Arthritis & Rheumatology最新文献

Objective: Information is limited on the natural history and current treatment patterns in macrophage activation syndrome (MAS), a life-threatening hyperinflammatory syndrome complicating Still's disease (systemic juvenile idiopathic arthritis [sJIA] and adult-onset Still's disease [AOSD]). AMETHYST aimed to describe real-world treatment patterns and outcomes in glucocorticoid (GC)-refractory MAS complicating Still's disease.

Methods: In this retrospective cohort study, medical data from January 1, 2012, to March 31, 2023, were abstracted from charts of all eligible patients across eight sites in Europe, Canada, and the United States for index MAS episodes (occurring between January 1, 2012, and September 30, 2022, and meeting eligibility criteria).

Results: Overall, 55 of 64 included patients (86%) had sJIA and 9 of 64 (14%) had AOSD. Most patients (53/64 [82.8%]) were children at index (median age: 7.0 years). MAS was characterized by rash (60.4%), fever (52.8%), and hepatic involvement (49.1%). All patients received GCs; most were also treated with anakinra (48/64 [75%]) and/or ciclosporin (33/64 [51.6%]). Normalization of seven (complete MAS laboratory remission) or at least three (partial remission) prespecified laboratory parameters occurred in 7 of 64 (10.9%) and 41 of 64 patients (64.1%), respectively. GCs were tapered in 50 of 64 patients (78.1%) (median: 39.9 days). Per investigator assessment of clinical signs/symptoms for the index MAS episode, 24 of 64 (37.5%) and 26 of 64 patients (40.6%) had a complete and partial response, respectively. MAS recurred in 20 of 64 patients (31.3%). Seven of 64 patients (10.9%) died, and the estimated one-year survival probability was 93.75%.

Conclusions: Low MAS laboratory remission rates and toxicities of high-dose GCs combined with other treatments highlight the need for safer, more effective therapies.

Objective: Systemic sclerosis (SSc) is a chronic autoimmune disorder characterized by immune dysregulation and fibrosis, with myeloid-derived suppressor cells (MDSCs) emerging as important regulators of immune responses. However, the role of MDSCs in SSc-associated fibrosis and their interactions with other immune cell populations remain poorly understood.

Methods: Peripheral blood (SSc: N=37, healthy: N=27) and skin biopsies (SSc: N=9, healthy: N=5) were analyzed using flow cytometry and fluorescence microscopy, respectively. Bleomycin-induced mouse models of fibrosis were used to validate findings, including pharmacological disruption of granulocytic MDSC (G-MDSC) activity via Bruton's tyrosine kinase inhibition (ibrutinib). Single-cell RNA sequencing data from SSc and control skin and lung samples (skin: 19 SSc, 20 healthy; lung: 7 SSc, 15 healthy), complemented by spatial transcriptomics analysis of skin (12 SSc, 7 healthy), were integrated to define cellular interactions relevant to disease pathogenesis. Functional studies and bulk RNA sequencing were conducted to dissect the underlying G-MDSC interactions.

Results: G-MDSCs were significantly enriched in the circulation and skin of SSc patients, correlating with disease severity. Experimental fibrosis revealed enrichment of G-MDSCs, whereas monocytic MDSCs remained stable. Transcriptomic data revealed a strong interaction between MDSCs and type 2 innate lymphoid cells (ILC2s), promoting a pro-fibrotic environment via IL-13-driven TGFβ, Arginase1 and CCL24. Functional assays confirmed that G-MDSCs promote Tgfb1 expression in ILC2s, further driving tissue fibrosis.

Conclusion: These findings explore a so far unknown G-MDSC-ILC2 axis as a driver of fibrosis in SSc. Targeting this interaction may represent a novel therapeutic strategy to mitigate fibrotic disease progression.

Objective: Sjögren's disease (SjD) is a heterogeneous autoimmune disorder characterized by substantial clinical and molecular diversity. This heterogeneity raises key questions regarding the existence of distinct pathogenic mechanisms underlying disease subtypes. The objective of this study was to comprehensively characterize peripheral immune cell states associated with SjD and to identify features that could enable better patient stratification for targeted treatments.

