第一部分 中国银屑病关节炎患者临床特征的性别差异

目的：

本研究旨在阐明中国银屑病关节炎患者在人口学特征、临床表现、关节功能状态、生活质量及治疗反应等方面的性别差异。

方法：

本研究基于中国银屑病关节炎注册队列（CREPAR），纳入从2018年12月至2021年6月期间注册进入CREPAR队列的1074例银屑病关节炎患者，收集他们的人口学特征、临床表现、实验室检验指标、合并症及生活质量评估等基线资料用于横断面分析。随后我们从中筛选出至少在1年内有1次随访且临床资料完整的369位患者，基于他们的随访数据对银屑病关节炎患者治疗达标情况的性别差异进行了分析。

结果：

本研究共纳入1074例银屑病关节炎患者，其中男性585例（54.47%），女性489例（45.53%）。男性患者的银屑病关节炎发病年龄早于女性患者（38.10±12.79岁vs 40.37±13.41岁，p=0.005）。在临床表现方面，男性患者中轴受累（43.89% vs 37.74%，p=0.044）和指/趾甲受累（66.15% vs 58.08%，p=0.006）的发生率较女性更高；而女性患者外周关节炎的发生率更高（89.57% vs 83.93%，p=0.007）。实验室检验方面，男性患者HLA-B27阳性率（24.65% vs 16.70%，p=0.002）和CRP水平（中位数9.70 vs 5.65，p<0.001）均显著高于女性。在疾病活动度评估方面，男性患者的PASI评分（中位数5.00 vs 3.00，p=0.007）和BASFI评分（中位数1.80 vs 1.40，p=0.012）较女性患者更高。两组患者在接受治疗后的达标率上没有明显差异。

结论：

银屑病关节炎患者在人口统计学特征及临床表现方面存在一定的性别差异。充分了解这些差异及其背后的潜在机制或许能为患者的个体化治疗提供一定的帮助。

第二部分 单细胞转录组测序揭示滑膜成纤维细胞在银屑病关节炎中的作用

目的：

解析银屑病关节炎患者滑膜成纤维细胞的异质性，探索其功能状态特征及关键调控因素，从而揭示银屑病关节炎的发病机制。

方法：

借助单细胞转录组测序技术检测活动期银屑病关节炎患者的滑膜组织并与骨关节炎进行对比。通过分析滑膜组织的细胞组成、滑膜成纤维细胞的转录特征、识别滑膜成纤维细胞的细分亚群、评估其功能表型的变化情况、借助细胞通讯与转录因子分析探索其功能表型的关键调控因素等，全面表征滑膜成纤维细胞在银屑病关节炎中的作用。针对关键的分析结果进一步应用免疫组织化学、免疫荧光、原代细胞模型等手段验证单细胞转录组测序的发现。

结果：

在数据质控、整合及其他预处理后，我们共获得了来自4例活动期银屑病关节炎及3例骨关节炎滑膜样本的包含了31270种基因和50755个细胞的单细胞转录组测序数据。滑膜组织的细胞组成主要包括巨噬细胞、成纤维细胞、T细胞、内皮细胞、壁细胞、B细胞和肥大细胞；其中T细胞在银屑病关节炎中的比例明显增加。对滑膜成纤维细胞的进一步分析鉴定出了6种不同的亚群，其中CD74+细胞及CXCL12+细胞在银屑病关节炎中的比例明显升高；两者在转录组特征方面具有一定的相似性，但同时也各自具有相对独特的功能表型。CD74+细胞高表达与抗原提呈相关的基因；而CXCL12+细胞则表现出明显的促炎特性和侵袭性的功能表型。通过转录因子分析发现NR2F2可能是调控其致病性表型的关键分子，随后在原代滑膜成纤维细胞上进行的功能实验证实了NR2F2对滑膜成纤维细胞侵袭表型的调控作用。通过细胞通讯分析及细胞实验，我们发现FGF7可能通过调控NR2F2影响滑膜成纤维细胞的功能表型。我们还通过拟时序分析揭示了滑膜成纤维细胞各个亚群之间的动态演化过程。

结论：

本研究借助单细胞转录组测序技术，较为深入地探索了银屑病关节炎滑膜成纤维细胞的异质性及功能特点，并结合组织学和细胞实验揭示了NR2F2对滑膜成纤维细胞功能表型的调控作用。本研究的发现有望成为未来新的治疗靶点。

Part I Sex‑specific differences in patients with psoriatic arthritis: a nationwide study from the Chinese Registry of Psoriatic Arthritis

Objective:

To elucidate the sex-specific differences in demographic features, clinical characteristics, quality of life and treatment response in Chinese patients with psoriatic arthritis.

