. This retrospective study included 115 newly diagnosed patients with WR-DLBCL, of whom 68 patients received R-CHOP, and 47 patients received DA-EPOCH-R as their first-line treatment. The baseline features of the two groups were well balanced using a 1:1 propensity score matching method, and a total of 84 cases were obtained, including respective 42 cases in the R-CHOP and DA-EPOCH-R groups, for further survival and prognosis analysis. The primary objectives included progression-free survival (PFS) and overall survival (OS). During a median follow-up of 45 months, there were nine (21.4%) deaths in the R-CHOP group and two (4.8%) in the DA-EPOCH-R group. Kaplan-Meier analysis showed statistically significant improvements in PFS and OS in patients with DA-EPOCH-R compared with those treated with R-CHOP (log-rank test, P = 0.025 and P = 0.035, respectively). The 2-year PFS and OS rates in the DA-EPOCH-R group were 90.1% (95% confidence interval [CI]: 81.4-99.8%) and 95.2% (95% CI: 89.0-100.0%), respectively, and 80.5% (95% CI: 69.3-93.6%) and 90.5% (95% CI: 52.8-99.8%) in the R-CHOP group. Patients without B symptoms and elevated lactate dehydrogenase levels had a higher PFS in the DA-EPOCH-R group, with P values of 0.038 (hazard ratio [HR]: 0.11; 95% CI: 0.01-0.88) and 0.042 (HR: 0.19; 95% CI: 0.04-0.94), respectively. There were no statistically significant differences in clinical responses and treatment-related toxicities between the two groups. Compared with patients received R-CHOP, those treated by DA-EPOCH-R had superior PFS, OS, and controlled toxicity in patients with WR-DLBCL.

Oral minoxidil use in androgenetic alopecia and telogen effluvium.

While current studies have supported oral minoxidil as a novel, adjunctive therapy in non-scarring forms of alopecia, there continues to be limited data on oral minoxidil for these conditions. To assess oral minoxidil use in the treatment of androgenetic alopecia and telogen effluvium, a multi-center, retrospective analysis was conducted in 105 adult patients treated for androgenetic alopecia and/or telogen effluvium with oral minoxidil (dose range 0.625-2.5mg) once daily for ≥ 52weeks, case matched by age (± 5years) and gender with 105 controls with androgenetic alopecia and/or telogen effluvium who were not treated with oral minoxidil. 80 women (76.2%) with a mean age of 57.5 ± 13.56 (range 24-80) and 25 men (23.8%) with a mean age of 40.4 ± 13.79 (range 19-63) were included. Efficacy was evaluated based on provider assessment of clinical response and clinical photographic evaluation using a 3-point scale (worsening, stabilization, and improvement). 52.4% of patients demonstrated clinical improvement and 42.9% demonstrated stabilization. There was a significant difference in clinical response between the patient and control group, p < 0.001. Retrospective study design. These results suggest that oral minoxidil can be an effective treatment in androgenetic alopecia and telogen effluvium.

A Monocentric Retrospective Study of AUC/MIC Ratio of Vancomycin Associated with Clinical Outcomes and Nephrotoxicity in Patients with Enterococcal Infections

