Jia, Li

Abstract Immune cell function is tightly coupled to cellular metabolism, with glycolysis, oxidative phosphorylation, and amino acid and lipid metabolism governing activation, differentiation, survival, and effector responses. In rheumatoid arthritis (RA), an autoimmune disease characterized by destructive joint inflammation, metabolic checkpoints have emerged as critical regulators of immune-cell behavior and drivers of tissue pathology. RA CD4+ T cells undergo profound metabolic reprogramming: glycolysis is suppressed, and glucose is redirected into the pentose phosphate pathway, resulting in NADPH accumulation, reduced ROS levels, and a highly reductive intracellular environment. Concurrent defects in mitochondrial DNA repair and electron transport chain function compromise mitochondrial fitness, leading to NAD+ depletion, altered tricarboxylic acid cycle activity, and metabolic exhaustion. The resulting accumulation of citrate and acetyl-CoA promotes lipogenesis and protein acetylation, driving membrane remodeling, tissue invasiveness, and proinflammatory effector functions. Depletion of oxaloacetate and aspartate limits NAD+ regeneration, inducing endoplasmic reticulum expansion and enhanced tumor necrosis factor production. Defective lysosomal coordination of AMPK and mTORC1 signaling uncouples energy sensing from anabolic programs, enabling cellular activation and proliferation despite metabolic insufficiency. Macrophage fate and function are similarly shaped by metabolic state. In synovial macrophages, GLUD1-dependent glutamine oxidation sustains mitochondrial respiration and ATP production, enabling survival under nutrient-deprived conditions while promoting antigen presentation. Conversely, metabolic stress in MerTK+ macrophages activates the NAD+ hydrolase SARM1, triggering NAD+ depletion, mitochondrial collapse, and PANoptotic cell death. Together, these findings identify NAD+ availability, mitochondrial fitness, and organelle-based signaling as central metabolic gatekeepers linking bioenergetic stress to immune-cell dysfunction and chronic inflammation in RA.

AbstractPurposeTo identify associations between implant failure and selective serotonin reuptake inhibitor (SSRI) medication use in a cohort of consecutive patients receiving dental implants during a 20‐year period.Materials and MethodsA retrospective review was conducted of all patients who received at least 1 dental implant from January 1, 1995, through December 31, 2014, assessing their history of SSRI use, active SSRI use, and SSRI use during follow‐up with implant failure. Cox proportional hazards regression models assessed associations between demographic characteristics and SSRI use with implant failure, and outcomes were summarized with hazard ratios (HRs) and 95% confidence intervals (CIs). Follow‐up SSRI use was analyzed with time‐dependent covariates.ResultsDuring the study period, 5456 patients received their first implant (median age, 53 years). The median duration of follow‐up was 5.3 years (interquartile range, 2.3‐10.2 years) for the 4927 patients who did not have implant failure. For the 529 patients who had implant failure, it occurred at a median of 0.5 years. After adjusting for age, sex, and era of implant, history of use of the SSRI sertraline was associated with an increased risk of implant failure among all patients (hazard ratio [HR], 1.60; 95% CI, 1.15‐2.23; p = 0.006) and among the subset of patients with a history of SSRI use (HR, 1.64; 95% CI, 1.07‐2.52; p = 0.02).ConclusionsIn the population reviewed, a history of sertraline use was associated with a 60% greater risk of implant failure; however, active SSRI use at the time of implant placement or during follow‐up was not significantly associated with an increased risk of implant failure.