ABSTRACT Introduction Pharmacodynamic drug–drug interactions (DDI) in patients receiving oral anticoagulants (OAC) may increase the risk of gastrointestinal bleeding (GIB). The purpose of this study was to develop and validate a GIB model for patients receiving OACs. Methods A risk model, D rug I nteractions in O ral A nti C oagulants for Risk of G astro i ntestinal B leeding (DIOAC‐GIB), was developed to predict GIB based on interacting medications and other patient‐specific risk factors for patients on OAC. Inputs for the model were obtained using random‐effect meta‐analysis or from the literature for the following attributes: exposure to nonsteroidal anti‐inflammatory drugs (NSAIDs); selective serotonin reuptake inhibitors/serotonin‐norepinephrine reuptake inhibitors (SSRI/SNRIs); aspirin, antiplatelet medications, and proton pump inhibitors (PPIs); age; and GIB history. The model was correlated to existing OAC models (HAS‐BLED and DOAC score). Results GIB risk for OACs was based on pivotal trials (1.16% for apixaban; 3.15% for rivaroxaban; 3.00% for dabigatran; 3.31% for edoxaban; and 2.00% for warfarin). The odds ratio (OR) of GIB for NSAIDs ranged from 1.16 (95% confidence interval [CI]: 0.84–1.61) for celecoxib to 20.67 (95% CI: 14.56–29.34) for ketorolac. ORs for GIB among SSRI/SNRIs ranged from 1.31 (95% CI: 1.07–1.62) for paroxetine to 1.50 (95% CI: 1.32–1.70) for venlafaxine. Risk of GIB also included persons > 65 years of age (relative risk = 2.50, 95% CI: 1.2–5.5); history of GIB (OR = 5.14, 95% CI: 3.92–6.73); exposure to aspirin (OR = 1.31, 95% CI: 0.93–1.85), antiplatelet medications (OR = 1.97, 95% CI: 1.73–2.25), and corticosteroids (OR = 1.69, 95% CI: 1.53–1.87); and PPIs reduced GIB risk (OR = 0.67, 95% CI: 0.62–0.74). Correlations between the DIOAC‐GIB and HAS‐BLED and DOAC scores were 0.5 for both ( p < 0.01). Conclusion DIOAC‐GIB is a novel GIB‐risk model that incorporates pharmacodynamic OAC DDIs to assist clinicians and patients to determine a therapeutic plan while accounting for GIB risk. DIOAC‐GIB correlates with other bleeding risk scores and may help identify high‐risk patients who may benefit from tailored prescribing.
ABSTRACT Objective To identify independent predictors of sustained glucocorticoid (GC) sparing in patients with rheumatoid arthritis (RA) initiating biological or targeted synthetic disease‐modifying antirheumatic drugs (b/tsDMARDs), specifically we evaluated whether the longitudinal platelet‐to‐lymphocyte ratio (ΔPLR) trajectory provides superior prognostic value compared to conventional measurements. Methods This multicenter retrospective study analyzed 264 patients from the Taipei Medical University Clinical Research Database. Sparing success was defined as achieving predefined dose reduction targets at month 6 and maintaining stability for ≥ 12 weeks. Candidate predictors were screened using least absolute shrinkage and selection operator (LASSO) regression, followed by multivariable logistic and Cox proportional hazards modeling. Clinical utility was assessed using “rescue rate” analysis. Results Sustained GC sparing was achieved by 139 (52.7%) patients. First‐line b/tsDMARD initiation was the strongest predictor (adjusted odds ratio [aOR] 4.23, p < 0.001) of GC‐sparing success. Although static baseline inflammatory markers were non‐predictive, every 10% reduction in 6‐month ΔPLR independently increased success odds (aOR 1.05 [inverted from 0.95 per 10% increase], p = 0.009) and significantly accelerated the sparing rate (hazard ratio [HR] 1.02, p = 0.021). Conversely, concomitant nonsteroidal antiinflammatory drug use hindered success. Notably, incorporating ΔPLR into the predictive model “rescued” 16.5% of unrecognized candidates for de‐escalation—patients capable of successful GC sparing who were misclassified by standard clinical models. Conclusion Although static baseline inflammatory markers are nonpredictive, 6‐month ΔPLR offers significant incremental prognostic value beyond conventional erythrocyte sedimentation rate (ESR) and C‐reactive protein (CRP). By identifying 16.5% of viable candidates overlooked by standard assessments, dynamic PLR monitoring offers a potential strategy to optimize precision steroid de‐escalation in RA.