Vancomycin is an antibiotic commonly used for the treatment of enterococcal infections. However, there is no clear correlation regarding of vancomycin area under the curve/minimum inhibitory concentration (AUC/MIC) ratio and clinical outcomes for the treatment of enterococcal infections. The aims of this study were to evaluate the relationship of vancomycin AUC/MIC ratio in patients with clinical outcomes and nephrotoxicity for patients with documented enterococcal infections. A Bayesian technique was used to calculate the average vancomycin AUC0–24. The MIC was determined using the VITEK 2 automated microbiology system, and the average AUC0–24/MIC value was calculated for the first 72 h of therapy. All medical records of patients prescribed vancomycin with therapeutic drug monitoring were collected during January 2010–October 2020 at Chiang Mai University Hospital (CMUH). A retrospective single-center cohort of 312 participants were met the inclusion criteria. The results of this study showed that, a vancomycin AUC/MIC of ≥400 mg·h/L was associated with significant differences in clinical response compared to a vancomycin AUC/MIC of <400 mg·h/L (aHR: 0.50, 95% CI: 0.26–0.97; p = 0.042). Likewise, a vancomycin AUC/MIC of ≥400 mg·h/L was associated with significant differences in the microbiological response (aHR: 0.37, 95% CI: 0.14–0.94; p = 0.036), compared to a vancomycin AUC/MIC of <400 mg·h/L. However, nephrotoxicity in patients with a vancomycin AUC/MIC of ≥400 mg·h/L was higher than those with a vancomycin AUC/MIC of <400 mg·h/L (aHR: 3.96, 95% CI: 1.09–14.47; p = 0.037). Declining renal function may be a result of high vancomycin concentrations. In addition, declining renal function (e.g., failure to resolve the focus of infection, co-administration of other antibiotics) might result in higher AUC/MIC. We found a target vancomycin AUC/MIC of ≥400 mg·h/L and this AUC/MIC target value could be optimal for the use for monitoring treatment of enterococcal infections. Thus, vancomycin dosage must be adjusted to achieve the AUC/MIC target and closely monitored for renal function. These findings are not transferable to critically ill patients.

Anti-MRSA Cephalosporin versus Vancomycin-Based Treatment for Acute Bacterial Skin and Skin Structure Infection: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

This systematic review and meta-analysis of randomized controlled trials (RCTs) compared the clinical efficacy and safety of anti-MRSA cephalosporin and vancomycin-based treatment in treating acute bacterial skin and skin structure infections (ABSSSIs). PubMed, Embase, Cochrane Central Register of Controlled Trials, Turning Research into Practice, and ClinicalTrials.gov databases were searched for relevant articles from inception to 15 June 2020. RCTs comparing the clinical efficacy and safety of anti-MRSA cephalosporin with those of vancomycin-based regimens in treating adult patients with ABSSSIs were included. The primary and secondary outcomes were clinical response at the test-of-cure assessments and risk of adverse events (AEs), respectively. Eight RCTs were enrolled. The clinical response rate was not significantly different between anti-MRSA cephalosporin and vancomycin-based treatments (odds ratio [OR], 1.05; 95% CI, 0.90–1.23; I2 = 0%). Except for major cutaneous abscesses in which anti-MRSA cephalosporin-based treatment was associated with a lower clinical response rate than vancomycin-based treatment (OR, 0.62; 95% CI, 0.40–0.97; I2 = 0%), other subgroup analyses according to the type of cephalosporin (ceftaroline or ceftobiprole), type of infection, and different pathogens did not show significant differences in clinical response. Anti-MRSA cephalosporin-based treatment was only associated with a higher risk of nausea than vancomycin-based treatment (OR, 1.41; 95% CI, 1.07–1.85; I2 = 0%). In treating ABSSSIs, the clinical efficacy of anti-MRSA cephalosporin is comparable to that of vancomycin-based treatment, except in major cutaneous abscesses. In addition to nausea, anti-MRSA cephalosporin was as tolerable as vancomycin-based treatment.

OP24 Efficacy and safety of upadacitinib induction therapy in patients with Moderately to Severely Active Ulcerative Colitis: Results from the phase 3 U-ACHIEVE study

