Risk Of Serious Infections Research Articles

Indoxyl sulfate (IS) mediates pro-inflammatory responses in severe pneumonia in patients with rheumatoid arthritis associated interstitial lung disease.

Patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD) have a high risk of serious infection, in particular severe pneumonia. This study aimed to investigate the transcriptional landscape, lower respiratory tract (LRT) microbiome and metabolomic profiles in the lung of RA-ILD patients with pneumonia. A total of 10 RA-ILD with pneumonia were enrolled in this study. In addition, 11 patients with COVID-19-associated pneumonia and 6 patients with non-autoimmune and non-COVID-19-related ILD with pneumonia were included as controls. Bronchoalveolar lavage fluid (BALF) was collected and prepared for metagenomic next-generation sequencing (mNGS), non-targeted metabolomics and bulk RNA-seq. Neutrophil-related genes were shared in the BALF cells of RA-ILD patients with pneumonia and patients with COVID-19-associated pneumonia. Carnobacterium, Wujia, Intestinimonas, Apibacter, Anaerotignum and Parvimonas were enriched in the LRT microbiome of RA-ILD, while Wujia, Apibacter, Pseudocitrobacter, and Thermobacillus were enriched in the LRT microbiome of COVID-19. Metabolomics analysis of BALF revealed significant elevation of indoxyl sulfate (IS) in the BALF of RA-ILD patients in comparison to COVID-19. Mechanistically, IS exerts an pro-inflammatory effect on macrophages and bronchial epithelial cells for pro-inflammatory cytokine production and potentiated neutrophils for neutrophil extracellular traps (NETs) formation. Our results demonstrated a significant differences in the LRT microbiome and BALF metabolites between RA-ILD and COVID-19 patients with pneumonia, although they displayed similar local immune responses against lung infection. Alterations of LRT microbiome and related metabolites may be implicated in the pathogenesis of pneumonia in RA-ILD.

Maternal-Newborn ABO Blood Group Congruence Among Consecutive Births and Risk of Serious Neonatal Infection: Retrospective Cohort Study.

Differing ABO blood groups between a mother and her fetus may confer a lower risk of serious neonatal infection. How sensitization in the first pregnancy influences this phenomenon in a subsequent pregnancy is unclear. Accordingly, this study determined whether maternal-newborn ABO blood group incongruence in a first pregnancy further modifies the risk of serious infection in a subsequent pregnancy marked by ABO incongruency. This population-based retrospective cohort study used linked patient-level datasets in Ontario, Canada, from 2008 to 2022. Included were mothers with 2 consecutive live births, with recorded maternal and newborn ABO blood group data. The exposure considered both first- and second-born siblings' ABO blood group congruency with their mother. The outcome was a serious neonatal infection within 27 days after birth. Logistic regression models generated adjusted odds ratios (aORs) and 95% confidence intervals (CIs), adjusted for gestational age at birth. Included were 14,739 mother-infant triads. Relative to maternal-newborn congruency in the second pregnancy, incongruent ABO blood groups in the second pregnancy were associated with an aOR of 0.72 (95% CI, 0.53-0.97) for a serious neonatal infection arising in the second-born infant. However, if the first and second siblings each had incongruent ABO blood groups with their mother, the aOR of serious infection in the second-born infant was not significantly lower [0.74 (95% CI, 0.52-1.06)]. Second-born infants whose ABO blood group was incongruent with that of their mother had a lower risk of serious neonatal infection. However, ABO incongruence from a prior birth did not modify that relation.

P1163 Treatment-based risk stratification of serious and opportunistic infections in IBD patients from an tertiary center in brazil: a comparison between advanced therapies and non-biologic exposure in real world setting

