Browsing by Author "Hess, Andreas (7202967911)"

Background: Rheumatoid arthritis is an inflammatory disease frequently treated with TNF inhibitors. Little is known about predictors of response to TNF inhibitors. Because clinical response in rheumatoid arthritis is measured by composite scores containing subjective patient-orientated domains (eg, pain and global disease perception), we hypothesised that patients with high disease representation in the CNS might respond better to TNF inhibitors than patients with less CNS disease representation. Methods: We did a phase 3, multicentre, double-blind, placebo-controlled, parallel-group randomised trial in patients with active rheumatoid arthritis at six rheumatology centres across Germany, Portugal, and Serbia. All patients had a functional MRI (fMRI) brain scan at baseline to measure CNS pain activation. Patients (aged ≥18 years) with active rheumatoid arthritis who have active disease despite the use of at least one conventional synthetic disease-modifying antirheumatic drug were stratified according to fMRI (high volume or low volume) and were randomly assigned 2:1 using a randomisation list generated by a study statistician to treatment with the TNF inhibitor certolizumab pegol (400 mg subcutaneously on weeks 0, 2, and 4, and 200 mg once every 2 weeks for maximum 24 weeks) or placebo. Patients and clinicians were masked to allocation. The primary outcome was the proportion of patients reaching low disease activity (Disease Activity Score in 28 joints ≤3·2) at week 12, analysed in the intention-to-treat population. There was no lived experience involvement in study design. The study was registered with EudraCT (2013-000337-13) and ClinicalTrials.gov (NCT01864265). Findings: Between Sept 3, 2013, and Jan 10, 2020, 148 patients with rheumatoid arthritis were screened and 139 (99 [71%] women and 40 [29%] men) were randomly assigned to the high-volume certolizumab pegol group (n=49), the low-volume certolizumab pegol group (n=43), or the placebo group (n=47). Low disease activity was reached by 28 (57%) in the high-volume certolizumab pegol group, 19 (44%) in the low-volume certolizumab pegol group, and 12 (26%) in the placebo group at week 12. Response in the high-volume certolizumab pegol group was significantly different (p=0·0017) to the placebo group, but not the low-volume certolizumab pegol group (p=0·063). There were 25 treatment-related adverse events: 22 in the certolizumab pegol groups and three in the placebo group. Interpretation: High disease-associated fMRI CNS pain activation might predict clinical response of patients with rheumatoid arthritis to TNF inhibitor treatment. Funding: UCB Biopharma. © 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0

Arthritis typically involves recurrence and progressive worsening at specific predilection sites, but the checkpoints between remission and persistence remain unknown. Here, we defined the molecular and cellular mechanisms of this inflammation-mediated tissue priming. Re-exposure to inflammatory stimuli caused aggravated arthritis in rodent models. Tissue priming developed locally and independently of adaptive immunity. Repeatedly stimulated primed synovial fibroblasts (SFs) exhibited enhanced metabolic activity inducing functional changes with intensified migration, invasiveness and osteoclastogenesis. Meanwhile, human SF from patients with established arthritis displayed a similar primed phenotype. Transcriptomic and epigenomic analyses as well as genetic and pharmacological targeting demonstrated that inflammatory tissue priming relies on intracellular complement C3- and C3a receptor-activation and downstream mammalian target of rapamycin- and hypoxia-inducible factor 1α-mediated metabolic SF invigoration that prevents activation-induced senescence, enhances NLRP3 inflammasome activity, and in consequence sensitizes tissue for inflammation. Our study suggests possibilities for therapeutic intervention abrogating tissue priming without immunosuppression. © 2021 Elsevier Inc.

Arthritis typically involves recurrence and progressive worsening at specific predilection sites, but the checkpoints between remission and persistence remain unknown. Here, we defined the molecular and cellular mechanisms of this inflammation-mediated tissue priming. Re-exposure to inflammatory stimuli caused aggravated arthritis in rodent models. Tissue priming developed locally and independently of adaptive immunity. Repeatedly stimulated primed synovial fibroblasts (SFs) exhibited enhanced metabolic activity inducing functional changes with intensified migration, invasiveness and osteoclastogenesis. Meanwhile, human SF from patients with established arthritis displayed a similar primed phenotype. Transcriptomic and epigenomic analyses as well as genetic and pharmacological targeting demonstrated that inflammatory tissue priming relies on intracellular complement C3- and C3a receptor-activation and downstream mammalian target of rapamycin- and hypoxia-inducible factor 1α-mediated metabolic SF invigoration that prevents activation-induced senescence, enhances NLRP3 inflammasome activity, and in consequence sensitizes tissue for inflammation. Our study suggests possibilities for therapeutic intervention abrogating tissue priming without immunosuppression. © 2021 Elsevier Inc.