BackgroundAn unmet therapeutic need remains in patients with ulcerative colitis (UC). U-ACHIEVE is one of two phase 3 induction trials evaluating the safety and efficacy of the selective Janus kinase–1 inhibitor upadacitinib (UPA) 45 mg once daily (QD) in adults with UC.MethodsU-ACHIEVE is a multicentre, double-blind, placebo (PBO)–controlled trial (NCT02819635) that randomized patients with moderately to severely active UC 2:1 to UPA 45 mg QD or PBO for 8 weeks. Patients were stratified by response to biologic therapy (inadequate vs non–inadequate responder), baseline corticosteroid use (yes or no), and baseline adapted Mayo score (≤7 or >7). The primary endpoint was proportion of patients achieving clinical remission (per adapted Mayo Score) at week 8.Ranked secondary endpoints included endoscopic improvement, endoscopic remission, and clinical response per adapted Mayo Score at week 8; clinical response per partial adapted Mayo Score at week 2; and histologic-endoscopic mucosal improvement at week 8. Non-responder imputation incorporating multiple imputations for missing data due to COVID-19 are reported. Safety was assessed through week 8.Results474 patients were randomized (UPA, n=319; PBO, n=155). Baseline characteristics were well balanced between groups (Table 1). A significantly higher proportion of patients receiving UPA (26.1%) vs PBO (4.8%) achieved clinical remission at week 8 (adjusted treatment difference [95% CI], 21.6% [15.8, 27.4]; P<0.001; Figure 1). For all ranked secondary endpoints, UPA was superior to PBO (P<0.001; Figure 1). A significant difference in clinical response favouring UPA vs PBO was seen as early as week 2 (60.1% vs 27.3%) and was sustained over 8 weeks (79.0% vs 41.6%; Figure 2). There were more serious adverse events (AEs), severe AEs, and AEs leading to study drug discontinuation with PBO (Table 2). The most common AEs were acne, creatine phosphokinase elevation, and nasopharyngitis with UPA and worsening of UC and anaemia with PBO. Incidence of serious infection was similar between UPA and PBO. Neutropenia and lymphopenia were reported more frequently with UPA vs PBO (Table 2).No adjudicated gastrointestinal perforation, major cardiovascular AEs, or thrombotic events and no active tuberculosis, malignancy, or deaths were reported. ConclusionIn patients with moderately to severely active UC, UPA 45 mg QD induction therapy was superior to PBO in inducing clinical remission/response, and endoscopic remission/response over 8 weeks; responses were significant and rapid. UPA 45 mg QD was well tolerated; safety was comparable with the known safety profile of UPA, and no new safety signals were identified.

Efficacy of clotrimazole for the management of oral candidiasis: A meta-analysis of randomized clinical trials

PurposeTo assess the efficacy and safety of topical application of clotrimazole versus others in the treatment of oropharyngeal candidiasis (OPC). MethodFour electronic databases, registries of ongoing trials, and manual search were used to identify randomized controlled trials (RCTs) that compared the efficacy of clotrimazole to other antifungal agents in patients who were clinically diagnosed with oral candidiasis up to November 1st, 2019. Primary outcomes were clinical response and mycological cure rates. Secondary outcomes include relapse rate, incidence of systemic infections, and compliance. Adverse effects were also evaluated. ResultsSixteen RCTs with a total of 1685 patients were included. Half of the eligible studies were considered at high risk of performance bias and more than a third, at high risk of reporting bias. Our analysis showed no significant difference in clinical response between clotrimazole and all other antifungal agents. However, clotrimazole was less effective in terms of mycologic cure and relapse rate. Sensitivity analysis comparing clotrimazole to other topical antifungal agents only showed no differences in clinical response, microbiologic cure or relapse. Further sensitivity analysis showed significant efficacy of fluconazole over clotrimazole. ConclusionThis meta-analysis indicated that clotrimazole is less effective than fluconazole but as effective as other topical therapies in treating OPC. Well-designed high-quality RCT is needed to validate these findings.