Abstract Background The risks of serious and opportunistic (OIs) infections associated with advanced therapies for IBD is one of the main concerns of both physicians and advanced practice clinicians in IBD care. We assessed the incidence and stratify the risk of serious infections or OIs in patients with IBD treated with advanced therapy. Methods We performed an ambispective observational study of adults patients with a diagnosis of IBD in a tertiary IBD center located in Brazil. We retrospectively analyzed the IBD patients from 2014 to 2017 and prospectively those from 2018 to 2022. Serious infections were defined as those requiring intravenous antibiotic therapy or hospitalization. The incidence (per 100 patient-years) and risks of serious and OIs associated with exposure to combination therapy (anti-TNF and thiopurines), monotherapies with anti-TNF, vedolizumab, ustekinumab or tofacitinib were compared with exposure to aminosalicylates using marginal structural Cox proportional hazard models adjusted for baseline characteristics and medications. Results Among the 504 patients, 75 serious infections and 35 OIs were observed, resulting in overall incidence rates of serious infections and OIs of 3.1 and 1.1 per 100 PY, respectively. Overall incidence rates of serious infections ranged from 0.1, 0.15, 0.13, 0.16, 1.2., and 3.1 per 100 PY in those exposed to aminosalicylates, ustekinumab, vedolizumab, tofacitinib, anti-TNF monotherapy, and combination therapy, respectively. Conversely, the overall incidence rates of OIs ranged from 0, 0.1, 0.1, 0.3, 0.9, and 2.1 per 100 PY in those exposed to aminosalicylates, ustekinumab, vedolizumab, tofacitinib, anti-TNF monotherapy, and combination therapy, respectively. OIs were mostly due to Mycobacterium tuberculosis (n=21) and herpes zoster (n=11). Compared with aminosalicylates, vedolizumab and ustekinumab therapy did not increase the risk of serious infections and OIs (HR, 0.93; 95% CI, 0.42-1.81). Conversely, tofacitinib, anti-TNF monotherapy and combination therapy were associated with increased risks of OIs (HR, 1.13; 95% CI, 1.05-2.01), HR, 2.13; 95% CI, 1.92-5.81 and HR, 32.3; 95% CI, 19.21-40.53, respectively). Conclusion Anti-TNF therapy and combotherapy were associated with an increased risk of serious infections and OIs, while vedolizumab and ustekinumab presented a insignificant risk of these infections. Tofacitinib was associated with a small increased risk of OIs. Tuberculosis was the main OI, and was associated exclusively with the use of anti-TNF monotherapy or combotherapy. In choosing advanced therapy for IBD, clinicians should consider, among other factors, the risk of serious infections and OIs and weighed against potential benefits of the various targeted therapies for IBD.

P0695 Quantifying the benefit-risk trade-offs adult patients and providers are willing to make when considering advanced therapies for moderate to severe Ulcerative Colitis: A discrete choice experiment

Abstract Background As advanced therapy options for ulcerative colitis (UC) increase, it is important to understand the benefit-risk trade-offs patients and providers are willing to make to better inform shared decision making. Methods We used a cross-sectional survey with a discrete choice experiment (DCE) design to quantify advanced UC therapy preferences in patients with moderate to severe UC and practicing providers from the US, UK, France, Germany, Italy and Spain. Respondents chose between hypothetical combinations of attributes that were informed by a targeted literature search and formative qualitative research with patients and clinicians. Attributes comprised of time until symptom improvement, probability of remission at one year, probability of corticosteroid (CS)-free remission at one year, annual risk of serious infection, five-year risk of cancer and annual risk of major adverse cardiovascular event (MACE). Relative importance (RI; scaled 0–100%) for each attribute was calculated as the difference in mean preference weights between the most and least preferred level divided by the sum of the differences; for RI, remission attributes were combined. The maximum-acceptable risk (MAR) for each risk attribute, and the simultaneous MAR thresholds (SMARTs) for all risk attributes considered jointly, in exchange for a 10-percentage point increase in probability of remission at one year were estimated. Results For treatment choices, combined remission and CS-free remission at one year was significantly prioritised by patients (N=557; RI 40.1%) and providers (N=500; RI 51.1%), followed by five-year risk of cancer (RI 31.7% and 25.7%, respectively) (Table). Time to symptom improvement was significantly preferred vs annual risk of MACE and serious infection for providers, but not patients (Table). For a 10-percentage point increase in probability of remission at one year, providers had a higher MAR for five-year risk of cancer vs patients (4.0% vs 2.5%); for the other two risk attributes, reported MARs were beyond the DCE-included limits (Figure). For a 10-percentage point increase in the probability of remission at one year when annual risk of serious infection was 1% or 3%, providers were willing to jointly accept higher annual risk of MACE and five-year risk of cancer vs patients (Figure). Conclusion Combined probability of remission and CS-free remission at one year had the strongest influence on treatment choice. Compared with patients, providers on average placed greater importance on benefits and had a higher tolerance of risks, particularly 5-year risk of cancer. These findings highlight the importance of shared clinical decision making. References Pfizer’s generative artificial intelligence tool MAIA was used to assist production of the abstract first draft. Authors reviewed/edited and take responsibility for the content.

Post-Marketing Pharmacovigilance of Canakinumab from the FDA Adverse Event Reporting System (FAERS).

