Dual-Targeted Therapy in Pediatric Inflammatory Bowel Disease: A Comprehensive Review.

Inflammatory bowel disease (IBD) is a chronic systemic immune-mediated disorder. The disease is triggered and perpetuated by a complex interplay between genetic predisposition, dysregulated immune responses, and environmental factors. Pediatric IBD is considered to be more aggressive compared with adult-onset IBD, and commonly requires more intensive pharmacological and surgical treatments. Although the use of targeted therapy, such as biologic therapy and small molecule therapy, is on the rise, there are children with IBD who are refractory to all current therapeutic options. For them, a combination of biologic agents or a biologic agent with small molecules as dual-targeted therapy (DTT) may be a possible therapeutic option. The main indications for DTT are high inflammatory burden and refractoriness to standard therapy, extra-intestinal manifestations of IBD, adverse effects of therapy, and co-existing immune-mediated inflammatory disorders. Several combination therapies were described for pediatric refractory IBD. The main ones were anti-tumor necrosis factor (TNF) agents and vedolizumab (VDZ), anti-TNF and ustekinumab (UST), VDZ and UST, and biologic agents with tofacitinib. DTT exhibits high efficacy, with high rates of clinical response and remission as well as biomarker remission. The data on endoscopic and radiologic remission are scarce. Most of the adverse effects reported under DTT were mild; however, the serious ones that had been observed mandate a profoundly cautious approach when considering it. Triple immunosuppressive therapy and combinations of biologics with emergent therapies such as selective Janus kinase inhibitors, sphingosine-1-phosphate receptor modulators, and anti-interleukin-23 agents, are potential future regimens for children with IBD who are refractory to current therapeutic options. This review provides an update of publications on these issues.

CXCL4 synergizes with TLR8 for TBK1-IRF5 activation, epigenomic remodeling and inflammatory response in human monocytes.

Regulation of endosomal Toll-like receptor (TLR) responses by the chemokine CXCL4 is implicated in inflammatory and fibrotic diseases, with CXCL4 proposed to potentiate TLR responses by binding to nucleic acid TLR ligands and facilitating their endosomal delivery. Here we report that in human monocytes/macrophages, CXCL4 initiates signaling cascades and downstream epigenomic reprogramming that change the profile of the TLR8 response by selectively amplifying inflammatory gene transcription and interleukin (IL)-1ß production, while partially attenuating the interferon response. Mechanistically, costimulation by CXCL4 and TLR8 synergistically activates TBK1 and IKKε, repurposes these kinases towards an inflammatory response via coupling with IRF5, and activates the NLRP3 inflammasome. CXCL4 signaling, in a cooperative and synergistic manner with TLR8, induces chromatin remodeling and activates de novo enhancers associated with inflammatory genes. Our findings thus identify new regulatory mechanisms of TLR responses relevant for cytokine storm, and suggest targeting the TBK1-IKKε-IRF5 axis may be beneficial in inflammatory diseases.