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Targeting MyD88 Downregulates Inflammatory Mediators and Pathogenic Processes in PBMC From DMARDs-Naive Rheumatoid Arthritis Patients.

ABSTRACT: MyD88-dependent intracellular signalling cascades and subsequently NF-kappaB-mediated transcription lead to the dynamic inflammatory processes underlying the pathogenesis of rheumatoid arthritis (RA) and related autoimmune diseases. This study aimed to identify the effect of the MyD88 dimerization inhibitor, ST2825, as a modulator of pathogenic gene expression signatures and systemic inflammation in disease-modifying antirheumatic drugs (DMARDs)-naïve RA patients. We analyzed bulk RNA-seq from peripheral blood mononuclear cells (PBMC) in DMARDs-naïve RA patients after stimulation with LPS and IL-1β. The transcriptional profiles of ST2825-treated PBMC were analyzed to identify its therapeutic potential. Ingenuity Pathway Analysis was implemented to identify downregulated pathogenic processes. Our analysis revealed 631 differentially expressed genes between DMARDs-naïve RA patients before and after ST2825 treatment. ST2825-treated RA PBMC exhibited a gene expression signature similar to that of healthy controls PBMC by downregulating the expression of proinflammatory cytokines, chemokines and matrix metalloproteases. In addition, B cell receptor, IL-17 and IL-15 signalling were critically downregulated pathways by ST2825. Furthermore, we identified eight genes (MMP9, CXCL9, MZB1, FUT7, TGM2, IGLV1-51, LINC01010, and CDK1) involved in pathogenic processes that ST2825 can potentially inhibit in distinct cell types within the RA synovium. Overall, our findings indicate that targeting MyD88 effectively downregulates systemic inflammatory mediators and modulates the pathogenic processes in PBMC from DMARDs-naïve RA patients. ST2825 could also potentially inhibit upregulated genes in the RA synovium, preventing synovitis and joint degeneration.

SUBMITTER: Ramirez-Perez S

PROVIDER: S-EPMC8735861 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectivesTo evaluate the 1-year cost-effectiveness between three different initial treatment strategies in autoantibody-negative RA patients, according to 2010 criteria.MethodsFor this analysis we selected all RA patients within the intermediate probability stratum of the treatment in the Rotterdam Early Arthritis Cohort (tREACH) trial. The tREACH had a treat-to-target approach, aiming for low DAS <2.4, and treatment adjustments could occur every 3 months. Initial treatment strategies consisted of MTX 25 mg/week (initial MTX, iMTX), iHCQ 400 mg/day or an oral glucocorticoids tapering scheme without DMARDs (iGCs). Data on quality-adjusted life-years, measured with the European Quality of Life 5-Dimensions 3 Levels (EQ-5D-3L), healthcare and productivity costs were used.ResultsAverage quality-adjusted life-years (s.d.), for iMTX, iHCQ and iGCs were respectively 0.71 (0.14), 0.73 (0.14) and 0.71 (0.15). The average total costs (s.d.) for iMTX, iHCQ and iGCs were, respectively, €10 832 (14.763), €11 208 (12.801) and €10 502 (11.973). Healthcare costs were mainly determined by biological costs, which were significantly lower in the iHCQ group compared with iGCs (P < 0.05). However, costs due to presenteeism were the highest in the iHCQ group (55%) followed by iMTX (27%) and iGCs (18%). The incremental cost-effectiveness ratios did not differ between treatment strategies. At a willingness-to-pay level of €50 000, the Dutch threshold for reimbursement of medical care, iHCQ had the highest probability (38.7%) of being cost-effective, followed by iGCs (31.1%) and iMTX (30.2%).ConclusioniHCQ had the lowest healthcare and highest productivity costs, resulting in a non-significant incremental cost-effectiveness ratio. However, iHCQ had the highest chance of being cost-effective at the Dutch willingness-to-pay threshold for healthcare reimbursement. Therefore, we believe that iHCQ is a good alternative to iMTX in autoantibody-negative RA patients, but validation is needed.Clinical trial registration numberISRCTN26791028.

Dataset Information

Targeting MyD88 Downregulates Inflammatory Mediators and Pathogenic Processes in PBMC From DMARDs-Naive Rheumatoid Arthritis Patients.

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