Background: Canakinumab, a humanized anti-IL-1β monoclonal antibody, is known for its ability to suppress IL-1β-mediated inflammation. However, continuous monitoring of its safety remains essential. Thus, we comprehensively evaluated the safety signals of canakinumab by data mining from FAERS. Methods: We used a disproportionate analysis to quantify canakinumab-related adverse events (AEs) using four algorithms. Clinical prioritization of the detected signals was assessed with a semiquantitative score method. Serious and non-serious outcomes were compared by statistical methods. Additionally, a stratification analysis of serious infections was conducted at the system organ class (SOC) level. Results: A total of 28,496 canakinumab-related AEs were collected, and 71 suspicious signals detected. Among these, 19 preferred terms (PTs) were identified as unexpected signals, including deafness, appendicitis, brain oedema, cushingoid, cellulitis, and papilledema. Of the AEs, 16 were more likely reported as serious outcomes, such as pneumonia, abdominal pain, deafness, and infection. Based on clinical priority score, 44 PTs were classified as weak, 27 as moderate, and none as strong. Furthermore, 30 PTs demonstrated a high level of evidence, primarily derived from FDA prescribing information, randomized controlled trials, and systematic reviews. Stratification analysis of infections and infestations (serious outcomes) revealed a stronger association of severe infections with canakinumab in older or heavier individuals. All positive signals followed an early failure pattern, with the incidence of canakinumab-associated AEs decreasing over time. Conclusions: We found that most of the suspicious signals were associated with infections. More attention should be paid to serious infections, particularly in males, individuals aged ≥60 years, or those weighing >100 kg, who demonstrated the highest risk of serious infections.

FC12 A systematic review and network meta-analysis on serious infection risk associated with biologics and systemic nonbiologics in patients with psoriasis

Abstract Psoriasis is a chronic inflammatory skin disorder. Biologics have excellent efficacy against moderate-to-severe psoriasis, but serious infection is a concern. The aim is to systematically search and collate evidence to evaluate the serious infection risk associated with biologics in people with psoriasis. Medline, Embase, CINAHL, Cochrane Register, and ClinicalTrials.gov were searched for randomized controlled trials (RCTs) and non-randomized studies of interventions (NRSIs) comparing biologics and systemic nonbiologics including novel targeted therapies licensed for psoriasis treatment in adults and children with psoriasis. Infections leading to hospitalization, intravenous antibiotics or death were considered serious. Number of patients with the outcome, sample size and person-time from RCTs and adjusted effect estimates from NRSIs were used to compute relative effects using the random-effects model. NRSIs with a critical risk of bias were excluded from the analysis. We conducted a frequentist network meta-analysis (NMA) using netmeta package in R. Three separate networks were fitted (RCT only; NRSI only; Combined RCTs and NRSIs). SIDE method was used to assess network coherence and P-scores for treatment ranking. Of 103 eligible RCTs, 71 with at least one serious infection event (n = 37 348; I2 ≤ 40%) and from 33 eligible NRSIs, seven without critical risk of bias (n = 308 901; I2 ≤ 71%) were included in the analysis. Patients were predominantly male (≤85%); mean age ranged from 13 to 52 years. Statistical incoherence was observed for three comparisons in the Combined network but not in the other two networks. The RCT-network found a higher risk with ustekinumab than IL-23 inhibitors (IRR 2.23; 95% CI 1.05–4.77). The NRSI-network found higher risk with infliximab and adalimumab [e.g. infliximab vs. methotrexate (IRR 2.85; 95% CI 1.48–5.46), infliximab vs. ustekinumab (IRR 2.73; 95% CI 1.94–3.84) and adalimumab vs. ustekinumab (IRR 1.51; 95% CI 1.25–1.83)]. In the Combined network, infliximab and adalimumab had a higher risk than bimekizumab, risankizumab, and secukinumab in addition to NRSI-network; IL-23 inhibitors had a lower risk than TNF-α inhibitors (IRR 0.53; 95% CI, 0.28–1.0). Sensitivity analysis with coherence achieved by removing two studies in the Combined network additionally found higher risk with certolizumab, etanercept, and secukinumab than risankizumab. In the treatment rankings, risankizumab had the highest probability of having the lowest risk of serious infection (P-score 0.87) followed by deucravacitinib, bimekizumab and tildrakizumab. Newer biologics, IL-23 inhibitors in particular, showed a lower risk of serious infection. However, these results should be interpreted with caution as there were no NRSIs for deucravacitinib and several newer biologics including bimekizumab, risankizumab and tildrakizumab. Large robust NRSIs are needed for these therapies for a reliable understanding of the relative risk of serious infection.

