Arthritis & Rheumatology最新文献

Macrophage activation syndrome (MAS) is a state of immune hyperactivation that can result in life-threatening multisystem end-organ dysfunction. Often termed a "cytokine storm", MAS occurs among the rheumatic diseases most typically in Still's disease but also in systemic lupus erythematosus and Kawasaki disease. MAS can also accompany infection, malignancy, and inborn errors of immunity. This review provides a practical, evidence-based guide to the understanding, recognition, and management of MAS in children and adults, with a primary focus on MAS complicating Still's disease.

Introduction: Emerging evidence suggests long non-coding RNA (lncRNA) H19 is associated with osteoarthritis (OA) pathology. However, how H19 contributes to OA has not been reported. This study aims to investigate the biological function of H19 in OA subchondral bone remodeling and OA progression.

Methods: Clinical joint samples and OA animal models induced by medial meniscus destabilization (DMM) surgery were used to verify the causal relationship between osteocyte H19 and OA subchondral bone and cartilage changes. MLO-Y4 osteocyte cells subjected to fluid shear stress were used to verify the mechanism underlying H19-mediated mechano-response. Finally, the antisense oligonucleotide (ASO) against H19 was delivered to mice knee joints by magnetic metal-organic framework (MMOF) nanoparticles in order to develop a site-specific delivery method for targeting osteocyte H19 for OA treatment.

Results: Both clinical OA subchondral bone and wildtype mice with DMM-induced OA exhibit aberrant higher subchondral bone mass with more H19 expressing osteocytes. On the contrary, osteocyte-specific deletion of H19 mice is less vulnerable to DMM-induced OA phenotype. In MLO-Y4 cells, H19-mediated osteocyte mechano-response through PI3K/AKT/GSK3 signals activation by EZH2-induced H3K27me3 regulation on PP2A inhibition. Targeted inhibition of H19 (using ASO-loaded MMOF) substantially alleviates subchondral bone remodeling and OA phenotype.

Discussion: In summary, our results provide new evidence that the elevated H19 expression in osteocytes may contribute to aberrant subchondral bone remodeling and OA progression. H19 appears to be required for the osteocyte response to mechanical stimulation, and targeting H19 represents a new promising approach for OA treatment.

Objective: To characterize non-articular pain (NAP) at early RA diagnosis, the evolution over the first year of treatment, associations with active RA inflammation and impact on remission.

Methods: This real-world, longitudinal multi-center cohort study followed participants with active early RA (symptoms<1 year, CDAI>2.8,) enrolled between 1/2017 and 1/2022, and who completed a body pain diagram (BPD) over 1-year. Participants were grouped by prespecified definitions of NAP: 1) none 2) regional or 3) widespread. Rheumatologists performed joint counts. Descriptive statistics summarized the frequency and evolution of NAP patterns over 1-year. Chi-square tests compared the proportions of tender and/or swollen joints by presence of pain in each NAP section. Multi-adjusted GEE regression models estimated associations of NAP patterns with remission outcomes.

Results: Participants (N=392) were 70% female, mean(Sd) age of 56(14) years and mean symptoms duration of 5.1(2.7) months. Over half reported NAP at baseline with most (73%) presenting with regional NAP. Common patterns of regional NAP were axial (40%) and pain in upper quadrants (17%). 43% of those with regional NAP persisted or worsened over 1-year, whereas 73% of those with widespread NAP resolved or improved. Joint inflammation was more frequently reported in areas with NAP vs areas without NAP. Regional and widespread NAP were associated with lower odds of reaching CDAI remission (adjusted OR [95%CI]):0.42[0.26 to 0.70] and 0.30[0.12 to 0.74], respectively.

Conclusion: Regional NAP is common and persistent in early RA and impacts remission. RA activity may contribute to NAP. More attention to NAP in RA care is warranted.

Objective: Non-genetic factors influence Systemic Sclerosis (SSc) pathogenesis, underscoring epigenetics as a relevant contributor to the disease. We aimed to unravel DNA methylation abnormalities associated with SSc through an epigenome-wide association study (EWAS).

Methods: We analyzed DNA methylation data from whole blood samples in 179 SSc patients and 241 unaffected individuals, to identify differentially methylated positions (DMPs) with a FDR<0.05. These results were further integrated with RNA-seq data from the same patients to assess their functional consequence. Additionally, we examined the impact of DNA methylation changes on transcription factors and analyzed the relationship between alterations of the methylation and gene expression profile and serum proteins levels.

Results: This analysis yielded 525 DMPs enriched in immune-related pathways, being leukocyte cell-cell adhesion the most significant (FDR=4.91x10^-9), prioritizing integrins as they were exposed by integrating methylome and transcriptome data. Furthermore, through this integrative approach we observed an enrichment of neutrophil related pathways, highlighting this myeloid cell type as a relevant contributor in SSc pathogenesis. In addition, we uncovered novel profibrotic and proinflammatory mechanisms involved in the disease. Finally, the altered epigenetic and transcriptomic signature revealed an increased activity of CCAAT/enhancer-binding protein (CEBP) transcription factor family in SSc, which is crucial in the myeloid lineage development.

Conclusion: Our findings uncover the impaired epigenetic regulation of the disease and its impact on gene expression, identifying new molecules for potential clinical applications and improving our understanding of SSc pathogenesis.