Significance of integrated clinical and proteomic characteristics analysis for pathogenesis and management of Crohn's disease with concomitant psoriasis.

BACKGROUND: Certain patients with Crohn's disease (CD) concomitantly develop psoriasis (PS), whilst the typical features and underlying mechanisms remain under investigation. The present study was intended to identify the clinical and proteomic features of CD with concomitant PS (CDPS) in order to enhance future diagnostic and therapeutic strategies for this type of comorbidity. METHODS: A retrospective, single-centre study was conducted for patients with CD, CDPS, and idiopathic PS. Student's t-test, Wilcoxon rank-sum test and the Chi-square test were employed to examine the similarities and differences of clinical characteristics of these patients. Intestinal mucosa, serum, urine proteomics and metaproteomics were conducted for healthy control (HC), CD and CDPS subjects. Wild-type (WT) C57BL/6J, Hgfac knockout and Krt7 knockout mice (male, 8-10 weeks old) were studied using the Dextran Sulfate Sodium (DSS) induced colitis model and imiquimod induced psoriasis model. FINDINGS: Ten patients with CDPS were enrolled. All patients had infliximab (IFX) exposure history but the IFX response rates were lower. The disease site (L3) and perianal lesions of the CDPS group showed statistically significant differences compared with those in the CD group. Moreover, blood inflammatory indicators and triglyceride levels were higher in the CDPS group. Meanwhile, significant differences were observed in the age of onset, PS type, and PS activity score between the CDPS group and the idiopathic PS group. Therapeutic response results showed that all the patients experienced improvement of their PS whilst some of their intestinal lesions remained active after the treatment with ustekinumab (UST). Additionally, Intestinal mucosa proteomic results showed that CDPS group exhibited higher activation of immune-related pathways, increased keratin formation and impaired intestinal mucosal mitochondrial function leading to reduced activity of metabolism-related pathways. Serum and urine proteomics revealed that the significant downregulation of hepatocyte growth factor activator (HGFAC) in patients with CDPS impedes lipid metabolism. Metaproteomic analysis showed that the CDPS group had reduced abundance of lipid metabolism-associated microbes, leading to increased lipid deposition in the intestinal mucosa and consequently, an enhanced inflammatory response. And in animal experiments, HGFAC knockout mice developed markedly more severe colitis and skin inflammation, whereas KRT7 knockout mice and those Megasphaera micronuciformis treated mice exhibited attenuated disease phenotypes. INTERPRETATION: Patients with CD who have extensive and perianal lesions are more likely to develop PS. Furthermore, patients with CDPS suffer from more severe disease progression, poorer prognosis and lower response rate to biological agents. Aberrant activation of immune signalling in the intestinal mucosa, increased expression of keratins and impaired mitochondrial metabolic function are potential reasons for the more severe intestinal inflammation in patients with CDPS. Downregulation of circulating HGFAC and reduction of microbes associated with lipid metabolism elevate blood triglyceride levels, and triglycerides lead to significant activation of immune cells in the skin, which is accompanied by an increase in circulating immunoglobulins, which may represent a key mechanism for the development of PS in patients with CD. Our study has elucidated the potential pathogenesis of CDPS, and the combination of clinical and proteomic analysis may provide valuable insights for reference into the management and therapeutic targets of this type of comorbidity. FUNDING: This work was supported by the National Natural Science Funds of China (82370529, 82303391), the Guangdong Basic and Applied Basic Research Fund (2022A1515111193), the Guangzhou Science and Technology Plan Project (2023A04J0581), the Featured Clinical Technique of Guangzhou (2023C-TS34), and the Science and Technology Projects in Guangzhou (202201020142 and 2024B03J0466).