Prenatal Exposure to Proton Pump Inhibitors and Risk of Serious Infections in Offspring During the First Year of Life: A Nationwide Cohort Study.

Proton pump inhibitor (PPI) use in children increases the risk of infections, prompting inquiry into the impact of prenatal PPIs exposure on serious infections in offspring. As a research gap in this area exists, this study aimed to address it by assessing the association between prenatal PPIs exposure and serious infections in infants during their first year of life. Using the French health insurance data warehouse (SNDS) (2013-2018), we conducted a retrospective cohort study on singleton, full-term liveborn non-immunocompromised infants, stratified by PPI use during the first three months of life (early-life use). Proton pump inhibitor dispensing in ambulatory care settings during pregnancy defined exposure. Outcomes concerned any serious infections in offspring aged between 3 and 12 months. Adjusted odds ratios (aORs) were estimated using logistic regression with multivariable models to control for potential confounders. Of the 2,485,545 infants included, 497,060 (23.3%) were prenatally exposed to PPIs and 97,767 (4.6%) had PPI use during the first three months of life. Prenatal PPI exposure was associated with serious infections in offspring (aOR, 1.09 [95% CI, 1.07-1.10]) in infants without early-life PPIs use. No association was found for infants with early-life PPI use (aOR, 1.05 [95% CI, 1.00-1.11]). Gastrointestinal infections were the sole site with persistent significance. Prenatal PPI exposure is common and is not associated with a major risk of serious infections in infants during their first year. However, even after adjusting for several confounding factors, a weak association remains, especially in infants without early-life PPI use. While offering reassurance, adherence to clinical guidelines is still crucial.

High efficacy disease-modifying agents increase risk of serious infection

High efficacy disease-modifying agents increase risk of serious infection

Frequency of upper respiratory tract infections in patients with myasthenia gravis compared to the general population

IntroductionPatients with myasthenia gravis (MG) undergoing immunomodulating therapies are at an increased risk of serious infections. However, the risk of developing self-limited infections, particularly upper respiratory tract infections (URTI), remains unclear. This study aimed to determine the frequency of URTI among patients with MG compared to the general population and to identify potential predisposing factors. MethodsA monthly questionnaire was administered to patients with MG and a control group over a period of 6 months. The questionnaire assessed the presence of URTI symptoms within the previous month. Statistical analysis was conducted using a chi-square or Fischer exact test, as appropriate. ResultsThe study included 161 participants (50 MG patients and 111 control subjects). The frequency of URTI was comparable between the MG group (70 %) and controls (82 %) (p = 0.09). Among patients with MG, a higher proportion of patients who received rituximab developed URTI (93 %) than those who did not (61 %), P = 0.04. ConclusionThe frequency of URTI was similar in patients with MG compared to the general population. Due to the small sample size and several other limitations, further research is warranted to validate these findings and explore associations between rituximab and URTI.

Comparison of the Safety and Efficacy of Ustekinumab and Vedolizumab in Patients with Crohn's Disease: A Systematic Review and Meta-Analysis of Propensity Score Matched Cohort Studies.

Background: Ustekinumab and vedolizumab represent both valid therapeutic options in patients with Crohn's Disease. Data comparing the safety and efficacy of these drugs are indirect, with conflicting results reported. We aim to conduct a systematic review and metanalysis to assess the safety and effectiveness profile of ustekinumab and vedolizumab in patients with Crohn's Disease, including only studies that applied propensity scores to reduce confounding bias. Methods: We identified 59 reports that compared ustekinumab and vedolizumab after a propensity score match analysis, of which 16 were assessed for eligibility, and finally, ten retrospective studies were included. The main outcomes considered were clinical steroid-free remission at 14 ± 4, 24 ± 4, and 52 ± 4 weeks, drug discontinuation rate, adverse events, serious infections, and hospitalization during the first year of treatment. Results: A total of 4398 patients were treated with ustekinumab (n = 2774, 63.1%) or vedolizumab (1624, 36.9%). Steroid-free clinical remission was not significantly different between ustekinumab and vedolizumab at 12 ± 4 weeks (OR 1.31, 95%CI 0.88-1.94, p = 0.180), at 24 ± 4 weeks (OR 1.18, 95%CI 0.79-1.75, p = 0.420), and at 52 ± 4 weeks (1.35, 95%CI 0.91-2.01, p = 0.140). In patients receiving ustekinumab, the rate of adverse events (OR 0.54, 95%CI 0.35-0.83, p = 0.005), infection (OR 0.61, 95%CI 0.47-0.80, p < 0.001) and the need of hospitalization at 1-year (OR 0.68, 95%CI 0.58-0.80, p < 0.001) appeared to be lower. Conclusion: Ustekinumab and vedolizumab do not significantly differ in inducing and maintaining clinical steroid-free remission, while ustekinumab was associated with a lower risk of serious infections and hospitalization during the first year of treatment.

