Objective Macrophage activation syndrome (MAS) is a rare, life‐threatening hyperinflammatory condition that complicates rheumatologic diseases, most commonly Still disease. Despite increasing awareness and emerging recommendations, MAS treatment remains heterogeneous worldwide. The METAPHOR project aimed to describe real‐life therapeutic strategies for MAS, exploring differences across underlying diseases, geographic regions, physician subspecialties, and drug availability. Methods An international web‐based survey was developed by a multidisciplinary expert panel together with a patient representative following a systematic literature review. The survey was anonymously completed through Paediatric Rheumatology European Society/Paediatric Rheumatology International Trial Organisation and the Histiocyte Society networks (October to December 2023). Treatment strategies for MAS across different rheumatologic contexts were explored. Responses were analyzed descriptively and stratified by geography, subspecialty, clinical experience, and underlying disease. Results A total of 287 physicians from 64 countries completed the survey, the majority being pediatric rheumatologists with more than five years of experience. Glucocorticoids, particularly intravenous methylprednisolone, were consistently identified as first‐line therapy across all MAS subtypes (for 44% of clinicians as monotherapy). Anakinra, ciclosporin, and intravenous Ig were the most frequently combined agents. However, their use varied markedly by underlying disease and geographic region, with anakinra preferentially used in Still disease–associated MAS. Striking global disparities in drug availability, particularly for anakinra and emapalumab, significantly influenced treatment choices and were associated with increased reliance on steroid monotherapy. Conclusion MAS management remains highly heterogeneous worldwide. Although glucocorticoids remain foundational, reducing steroid reliance through equitable access to immunomodulatory therapies and advancing mechanism‐based strategies represent critical priorities in optimizing MAS care. image
Objective In APEX, guselkumab, which binds to the IL‐23p19 subunit and CD64 on IL‐23‐producing cells, demonstrated significant joint efficacy and inhibition of structural damage progression in participants with active and erosive PsA through Week (W)24; W48 findings are reported herein. Methods The APEX modified full analysis set included 1020 biologic‐naïve adults with active PsA (≥3 tender joints; ≥3 swollen joints; CRP ≥0.3mg/dL; ≥2 erosive joints) randomized to guselkumab every (Q)4W (N=273), guselkumab at W0,4 then Q8W (N=371), or placebo followed by guselkumab Q4W beginning at W24 (N=376). Outcomes through W48 included ACR20/50/70 response rates (using multiple/nonresponder imputation); least squares mean (LSM) change in PsA‐modified van der Heijde‐Sharp score (vdH‐S); achievement of clinically meaningful improvement (CMI; ≥0.35‐point) in HAQ‐DI, ≥90% improvement in Psoriasis Area and Severity Index (PASI90), and minimal disease activity (MDA). Results Through W48, 93% (950/1020) of participants completed study intervention. Guselkumab Q4W and Q8W through W48 demonstrated durable ACR20/50/70 response rates (71‐74%/51‐56%/31‐35%), and low rates of structural damage progression (vdH‐S LSM change: 0.60‐0.78); 60‐64% of participants reported HAQ‐DI CMI, 74‐80% achieved PASI90, 36‐41% achieved MDA. Following transition to guselkumab, structural damage progression among placebo‐randomized participants diminished (vdH‐S LSM change W0‐24: 0.96; W24‐48: 0.41) and clinical response rates increased through W48. Adverse event rates were consistent with placebo and guselkumab through W24 and stable through W48 of guselkumab. Conclusion APEX W48 findings further support guselkumab use for durable and comprehensive treatment of diverse PsA manifestations. Inhibition of cumulative joint damage with guselkumab may optimize outcomes.
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. image
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.