Methods:

A total of 1,074 patients with psoriatic arthritis registered between December 2018 and June 2021 from the Chinese REgistry of Psoriatic ARthritis (CREPAR) cohort were selected. The baseline data on demographics, clinical characteristics, commonly used laboratory tests, comorbidities, and quality of life assessments were collected for this cross-sectional analysis. 369 patients with relatively complete data of follow-up visits were selected for further sex-stratified analyses of rates of treatment target achievement.

Results:

A total of 1,074 patients were included in this study, 585 (54.47%) of them were male and 489 (45.53%) were female. The age at psoriatic arthritis onset in male patients was earlier than that in female patients (38.10±12.79 vs 40.37±13.41, p=0.005). For clinical characteristics, male patients presented with higher rates of axial involvement (43.89% vs 37.74%, p=0.044) and nail involvement (66.15% vs 58.08%, p=0.006), while female patients presented with higher rates of peripheral arthritis (89.57% vs 83.93%, p=0.007). For laboratory tests, men presented with a higher percentage of HLA-B27 positivity than women (24.65% vs 16.70%, p=0.002) and had higher levels of CRP (median 9.70 vs 5.65, p<0.001). Regarding disease assessment indices, male patients scored higher in PASI and BASFI (median 5.00 vs 3.00, p=0.007 and 1.80 vs 1.40, p=0.012, respectively). No sex difference was found in rates of achieving MDA, DAPSA remission or low disease activity.

Conclusions:

Demographic and clinical characteristics tend to vary between male and female patients with psoriatic arthritis. A comprehensive understanding of these disparities and the underlying mechanisms may facilitate the development of personalized therapeutic strategies for psoriatic arthritis patients.

Part II Single-cell RNA sequencing technology reveals the key role of fibroblast-like synoviocytes in psoriatic arthritis

Objective:

To elucidate the heterogeneity of fibroblast-like synoviocytes, investigate their characteristics of functional phenotype and key regulatory factors in psoriatic arthritis, thereby uncovering the pathogenesis of psoriatic arthritis and finding new therapeutic targets.

Methods:

Using single-cell RNA sequencing (scRNA-seq), we examined synovial tissues from patients with active psoriatic arthritis and compared them with those from osteoarthritis patients. Through comprehensive analysis of cellular composition of synovial tissue and transcriptional profiles of synovial fibroblasts, identification of fibroblast subgroups, and assessment of their functional phenotypic changes—combined with cell-cell communication and transcription factor analyses to explore key regulatory mechanisms—we systematically characterized the role of synovial fibroblasts in psoriatic arthritis pathogenesis. Key findings from the bioinformatic analysis were further validated using immunohistochemistry (IHC), immunofluorescence (IF), and primary cell model to confirm the scRNA-seq results.

Results:

Following data preprocessing, we obtained scRNA-seq data comprising 31,270 genes and 50,755 cells from synovial membrane samples of four patients with active psoriatic arthritis and three with osteoarthritis. The cellular composition of synovial membrane primarily included macrophages, fibroblasts, T cells, endothelial cells, mural cell, B cells, and mast cells, with T cells exhibiting a significantly increased proportion in psoriatic arthritis. Further analysis of synovial fibroblasts identified six distinct subpopulations, among which CD74+ and CXCL12+ subsets were markedly expanded in psoriatic arthritis. These two subpopulations shared transcriptional characteristics to some extent but also exhibited unique functional phenotypes respectively. CD74+ fibroblasts displayed high expression of antigen presentation-related genes, while CXCL12+ fibroblasts demonstrated pro-inflammatory and invasive phenotypes. Transcriptional factor analysis revealed NR2F2 as a potential key modulator of its invasive phenotype, which was further validated in primary synovial fibroblasts. Cell-cell communication analysis and in vitro experiments further suggested that FGF7 may influence the phenotype of synovial fibroblast via the regulation of NR2F2. Additionally, pseudotime trajectory analysis delineated the dynamic transitions among synovial fibroblast subgroups.

Conclusions:

This study employed scRNA-seq to comprehensively investigate the heterogeneity and functional characteristics of synovial fibroblasts in psoriatic arthritis and elucidated the key role of NR2F2 in modulating the functional phenotypes of synovial fibroblasts. The findings from this research may provide potential novel therapeutic target for future investigations.