Infection Risk Associated with High-Efficacy Disease-Modifying Agents in Multiple Sclerosis: A Retrospective Cohort Study.

In patients with multiple sclerosis (MS), infections represent a significant concern, particularly given the immunomodulatory effects of disease-modifying agents (DMAs). High-efficacy DMAs (heDMAs) play a pivotal role in delaying MS progression, yet their use also raises concerns regarding the risk of infection. This study aimed to compare the infection risk with the use of heDMA and moderate-efficacy disease-modifying agents (meDMAs) in MS patients. This retrospective cohort study involved adult (18-64 years) MS patients with incident DMA use based on the 2015-2019 MarketScan Commercial Claims and Encounters Database. Patients initiating heDMAs (natalizumab, alemtuzumab, and ocrelizumab) or meDMAs (interferon beta-1a, interferon beta-1b, fingolimod, teriflunomide, dimethyl fumarate, and glatiramer acetate) were included. The outcomes of interest were comparative risk of overall infection, serious infection, and frequently reported types of infection. Adjusted hazard ratios (aHR) were estimated in inverse probability treatment weighting (IPTW) based on Cox proportional hazard models. Among 10,003 eligible incident DMA users, 22.92% of patients initiated heDMAs. The IPTW-CPH model revealed that patients with heDMAs were associated with a higher risk of serious infection (aHR: 1.24, 95% confidence interval (CI): 1.06-1.44) and urinary tract infection (UTI; aHR: 1.21, 95% CI: 1.14-1.30). Sensitivity analyses with different follow-up periods yielded consistent findings with the main analyses. In MS, heDMAs were associated with a greater risk of serious infection and UTI compared with meDMAs. These findings suggest the need to carefully monitor and manage the infection risk to optimize the use of heDMAs in MS.

Association of CD19+-targeted chimeric antigen receptor (CAR) T-cell therapy with hypogammaglobulinemia, infection, and mortality

BackgroundCD19-targeted chimeric antigen receptor T-cell therapy (CAR-T therapy) has revolutionized the treatment of hematologic malignancies. As these cells target CD19+ receptors on B-cells, there is the potential for B-cell aplasia and hypogammaglobulinemia. Data on the degree and clinical significance of hypogammaglobulinemia are sparse. ObjectiveTo evaluate hypogammaglobulinemia after CD19-targeted CAR-T therapy and risk factors for hypogammaglobulinemia, infections, and mortality. MethodsWe performed a retrospective evaluation of 579 patients receiving CD19-directed CAR-T therapy and evaluated demographics, hypogammaglobulinemia (immunoglobulin G [IgG]≤600mg/dL), infections pre- and post-CAR-T therapy, and risk factors for hypogammaglobulinemia, infection, hospitalizations, and mortality. ResultsPatients had a mean age of 64 years and 64% were male. Prior to CAR-T therapy, 60% of patients had hypogammaglobulinemia, which increased to 91% post-CAR-T therapy. Mean IgG levels decreased from pre- to post-CAR-T therapy (587 to 362 mg/dL; p<0.0001). 37% of patients developed a serious infection post-CAR-T therapy. Hypogammaglobulinemia pre-CAR-T therapy was associated with worsening hypogammaglobulinemia post-CAR-T therapy. Hypogammaglobulinemia post-CAR-T therapy was associated with an increased risk of serious infection post-CAR-T therapy (IRR=2.7; 95% CI=1.5-5.2; p=0.002). Risk factors for mortality included mild hypogammaglobulinemia (400mg/dL<IgG≤600mg/dL), infections ≤100 days post-CAR-T therapy, and hospitalizations for infections. Immunoglobulin replacement was associated with a decreased risk of mortality. ConclusionsWe identified ∼90% of patients with hypogammaglobulinemia after CAR-T therapy. Hypogammaglobulinemia pre-CAR-T therapy was strongly predictive of worsening hypogammaglobulinemia post-CAR-T therapy, which was associated with an increased risk of serious infection and mortality post-CAR-T therapy. Increased immunological monitoring is needed to identify high-risk patients who may benefit from interventions to decrease morbidity and mortality.

The Incidence, Aetiology and Clinical Course of Serious Infections Complicating Biological and Targeted Synthetic Disease-Modifying Antirheumatic Drug Therapy in Patients with Rheumatoid Arthritis in Tropical Australia.

