Arthritis & Rheumatology最新文献

Systemic sclerosis–associated interstitial lung disease (SSc-ILD) is one of the leading causes of morbidity and mortality in SSc, affecting up to three-quarters of patients. The disease course is highly heterogeneous, ranging from indolent, nonprogressive forms to rapidly progressive pulmonary fibrosis (PPF). Identifying patients at risk for progression remains a key clinical challenge. Routine screening with high-resolution computed tomography at diagnosis and regular pulmonary function test monitoring are essential for early detection and timely management. Recent efforts have sought to harmonize the definition of PPF across fibrosing ILDs, recognizing shared clinical and pathophysiological mechanisms beyond idiopathic pulmonary fibrosis. Approximately 20% to 30% of patients with SSc-ILD develop PPF, yet reliable predictors of progression remain elusive. Advances in imaging, functional assessment, and molecular biomarkers hold promise for improving risk stratification. Therapeutic approaches have evolved from conventional immunosuppression toward combination and antifibrotic strategies. Mycophenolate mofetil remains the preferred first-line therapy, whereas nintedanib is the only antifibrotic agent approved for both SSc-ILD and PPF, having demonstrated efficacy in slowing lung function decline. Combination therapy, particularly mycophenolate mofetil with nintedanib or biologics such as rituximab and tocilizumab, is gaining traction in clinical practice despite limited comparative data. Emerging antifibrotic and anti-inflammatory agents offer new therapeutic prospects. This review summarizes current understanding of PPF in SSc-ILD, focusing on its evolving definition, prognostic determinants, and treatment landscape, and highlights unmet needs for personalized, evidence-based management.

Objective: Psoriatic arthritis (PsA) is a chronic immune-mediated arthritis affecting approximately 30% of individuals with psoriasis. The mechanisms driving PsA joint inflammation remain incompletely defined.

Methods: To address this gap, we performed multimodal single-cell sequencing of immune cells from matched peripheral blood and synovial fluid (SF) from 6 PsA patients, with comparisons to a rheumatoid arthritis (RA) patient and 6 healthy controls (HC).

Results: SF CD4 and CD8 T cells displayed elevated expression of TOX, PDCD1, CTLA4, GZMK, CXCR3, and CXCR6, reflecting a tissue-specific activation state. CD4 T cell sub-clustering revealed clonally expanded populations enriched for GZMK and cytotoxic gene programs, suggesting antigen-driven activation. In contrast, CD8 T cell clonality showed a significant correlation with GZMK expression, however GZMK⁺ CD8 T cells in the joint exhibited a transcriptional signature consistent with functional exhaustion. Concurrently, SF was enriched for CD141⁺, CD1c⁺, CCR7⁺, and SIGLEC6⁺ dendritic cells (DCs), characterized by increased CXCL16 expression and antigen presentation pathways. Flow cytometry and ELISA in an additional 25 PsA patients and 16 HCs confirmed protein-level enrichment of key chemokines and GZMK⁺ T cells. Cell-cell communication analysis highlighted CXCR6-CXCL16 and CXCR3-CXCL10 chemokine axes as mediators of immune cell recruitment and retention, while in vitro assays showed enhanced migration of PsA SF T cells toward a CXCL16 gradient relative to paired blood.

Conclusion: Together, these findings suggest that clonally expanded GZMK⁺ CD4 T cells in PsA are cytotoxic and antigen-responsive, contributing to joint inflammation following recruitment by CXCL16-producing dendritic cells.

OBJECTIVE: We previously showed that Semaphorin4A (Sema4A) is elevated in patients with systemic sclerosis (SSc) and promotes inflammation and fibrosis in vitro. Here, we examined the effect of Sema4A neutralization in vivo and in 3D fibrosis models.

Methods: Sema4A plasma levels were measured by ELISA in healthy controls (n=31) and patients with SSc (n=30). In the bleomycin SSc-model, mice were treated with an anti-Sema4A neutralizing antibody or its respective isotype control (n=6-7). The 3D fibrosis models, consisting of collagen hydrogel, dermal fibroblasts, and peripheral blood mononuclear cells, were stimulated with recombinant Sema4A, rapamycin, or antibodies neutralizing Sema4A, PlexinD1, PlexinB2, Neuropilin-1 or their respective isotype controls (n=6-10). Collagen content was determined by trichrome staining and hydroxyproline assay. Gene expression was determined by RT-qPCR and obtained from GEO-NCBI expression arrays, while protein expression by immunohistochemistry, immunoblotting and flow cytometry.

Results: Circulating Sema4A was elevated in patients with SSc (p<0.0001), while Sema4A receptors were elevated in SSc skin and lung (p ranged from <0.05 to 0.0001). Anti-Sema4A administration significantly reduced skin and lung collagen content in bleomycin-treated mice (p<0.01), as well as the expression of extracellular matrix components, fibrotic and inflammatory mediators, and immune cell infiltration. In the 3D models, SSc serum and SSc PBMCs induced cell contraction, which was drastically abrogated by blocking Sema4A (p<0.01). This effect was associated with reduced expression of fibrotic mediators and attenuated mTORC1 pathway activation.

Conclusions: We confirmed the pro-fibrotic and pro-inflammatory role of Sema4A, postulating Sema4A neutralization as a novel approach for the treatment of SSc.