Methods: We performed single-cell RNA sequencing with surface protein profiling on 1.5 million peripheral blood mononuclear cells from 333 participants. Individuals were stratified by SjD diagnosis and anti-SSA status to enable comparative analyses between disease subgroups and controls.

Results: Our analysis identified two immunologic endotypes of SjD, with SSA-positive participants exhibiting a dominant and persistent type I interferon signature that was also associated with altered immune cell composition. Transitional B cells were particularly affected, displaying altered developmental states, reduced BCR diversity, shorter CDR3 regions, and increased predicted interactions with activated immune cell populations, findings consistent with perturbations of early B cell selection processes. By contrast, SSA-negative participants with SjD exhibited limited transcriptional differences compared with symptomatic non-SjD controls, highlighting substantial biologic heterogeneity within SjD.

Conclusion: These findings support a two-disease model of SjD and highlight transitional B cells as both a key biomarker and a therapeutic target.

Objective: Glucocorticoids remain essential therapies for immune and inflammatory diseases such as rheumatoid arthritis (RA) but are notorious for their metabolic side effects. Given the anti-inflammatory and metabolically favorable actions of peroxisome proliferator-activated nuclear receptor (PPAR) agonists, we investigated whether PPARα agonism could enhance the therapeutic efficacy and/or mitigate the metabolic side effects of glucocorticoids.

Methods: We evaluated the effects of the synthetic glucocorticoid dexamethasone and the PPARα agonist GW7647 across four model systems: tumor necrosis factor-α (TNFα)-stimulated L929sA fibroblasts, primary human fibroblast-like synoviocytes (FLS) from patients with osteoarthritis (OA) and RA, and collagen-induced arthritis mice.

Results: Dexamethasone reduced the inflammatory TNFα response in L929sA cells, which was further potentiated by GW7647. In vivo, dexamethasone induced adiposity and hypertriglyceridemia, which GW7647 counteracted without affecting arthritis severity. In both OA-FLS and RA-FLS, dexamethasone and GW7647 cooperatively regulated metabolic genes expression. Proteomic profiling of TNFα-stimulated human OA-FLS revealed that combined use of dexamethasone and GW suppressed interferon-stimulated proteins. In line herewith, suppression of proinflammatory gene expression upon combined dexamethasone and GW7647 treatment was more outspoken in L929sA co-stimulated with TNFα and interferon-β compared to TNFα alone.

Conclusion: GW enhances the anti-inflammatory effects of glucocorticoids in L929sA cells and mitigates metabolic side effects of dexamethasone in vivo, without compromising efficacy. In human OA-FLS and RA-FLS, this combination cooperatively regulates metabolic gene expression. Moreover, PPARα agonism permits to broaden its anti-inflammatory profile to interferon-driven pathways. Because both glucocorticoids and PPAR agonists are already widely used in clinical practice, these findings offer a promising strategy to optimize glucocorticoid-based therapies.

Objective: VEXAS syndrome is a severe X-linked autoinflammatory disorder caused by somatic mutations in ubiquitin-like modifier activating enzyme 1 (UBA1), with clinical outcomes that vary by UBA1 genotype. We aimed to elucidate genotype-specific inflammatory programs and identify potential therapeutic targets.

Methods: We conducted longitudinal deep phenotyping, including whole blood RNA sequencing (RNA-seq) and clinical activity assessment. Peripheral blood samples were analyzed by single-cell RNA-seq. Human monocytic cell lines harboring each major UBA1 mutation (p.Met41Val, p.Met41Thr, or p.Met41Leu) were generated and subjected to transcriptomic and functional analyses.

Results: Thirteen patients with VEXAS syndrome contributed a total of 79 RNA-seq samples. Among genes up-regulated in VEXAS syndrome, RNASE1 showed the strongest correlation with longitudinal disease activity (r = 0.70, false discovery rate < 0.05) and was up-regulated in patients' monocytes. In UBA1-mutant monocytic cell lines, genotype-dependent ubiquitination defects were observed in a graded manner (p.Met41Val > p.Met41Thr > p.Met41Leu), even in the absence of exogenous stimuli. These defects were accompanied by unfolded protein response activation, increased pro-inflammatory cytokine production, progressive cell death, and RNASE1 up-regulation, all following the same graded pattern of recapitulating patient genotype-phenotype associations. Transcriptomic analyses demonstrated enrichment of pro-inflammatory, interferon, and necroptosis signatures in more severe genotypes. Notably, inhibition of receptor-interacting protein kinase 3 (RIPK3) markedly attenuated all pathologic features, including RNASE1 up-regulation.