Introduction: Patients receiving biological and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) for rheumatological conditions are at an increased risk of serious, potentially life-threatening, infection. However, the incidence, aetiology, and clinical course of serious infection in patients receiving b/tsDMARDs in tropical settings are incompletely defined. Methods: We retrospectively reviewed all patients with rheumatoid arthritis receiving b/tsDMARDs between October 2012 and October 2021, at Cairns Hospital in tropical Australia. The incidence, aetiology, and clinical course of serious infections (those requiring admission to hospital or parenteral antibiotics) were determined. Results: 310 patients had 1468 patient years of b/tsDMARD therapy during the study period; 74/310 (24%) had 147 serious infections translating to an overall risk of 10.0 episodes of serious infection per 100 patient years. The respiratory tract (50/147, 34%) and skin (37/147, 25%) were the most frequently affected sites. A pathogen was identified in 59/147 (40%) episodes and was most commonly Staphylococcus aureus (24/147, 16%). Only 2/147 (1%) were confirmed "tropical infections": 1 case of Burkholderia pseudomallei and 1 case of mixed B. pseudomallei and community-acquired Acinetobacter baumannii infection. Overall, 13/147 (9%) episodes of serious infection required Intensive Care Unit admission (0.9 per 100-patient years of b/tsDMARD therapy) and 4/147 (3%) died from their infection (0.3 per 100-patient years of b/tsDMARD therapy). The burden of comorbidity and co-administration of prednisone were the strongest predictors of death or a requirement for ICU admission. Conclusions: The risk of serious infection in patients taking b/tsDMARDs in tropical Australia is higher than in temperate settings, but this is not explained by an increased incidence of traditional tropical pathogens.

Effect of correcting iron deficiency on the risk of serious infection in heart failure: Insights from the IRONMAN trial.

Concerns exist that intravenous (IV) iron might increase the risk of infections. The IRONMAN trial provided an opportunity to investigate whether giving IV ferric derisomaltose (FDI) to patients with heart failure and iron deficiency alters the rate of hospitalization or death due to infections. IRONMAN was a randomized trial of IV FDI versus usual care in patients with symptomatic heart failure, left ventricular ejection fraction (LVEF) ≤45%, and transferrin saturation (TSAT) <20% or ferritin <100 μg/L. Infection was a pre-specified, blindly-adjudicated, safety endpoint. The primary analysis of interest was infection as the main reason for hospitalization or death, using first and recurrent events analyses. The composite primary event of interest tended to be lower in those randomized to FDI when analysed as first (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.62-1.01, p = 0.055) or recurrent event (rate ratio 0.85, 95% CI 0.64-1.13, p = 0.089). The composite results were driven by fewer hospitalizations for infection (HR 0.76, 95% CI 0.49-0.98, p = 0.032), with 5% fewer patients (absolute reduction) experiencing such an event if assigned to FDI. Similar trends were observed for recurrent events (HR 0.82, 95% CI 0.62-1.10). Further analyses suggested that the reduction in hospitalizations due to infection with FDI was restricted to patients with TSAT <20%. In patients with heart failure and a reduced LVEF, correction of iron deficiency is not associated with an increased risk of hospitalization or death from infection, and may reduce such events, especially when TSAT is <20%. ClinicalTrials.gov, NCT02642562.

Recovery from rituximab-associated persistent hypogammaglobulinaemia in children with nephrotic syndrome.

There are limited data on the long-term outcomes and risk factors for non-recovery after development of rituximab (RTX)-associated persistent hypogammaglobulinaemia among children with idiopathic nephrotic syndrome (NS). A nationwide Japanese survey was conducted to determine the prognosis of patients with childhood-onset idiopathic NS who developed persistent hypogammaglobulinaemia after RTX administration. Specifically, predictors of IgG level recovery and risk factors for serious infection were examined. The cohort comprised 118 patients (66.1% boys; median age at initial RTX administration, 7.5 years). Among the 121 patients diagnosed with persistent hypogammaglobulinaemia, only 31 (26.3%) recovered within a median observation period of 2.8 years; approximately 70% of patients continued to exhibit persistent hypogammaglobulinaemia. Among the patients who recovered from hypogammaglobulinaemia, the median time to recovery was 14.1 months. Patients with a history of steroid-resistant NS were less likely to recover from persistent hypogammaglobulinaemia (hazard ratio, 0.28; 95% CI, 0.09-0.87). In addition, of the 118 eligible patients, 18 (15.3%) developed serious infections requiring hospitalization, and the main risk factor for infection during hypogammaglobulinaemia was agranulocytosis (a well-known adverse effect of RTX in children). A significant portion of patients with RTX-associated persistent hypogammaglobulinaemia did not exhibit recovery even after 1 year. Moreover, the data indicate that patients with a history of steroid-resistant NS have a significantly lower probability of recovering from this condition. Agranulocytosis under hypogammaglobulinaemia was significantly associated with an elevated risk of serious infections.