Efficacy and safety of eravacycline: A meta-analysis

ObjectivesThis study was conducted to evaluate the efficacy and safety of eravacycline, a recently approved fluorocycline for treatment of complicated intra-abdominal infections (cIAIs). MethodsPubMed, EMBASE and three trial registries were searched for randomised controlled trials (RCTs) comparing the efficacy and safety of eravacycline versus comparators. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using random-effects models. The study outcomes included clinical response, all-cause mortality and adverse events (AEs). ResultsThree RCTs (1128 patients) with cIAIs were included. There were no significant differences in clinical response in the modified intention-to-treat (ITT) (OR, 0.91, 95% CI 0.62–1.35; I2 = 0%), microbiological ITT (OR, 0.93, 95% CI 0.61–1.41; I2 = 0%) and clinically evaluable (OR, 0.98, 95% CI 0.55–1.75; I2 = 0%) populations or in all-cause mortality (OR, 1.18, 95% CI 0.16–8.94; I2 = 0%). Eravacycline was associated with significantly greater odds of total AEs (OR, 1.55, 95% CI 1.20–1.99; I2 = 0%) and nausea (OR, 5.29, 95% CI 1.77–15.78; I2 = 1.70%) but the increase in vomiting was non-significant (OR, 1.44, 95% CI 0.73–2.86; I2 = 1.70%). There were no significant differences in serious AEs or discontinuation due to AEs. ConclusionThis meta-analysis of RCTs found similar clinical efficacy and mortality for eravacycline compared with carbapenems for treatment of cIAIs. However, the odds of total AEs and specifically nausea was higher with eravacycline, while no significant differences were observed in vomiting (although numerically higher), serious AEs or discontinuation due to AEs.

Modification of the association between paroxetine serum concentration and SERT-occupancy by ABCB1 (P-glycoprotein) polymorphisms in major depressive disorder

Selective serotonin reuptake inhibitors (SSRIs) exert substantial variability in effectiveness in patients with major depressive disorder (MDD), with up to 50-60% not achieving adequate response. Elucidating pharmacokinetic factors that explain this variability is important to increase treatment effectiveness. To examine potential modification of the relationship between paroxetine serum concentration (PSC) and serotonin transporter (SERT)-occupancy by single nucleotide polymorphisms (SNPs) of the ABCB1 gene, coding for the P-glycoprotein (P-gp) pump, in MDD patients. To investigate the relationship between ABCB1 SNPs and clinical response. Patients had MDD and received paroxetine 20 mg/day. We measured PSC after 6 weeks. We quantified SERT-occupancy with SPECT imaging (n = 38) and measured 17-item Hamilton Depression Rating Scale (HDRS17)-scores at baseline and after 6 weeks (n = 81). We genotyped ABCB1 at rs1045642 [3435C>T], rs1128503 [1236C>T], rs2032582 [2677G>T/A] and rs2235040 [2505G>A]. For our primary aim, we modeled mean SERT-occupancy in an Emax nonlinear regression model with PSC and assessed whether the model improved by genetic subgrouping. For our secondary aim, we used multivariate linear regression analysis. The rs1128503 and rs2032582 SNPs modified the relationship between PSC and SERT-occupancy in both our intention-to-treat and sensitivity analyses at the carriership level. However, we could not detect significant differences in clinical response between any of the genetic subgroups. Pharmacokinetic influences of the ABCB1 rs1128503 and rs2032582 represent a potentially relevant pharmacogenetic mechanism to consider when evaluating paroxetine efficacy. Future studies are needed to support the role of ABCB1 genotyping for individualizing SSRI pharmacotherapy.

P045 Do Levels Matter? Maintaining Anti-TNF Class After Secondary Loss of Response to Adalimumab in Inflammatory Bowel Disease