Conclusion: Our UBA1-mutant monocytic cell-line models, representing three distinct genotypes, recapitulate genotype-dependent inflammatory phenotypes that can be modulated by RIPK3 inhibition, providing a translational platform for mechanistic investigation and precision therapy development in VEXAS syndrome.

Objective: Synovial fibroblasts directly contribute to inflammation and damage in immune-mediated inflammatory arthritis. CD248/endosialin is expressed by fibroblasts in the synovium, is highly up-regulated during inflammation, and has been proposed as a potential therapeutic target. This study aimed to map the expression of CD248 in disease-associated fibroblast states and to elucidate its role in pathology.

Methods: Molecular profiling of stromal cells from healthy and arthritic (K/BxN serum transfer-induced arthritis) wildtype (Cd248^+/+) and Cd248^-/- mice was performed using 3' single-cell RNA sequencing. Arthritis trajectory and severity were assessed in both genotypes by clinical scoring, microcomputed tomography (micro-CT), histology, and flow cytometry of dissociated synovium. Additionally, healthy mice of each genotype were aged to 20 months and hind limbs assessed by micro-CT and histology.

Results: Cells expressing high levels of Cd248 also express the "Pi16" fibroblast progenitor gene signature. Genetic deletion of Cd248 in mice altered the differentiation trajectory of these progenitors, predisposing them to become destructive lining layer fibroblasts. Consequently, Cd248^-/- arthritic mice showed a phenotype of rapid, extensive bone damage. Unexpectedly, bone erosion and resultant deformity were also observed in aged Cd248^-/- mice in the absence of an inflammatory stimulus.

Conclusion: Genetic deletion of Cd248^-/- results in uncoupling of inflammation and damage due to dysregulated fibroblast progenitor differentiation. Our data suggest that the high levels of CD248 expression seen on synovial fibroblasts provides a protective brake that attenuates bone damage by preventing the polarization of emergent fibroblasts toward a destructive phenotype. Therapeutic targeting of this protein may exacerbate disease.

Objective: CASTOR1 senses arginine and regulates mammalian target of rapamycin complex 1 (mTORC1), a central metabolic signaling molecule. This study aimed to elucidate the roles of CASTOR1 in humoral immune responses.

Methods: We analyzed human B cell transcriptomes from healthy controls and patients with systemic lupus erythematosus (SLE) via correlation analysis and gene set variation analysis using our database, Immune Cell Gene Expression Atlas from the University of Tokyo. Castor1-deficient and B cell-specific Castor1-deficient mice were used for analyses of serum immunoglobulins and autoantibodies, urinary proteins, renal pathology, gene expression, and flow cytometry in spleen and bone marrow cells. The culture supernatant of splenic B cells was used for immunoglobulin (Ig) analysis.

Results: Transcriptomic analysis of bulk RNA sequencing data from various B cell subsets in patients with SLE (n = 136; n = 129 included in the primary analysis) revealed a correlation between CASTOR1 expression and disease activity, with CASTOR1 expression in plasmablasts inversely correlated with Systemic Lupus Erythematosus Disease Activity Index 2000 (r = -0.32, P = 0.00031). Castor1-deficient mice exhibited increased plasma cell populations in the spleen and bone marrow, elevated serum IgG levels, production of anti-double-stranded DNA antibodies, and glomerulonephritis with IgG deposits, reflecting SLE-like autoimmunity. Moreover, B cell-specific Castor1-deficient mice showed increased plasma cell counts, elevated serum IgG levels, and glomerulonephritis, indicating that Castor1 might regulate systemic humoral immunity via a B cell-intrinsic mechanism.

Conclusion: CASTOR1 plays a regulatory role in humoral immunity and may contribute to the pathogenesis of autoimmune diseases such as SLE, representing a potential therapeutic target.