First Report of a Fatal Septicemia Case Caused by Vibrio metoecus: A Comprehensive Functional and Genomic Study

Abstract Background In recent years, we have witnessed an unprecedented increase in the incidence of vibriosis due to global warming. Vibrio metoecus is a recently described Vibrio cholerae-like species that has not been associated with septicemia death in humans. During follow-up of human vibriosis, we received a blood isolate from a patient with secondary septicemia who died a few hours after admission. Methods Phenotypic and genotypic methods failed to identify the isolate, which could only be identified by average nucleotide identity after genome sequencing. The isolate was subjected to in vitro and ex vivo assays, complemented by comparative genomics focused on the identification of unique genetic traits. Strains and genomes from the same and related species (V. cholerae and Vibrio mimicus) were used for analyses. Results The isolate was the only one able to resist and multiply in human serum. Its genome contained virulence genes shared with V. mimicus and/or V. cholerae, with those associated with sialic acid degradation within pathogenicity island 2 standing out. However, it also presented a unique gene cluster, flanked by a transposase gene, putatively related to surface polysaccharide pseudosialyzation. Conclusions We document the first case of death caused by septicemia due to V. metoecus and propose that the acquisition of surface pseudosialyzation genes explains the ability of certain isolates of this species to survive in blood. Our discovery underscores the urgent need to monitor and study newly emerging pathogenic species, as climate change may be facilitating their spread and increasing the risk of serious infections in humans.

Prodrug Nanomedicine for Synovium Targeted Therapy of Inflammatory Arthritis: Insights from Animal Model and Human Synovial Joint Fluid.

Many patients cannot tolerate low-dose weekly methotrexate (MTX) therapy for inflammatory arthritis treatment due to life-threatening toxicity. Although biologics offer a target-specific therapy, it raises the risk of serious infections and even cancer due to immune system suppression. We introduce an anti-inflammatory arthritis MTX ester prodrug using a long-circulating biocompatible polymeric macromolecule: folic acid (FA) functionalized hyperbranched polyglycerol (HPG). In vitro the drug MTX is incrementally released through pH and enzymatic degradation over 2 weeks. The role of matrix metalloproteinases (MMPs) in site-specific prodrug activation was verified using synovial fluid (SF) of 26 rheumatology patients and 4 healthy controls. Elevated levels of specific MMPs-markers of joint inflammation-positively correlated with enhanced prodrug release explained by acid-catalyzed hydrolysis of esters by proteases. Intravenously administered 111In-radiolabeled prodrug confirmed by SPECT/CT imaging that it accumulated preferentially in inflamed joints while reducing off-target side-effects in a mouse model of rheumatoid arthritis (RA). Added FA as a targeting vector prolonged prodrug action; prodrug with 4x less MTX applied every 2 weeks was as effective as weekly MTX therapy. The preclinical results suggest a prodrug-based strategy for the treatment of inflammatory joint diseases, with potential for other chronic inflammatory diseases and cancer.

Incident Benzodiazepine and Z-Drug Use and Subsequent Risk of Serious Infections.