BACKGROUND: Anti-tumor necrosis factor (Anti-TNF) biologic therapies have evolved as a mainstay of treatment for inflammatory bowel disease (IBD). However, 10%–20% of patients are primary non-responders to anti-TNF in clinical series and up to 40% of patients lose response to treatment over time. Current guidelines suggest that treatment failure in the setting of adequate drug concentrations are due to mechanistic failure and should be switched out of the anti-TNF class. Our aim was to assess the efficacy of switching to infliximab, rather than changing out of class, in patients with secondary loss of response to adalimumab who had a therapeutic drug level. METHODS: A retrospective chart review identified patients with ulcerative colitis (UC) and Crohn's disease (CD) treated with adalimumab within the University of North Carolina Inflammatory Bowel Disease clinic between January 1, 2007 and December 31, 2017. Patients with a therapeutic adalimumab level and treatment failure and who were subsequently treated with infliximab were included in the study. RESULTS: There were a total of 16 patients with therapeutic adalimumab levels (&gt;5 μg/mL) and no antibody formation with treatment failure. In this population, 11 of the patients had CD, 3 patients had inflammatory bowel disease undifferentiated (IBDU) and 2 had UC. Ileocolonic CD (45.5%) and penetrating disease (54.4%) were the most common phenotypes. All patients had secondary loss of response to adalimumab and 87.5% had been increased to weekly dosing. Mean adalimumab level was 9.8 ± 6.8 μg/mL prior to switching to infliximab. Thirteen patients (81.3%) achieved clinical response with infliximab at 14 weeks and of the 8 patients with endoscopic assessments, 100% achieved endoscopic remission (5 with UC/IBDU and 3 with CD). There were a total of 6 patients in a sensitivity analysis assessing therapeutic levels &gt;7 μg/mL. All patients were female, however all other characteristics in this group were similar to those patients evaluated with a therapeutic threshold of 5 μg/mL, including the rate of clinical response at 14 weeks (83.3%). When compared to 28 patients with adalimumab levels &lt;5 μg/mL, there was no significant difference in clinical response at 14 weeks (P = 0.692). CONCLUSION(S): Switching within class to infliximab after secondary loss of response to adalimumab with a therapeutic level achieved clinical remission at 14 weeks in 81.3% of patients, and appears to be an acceptable strategy in selected patients. Therapeutic drug levels alone are not predictive of clinical response to a second anti-TNF.

Clinical Consequences of Antibody Formation, Serum Concentrations, and HLA-Cw6 Status in Psoriasis Patients on Ustekinumab.

Background:Ustekinumab for the treatment of psoriasis is currently administered in a standard dosing regimen. However, some patients tend to benefit from alternative dosing regimens, a step toward personalized medicine.Methods:To investigate the role of ustekinumab serum concentrations, anti-ustekinumab antibodies [AUA] and HLA-Cw6 status as tools for optimizing ustekinumab treatment, a multicenter prospective cohort study was conducted at an academic hospital with affiliated nonacademic hospitals in Belgium (cohort 1) and 2 academic hospitals in the Netherlands (cohort 2 and 3). Patients with plaque-type psoriasis were eligible if treated with ustekinumab for ≥16 weeks. Serum samples and Psoriasis Area and Severity Index scores were obtained at baseline, week 16, 28, 40, 52, and/or ≥64 of ustekinumab treatment.Results:A total of 137 patients with 229 observations for serum concentrations and AUA and 61 observations for HLA-Cw6 status were included. Presence of AUA (prevalence of 8.7%) was significantly associated with a diminished clinical response (P = 0.032). The median ustekinumab trough concentration was 0.3 mcg/mL (<0.02–3.80). No differences in serum concentrations were observed between moderate to good responders and nonresponders (P = 0.948). Serum trough concentrations were not affected by methotrexate comedication. Prevalence of HLA-Cw6 positivity was 41% with no statistically significant difference in clinical response between HLA-Cw6–positive and HLA-Cw6–negative patients (P = 0.164).Conclusions:The presence of AUA was associated with treatment failure in this patient population; measurement of AUA may therefore be a candidate marker for personalized pharmacotherapy. The clinical utility of ustekinumab serum trough concentrations or HLA-Cw6 status determination remains less clear. Further exploration on the potential of measuring ustekinumab serum concentrations and other biomarkers in predicting therapy outcomes should be encouraged.

Echinocandins vs. amphotericin B against invasive candidiasis in children and neonates: A meta-analysis of randomized controlled trials

The aim of this meta-analysis was to assess the efficacy and safety of treatment with echinocandins compared with amphotericin B in paediatric patients with invasive candidiasis. PubMed, Embase and Cochrane databases were searched up to August 2018. Only randomized controlled trials (RCTs) evaluating echinocandins and amphotericinB in the treatment of paediatric patients with invasive candidiasis were included. The outcomes were clinical responses and adverse effects. Five RCTs of 354 patients (191 patients in the echinocandins group and 163 patients in the amphotericin B group) were included in this study. Overall, no significant differences in clinical response were found between echinocandins and amphotericin B (odds ratio [OR], 1.38; 95% confidence interval [CI], 0.68-2.80; I2 = 39%). Similar results were also observed in the high-risk group (OR, 3.10; 95% CI, 0.10-97.23; I2 = 76%), the low-risk group (OR, 1.29; 95% CI, 0.36-4.62; I2 = 21%) and the neutropenia group (OR, 1.56; 95% CI, 0.75-3.26; I2 = 0%). The risk of discontinuing treatment because of adverse effects was significantly lower in the echinocandins group than in the amphotericin B group (OR, 0.30, 95% CI, 0.12-0.76; I2 = 0%). There were no differences in efficacy between the echinocandins group and the amphotericin B group in the treatment of invasive candidiasis in paediatric patients. However, the echinocandins group had a significantly lower risk of discontinuing treatment than the amphotericin B group.

