Arthritis Research & Therapy最新文献

Background: Dysregulation of N6-methyladenosine (m6A) has been implicated in the pathophysiology of various autoimmune diseases. However, its role in dermatomyositis (DM), particularly in cases associated with anti-MDA5 antibodies, remains unclear. This study aimed to elucidate the potential involvement of m6A modifications of mRNAs in the pathogenesis of anti-MDA5⁺DM.

Methods: We assessed mRNA m6A methylation levels in peripheral blood mononuclear cells (PBMCs) from anti-MDA5⁺DM patients and healthy controls (HC) using LC-MS/MS assay. Quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and Western blotting were conducted to determine the mRNA and protein expression levels of YTHDF2 in PBMCs and monocytes from anti-MDA5⁺DM patients and HC. RNA sequencing (RNA-seq) was performed to identify differentially expressed genes and signaling pathways in siYTHDF2-THP-1 cells. RNA immunoprecipitation and quantitative PCR (RIP-qPCR) were used to explore the interaction between YTHDF2 protein and IFNB mRNA in THP-1 cells.

Results: The overall level of mRNA m6A methylation was found to be decreased in PBMCs of anti-MDA5⁺ DM compared to HC. The expression levels of YTHDF2 were downregulated in PBMCs and monocytes of anti-MDA5⁺DM patients compared with HC. The expression of IFNB was increased in PBMCs and monocytes of anti-MDA5⁺DM. Knockdown of YTHDF2 in THP-1 cells significantly increased IFNB expression and activated the JAK-STAT signaling pathway. The interaction between YTHDF2 protein and IFNB mRNA was confirmed by RIP-qPCR. The upregulated expression of type I IFN caused by YTHDF2 knockdown in THP-1 cells could be inhibited by JAK inhibitors.

Conclusions: Our findings suggest a decrease in YTHDF2 expression in anti-MDA5⁺DM monocytes, potentially enhancing IFNB expression and promoting the activation of JAK-STAT signaling pathway.

Background: Difficult to manage (D2M) axial spondyloarthritis (axSpA) is an evolving clinical concept. We aimed to assess the prevalence, predictors and long-term outcomes of D2M axSpA.

Methods: Prospective single center cohort study of axSpA patients starting targeted agents (01/01/2007 until 28/02/2024). The ASAS criteria were applied to classify D2M. Baseline parameters were assessed as predictors of D2M development by multivariate logistic regression models. To identify comorbidity clusters and their contribution to D2M, a K-means cluster analysis on binary indicators of most prevalent chronic illnesses was performed. Long-term functional evolution and adverse events' rate were compared between D2M and non-D2M.

Results: Out of 434 patients, 50 (11.5%) developed D2M disease. Compared to non-D2M, they had higher disease activity at baseline (p = 0.01) and failed to improve at 6 months (p < 0.0001), while dyslipidemia, osteoarthritis and fibromyalgia were more prevalent (p < 0.0001). Independent predictors for developing D2M axSpA were the presence of fibromyalgia (OR 3.55), osteoporosis (OR 5.67) and dyslipidemia (OR 2.70), while two clusters of comorbidities ("chronic pain syndromes" and "metabolic") significantly contributed to D2M (OR 2.52 and OR 3.30; p = 0.010 and 0.013 respectively). During a total follow-up period of 2312 patient-years, D2M patients developed higher functional impairment and had more serious adverse events and hospitalizations (p = 0.016) compared to non-D2M patients.

Conclusion: 11.5% of axSpA patients developed D2M disease and showed adverse long-term outcome compared to non-D2M. While D2M patients had at baseline higher disease's burden, comorbidities mostly related to chronic pain syndromes predicted D2M development, supporting their significance for D2M axSpA evolution.

Background: Subchondral insufficiency fracture of the knee (SIFK) is a rare and rapidly progressing knee joint disease. The typical diagnostic finding of SIFK by magnetic resonance imaging (MRI) is a subchondral hypointense line around the bone marrow lesions (BMLs), which are also commonly observed in knee osteoarthritis (OA). Subchondral bone fracture and its repair reactions are implicated for SIFK. However, pathological changes of SIFK and BMLs and the mechanism by which SIFK is induced remain elusive. We aimed to examine characteristics of SIFK and OA by micro-computed tomography (micro-CT) and histology together with biomarker analysis.

Methods: Nineteen patients with femoral or tibial SIFK (10 F-SIFK and 9 T-SIFK patients) and 24 knee OA patients, who were diagnosed by radiography and MRI and underwent unicompartmental knee arthroplasty, were enrolled for this study, and their medial tibial plateaus were examined by micro-CT and pathology. Serum and urine biomarkers were also analyzed.

Results: All the T-SIFK patients showed BMLs with a subchondral hypointense line by MRI. Micro-CT analysis revealed that the T-SIFK lesion comprises multiple subchondral bone fragments covered with articular cartilage. Histologically, the lesion was composed of articular cartilage-covered subchondral bone fragments, debris of bone and bone marrow, fibrogranulation tissue, cartilage and woven bone. The medial tibial plateaus from OA patients frequently exhibited eburnation, which was commonly accompanied by microfracture. All the BMLs observed in T-SIFK and OA were associated with fat necrosis, which was characterized by disrupted fat cells and foamy macrophage infiltration. The posterior tibial slope angle (12.84 ± 2.34° vs 9.58 ± 2.84°) and the rate of medial meniscal posterior root tears (68.4% vs 25.0%) were significantly higher in T-SIFK than OA. Numbers of grade 2 subchondral bone resorption pits in uninvolved areas of the medial tibial plateaus (2.32 ± 1.43 vs 0.72 ± 0.66) and the femoral condyles (5.53 ± 3.73 vs 1.50 ± 2.10) were significantly higher in T-SIFK than OA.

Conclusions: Our data demonstrate that T-SIFK is generated by subchondral bone fracture and its repair reaction and suggest that fat necrosis of the bone marrow is involved in BML formation in T-SIFK and OA.