Animal studies have suggested a link between benzodiazepine and related Z-drug (BZDR) use and immune dysfunction. Corresponding evidence in humans is limited and focuses mainly on pneumonia. This study aimed to assess the association of incident BZDR use with subsequent development of serious infections. This Swedish register-based study included a population-based demographically matched cohort, a co-twin control cohort, and an active comparator cohort. Out of 7,362,979 individuals aged below 65 years who were BZDR naïve by 2007, 713,896 BZDR recipients with incident dispensation of any BZDRs between 2007 and 2019 were 1:1 matched to 713,896 nonrecipients from the general population; 9197 BZDR recipients were compared with their 9298 unexposed co-twins/co-multiples; and 434,900 BZDR recipients were compared with 428,074 incident selective serotonin reuptake inhibitor (SSRI) recipients. The outcomes were identified by the first inpatient or specialist outpatient diagnosis of serious infections in the National Patient Register, or death from any infections recorded as the underlying cause in the Cause of Death Register. Cox proportional hazards regression models were fitted and controlled for multiple confounders, including familial confounding and confounding by indication. To study a possible dose-response association, the cumulative dosage of BZDRs dispensed during the follow-up was estimated for each BZDR recipient and modeled as a time-varying exposure with dose categories in tertiles [≤ 20 defined daily doses (DDDs), > 20 DDDs ≤ 65, and > 65 DDDs). The risk of infections was assessed in BZDR recipients within each category of the cumulative BZDR dosage compared to their demographically matched nonrecipients. In the demographically matched cohort (average age at incident BZDR use 42.8 years, 56.9% female), the crude incidence rate of any serious infections in BZDR recipients and matched nonrecipients during 1-year follow-up was 4.18 [95% confidence intervals (CI) 4.13-4.23] and 1.86 (95% CI 1.83-1.89) per 100 person-years, respectively. After controlling for demographic, socioeconomic, clinical, and pharmacological confounders, BZDR use was associated with 83% relative increase in risk of any infections [hazard ratio (HR) 1.83, 95% CI 1.79-1.89]. The risk remained increased, although attenuated, in the co-twin cohort (HR 1.55, 95% CI 1.23-1.97) and active comparator cohort (HR 1.33, 95% CI 1.30-1.35). The observed risks were similar across different types of initial BZDRs and across individual BZDRs, and the risks increased with age at BZDR initiation. We also observed a dose-response association between cumulative BZDR dosage and risk of serious infections. BZDR initiation was associated with increased risks of serious infections,even when considering unmeasured familial confounding and confounding by indication. The exact pathways through which BZDRs may affect immune function, however, remain unclear. Further studies are needed to explore the neurobiological mechanisms underlying the association between BZDR use and serious infections, as it can lead to safer therapeutic strategies for patients requiring BZDR.

Efficacy and Safety of Biologic Therapies for Treatment of Psoriasis: A Systematic Review and Observational Meta-Analysis

Abstract Background Psoriasis is a chronic, systemic, immune-mediated inflammatory skin disease of unknown etiology, however, several cytokines were reported to share in the pathogenesis of psoriasis as IL-12, IL- 23 and TNF-α. Biologics targeting these cytokines showed effective results in treatment of psoriasis patients. However, long term efficacy and tolerability of these agents is still questionable. Objective To compare the efficacy and safety of anti-TNF alpha, anti IL12/23, anti IL17, anti IL23 in moderate to severe psoriasis over long periods of treatment in order to complete the efficacy and safety profile of biologic therapies. Patients and Methods We searched ClinicalTrials.gov register (www.clinicaltrials.gov) up to July 2022 with the following search terms: psoriasis AND one by one each biologic therapy name listed in types of interventions. Results Regarding rate of PASI 75 at year 1, IL-12/23 inhibitors have a greater probability of achieving a PASI 75 response than anti-TNF alpha, with the pooled PASI 75 estimate at 84% and 76.18%, respectively. While, regarding rate of PASI 75 at year 2, 3, 4 and 5, there are no studies that assess the PASI 75 at year 2 or more for anti-TNF. The PASI 75 at years 2, 3, and 5 for IL- 12/23 inhibitors appeared to be stable at about 80 %, while it reached 91% at year 4. Rate of serious infections was 2.9% and 2.4% with anti-TNF alpha and IL-12/23 inhibitors respectively. There was showing no significant difference in the risk of serious infection between the two classes. In the current study, the rate of malignancy showed no-significant difference in psoriatic patients as patients receiving anti-TNF-alpha had 3.7% rate while in patients receiving IL 12/23 inhibitors the rate was 3.9%. Data Sources Medline databases (PubMed, Medscape, ScienceDirect. EMF-Portal) and all materials available in the Internet till 2023. Conclusion In the current meta-analysis we compare the efficacy and safety of anti-TNF alpha and anti IL12/23 in moderate to severe psoriasis over long periods of treatment in order to complete the efficacy and safety profile of biologic therapies. IL-12/23 inhibitors have a greater probability of achieving a PASI 75 response than anti-TNF alpha. There was no significant difference in the risk of serious infection or rate of malignancy between the two classes. Moreover, there was insignificant risk of MACEs with IL12/23 inhibitors and a slight increased risk with anti-TNF alpha. There was significant rate of common adverse events in patients receiving anti-TNF-alpha compared to patients receiving IL 12/23 inhibitors.

S1059 Risk of Serious Infections in Patients with Ulcerative Colitis Treated with Tofacitinib Compared to Biologic Treatments in the United States

S1059 Risk of Serious Infections in Patients with Ulcerative Colitis Treated with Tofacitinib Compared to Biologic Treatments in the United States