Efficacy and safety of ceftazidime/avibactam: a systematic review and meta-analysis.

Ceftazidime/avibactam is approved for complicated intra-abdominal and urinary tract infections (UTIs) based on results from randomized controlled trials (RCTs). Data regarding its effectiveness in treating hospital-acquired infections or resistant pathogens have not been systematically compiled. A systematic review and meta-analysis including RCTs evaluating ceftazidime/avibactam versus comparator for the treatment of any infection. Primary outcome was 30 day all-cause mortality. Subgroups of hospital-acquired infections and specific resistance phenotypes were planned. Seven publications (eight trials, 4093 patients) were included, reporting a baseline ∼25% of ESBL-carrying Enterobacteriaceae. No significant difference between ceftazidime/avibactam and comparator (mostly carbapenem) was demonstrated for 30 day all-cause mortality, late follow-up mortality and clinical response [relative risk (RR) 1.10, 95% CI 0.70-1.72, P = 0.69; RR 1.23, 95% CI 0.87-1.76, P = 0.25; RR 0.98, 95% CI 0.96-1.01, P = 0.21, respectively, without significant heterogeneity]. Higher microbiological response rate was demonstrated with ceftazidime/avibactam in patients with UTI (RR 1.14, 1.0-1.29, P = 0.05, I2 = 51%). No significant difference in clinical response was demonstrated for patients with ceftazidime-resistant pathogens (RR 1.02, 95% CI 0.94-1.10, P = 0.66, I2 = 0%). Results for other subgroups of resistant pathogens or hospital-acquired infection were not available. Serious adverse events (SAEs) were significantly more common with ceftazidime/avibactam (RR 1.24, 95% CI 1.00-1.54, P = 0.05, I2 = 0%). Ceftazidime/avibactam is clinically and microbiologically as effective as carbapenems for treatment of infections in a setting of ∼25% ESBL-carrying Enterobacteriaceae. Safety of the drug should be further evaluated owing to a higher rate of SAEs compared with carbapenems. Further studies should assess the drug's effectiveness in the treatment of carbapenemase-producing Enterobacteriaceae.

Ki-67 expression and its effect on response to neo-adjuvant chemotherapy in invasive breast cancer

Objective: To investigate the response to neoadjuvant chemotherapy (NAC) among different molecular subtypes of breast cancers using molecular classification with Ki-67 (ER+ PR+ HER2+ Ki-67) or without Ki-67 (ER+ PR+ HER2). Methods: One hundred and twenty-seven cases of invasive breast cancer confirmed by core needle biopsy before NAC were collected from January 2007 to December 2009 and diagnosed at West China Hospital, Sichuan University. The cases were classified into different molecular subtypes using molecular classifications with or without Ki-67. Their clinical and pathological response to NAC was evaluated and compared. Results: The different subtypes using both molecular classifications showed significant difference in clinical response(with Ki-67: χ(2)=22.40, P<0.01; without Ki-67: χ(2)=9.202, P=0.027)but not pathological(P>0.05) response to NAC. By multivariate analysis, Ki-67 was predictive for a clinical complete response (P=0.041) and clinical overall response (P<0.01); also Ki-67 was the only clinicopathological factor predictive of pathological response(P=0.041). Conclusion: The molecular classification with Ki-67 is better to predict breast cancers responsiveness to NAC than the molecular classification without Ki-67.