ABSTRACT Introduction Non‐infectious uveitis (NIU) is a chronic immune‐mediated ocular inflammatory disease that may cause irreversible visual impairment. The comparative efficacy and safety of systemic immunomodulatory therapies, including conventional agents and biologics, remain incompletely defined. This systematic review and network meta‐analysis evaluated systemic immunosuppressive therapies for NIU. Methods PubMed/MEDLINE, Cochrane CENTRAL, Scopus and Web of Science Core Collection were searched from inception to May 2, 2026. Randomized controlled trials and prospective comparative cohort studies evaluating systemic immunomodulatory or biologic therapies for NIU were included. The primary efficacy outcome was treatment failure. Safety outcomes included mortality, urinary tract infection, upper respiratory tract infection, injection‐site reactions, ocular hypertension, macular edema, and headache. Random‐effects pairwise meta‐analysis and frequentist network meta‐analysis were performed using risk ratios (RRs) with 95% confidence intervals (CIs). Results Seven studies including 992 participants were included; six were randomized controlled trials and one was a prospective cohort. In the pairwise meta‐analysis, adalimumab significantly reduced treatment failure compared with placebo (RR, 0.67; 95% CI, 0.58–0.78; p < 0.0001; I² = 28.1%). The mortality estimate was inconclusive (RR, 3.80; 95% CI, 0.42–34.15), with three deaths in the adalimumab groups and none in the placebo groups. Adalimumab was associated with a higher risk of injection‐site reactions than placebo (RR, 2.67; 95% CI, 1.73–4.12). Network meta‐analysis showed no significant differences for most safety outcomes, including upper respiratory tract infection, ocular hypertension, macular edema, and headache. Infliximab showed an imprecise urinary tract infection signal versus placebo (RR, 40.98; 95% CI, 1.82–922.17), based on sparse events and one nonrandomized comparison. Conclusion Adalimumab provides the most consistent evidence for reducing treatment failure in NIU. Comparative safety estimates, particularly for infliximab, remain uncertain and hypothesis‐generating. Larger, long‐term, head‐to‐head trials are required.
ABSTRACT Carbapenem resistance among Gram‐negative bacteria remains a serious public health threat, with metallo‐β‐lactamase (MBL)‐producing organisms increasing substantially in prevalence and few therapeutic options available to adequately address these difficult‐to‐treat pathogens. Cefepime‐zidebactam (FEP‐ZID) is a novel β‐lactam/β‐lactam enhancer combination that offers a mechanistically distinct approach to overcoming resistance in Gram‐negative organisms. Zidebactam contributes three complementary mechanisms: inhibition of Class A and C β‐lactamases, direct antibacterial activity via PBP2 inhibition, and enhancement of cefepime activity through a reduction in the pharmacodynamic exposure required for bactericidal effect, allowing FEP‐ZID to achieve substantial reductions in bacterial burden even in isolates with elevated minimum inhibitory concentrations (MICs). FEP‐ZID was recently approved in the United States for the treatment of complicated urinary tract infection (cUTI), including acute pyelonephritis, caused by Enterobacterales and/or Pseudomonas aeruginosa . FEP‐ZID demonstrates broad in vitro and in vivo activity against isolates producing Class A, B, C, and D β‐lactamases, as well as organisms harboring PBP3 alterations that are otherwise associated with reduced susceptibility to currently available MBL‐active therapies. This spectrum extends across carbapenem‐resistant Enterobacterales, P. aeruginosa , and Acinetobacter baumannii , and includes activity against isolates with porin loss and efflux upregulation, resistance mechanisms that commonly limit the utility of other β‐lactam‐based agents. In vivo infection models utilizing humanized regimens have demonstrated bactericidal activity against isolates with FEP‐ZID MICs up to 64 μg/mL. The Phase 3 ENHANCE I trial demonstrated noninferiority and subsequent superiority over meropenem in cUTI (including acute pyelonephritis), driven primarily by microbiological response, with favorable outcomes observed across many baseline pathogens, including extended‐spectrum β‐lactamase‐producing isolates and patients with concomitant bacteremia. Compassionate use experience further suggests possible utility in severe multidrug‐resistant infections across multiple infection types, including bloodstream, osteoarticular, and intra‐abdominal infections caused by MBL‐producing organisms. Collectively, available preclinical and clinical evidence positions FEP‐ZID as a mechanistically distinct option for difficult‐to‐treat Gram‐negative infections, with additional clinical study needed to define its role beyond the currently approved indication.
