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Background and aims <p>Perianal fistulas in Crohn’s disease (PFCD) continue to pose a therapeutic challenge owing to low rates of healing and remission. Identifying biomarkers involved in their pathogenesis and diagnosis is essential for personalising care and improving treatment outcomes. This systematic review aims to highlight PFCD biomarkers and provide insights for clinical practice.</p> Methods <p>This systematic review, registered at PROSPERO (CRD42024575480) and conducted in accordance with PRISMA guidelines, includes English-language studies on PFCD biomarkers published through May 2025. Searches were performed in PubMed and Scopus. Study selection and risk-of-bias assessment were conducted independently by two reviewers, according to prespecified search and eligibility criteria.</p> Results <p>Of 5242 records initially identified, 3700 were screened, and 33 studies were included (24 addressing pathogenesis and 9 diagnostic biomarkers). Variants in <i>OCTN1/2</i>, <i>NOD2, IRGM, TYK2</i>, and <i>VDR</i> genes influence fistula risk and severity in Crohn’s disease, particularly polymorphisms in <i>IRGM, NOD2</i>, and genes within the JAK–STAT signalling pathway. Altered microbiota and the presence of antibiotic resistance genes support a bacterial role in pathogenesis. Key pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) and cellular populations (CD4⁺ T-cells, macrophages) drive inflammation, while epithelial-mesenchymal transition and extracellular matrix remodelling contribute to fistula persistence. Recent evidence suggests that PFCD arises from complex immune-stromal cell interactions, involving cellular senescence, epigenetic alterations, and population heterogeneity. Diagnostic advances include metabolic profiling and urinary Raman spectroscopy, alongside established biomarkers such as granulomas, faecal calprotectin, and NGAL.</p> Conclusions <p>This review highlights several promising biomarkers involved in the pathogenesis and diagnosis of PFCD; however, heterogeneity across studies limits their immediate translation into clinical guidelines. Larger, well-designed studies are needed to validate these biomarkers and support personalised treatment strategies.</p> Graphical abstract <p></p>

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Biomarkers in the pathogenesis and diagnosis of Crohn’s perianal fistulas: a systematic review

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月22日

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  • A. C. Silva,
  • R. Magalhães,
  • L. Lacerda,
  • C. Robalo,
  • P. Lago,
  • M. D. Santos

摘要

Background and aims

Perianal fistulas in Crohn’s disease (PFCD) continue to pose a therapeutic challenge owing to low rates of healing and remission. Identifying biomarkers involved in their pathogenesis and diagnosis is essential for personalising care and improving treatment outcomes. This systematic review aims to highlight PFCD biomarkers and provide insights for clinical practice.

Methods

This systematic review, registered at PROSPERO (CRD42024575480) and conducted in accordance with PRISMA guidelines, includes English-language studies on PFCD biomarkers published through May 2025. Searches were performed in PubMed and Scopus. Study selection and risk-of-bias assessment were conducted independently by two reviewers, according to prespecified search and eligibility criteria.

Results

Of 5242 records initially identified, 3700 were screened, and 33 studies were included (24 addressing pathogenesis and 9 diagnostic biomarkers). Variants in OCTN1/2, NOD2, IRGM, TYK2, and VDR genes influence fistula risk and severity in Crohn’s disease, particularly polymorphisms in IRGM, NOD2, and genes within the JAK–STAT signalling pathway. Altered microbiota and the presence of antibiotic resistance genes support a bacterial role in pathogenesis. Key pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) and cellular populations (CD4⁺ T-cells, macrophages) drive inflammation, while epithelial-mesenchymal transition and extracellular matrix remodelling contribute to fistula persistence. Recent evidence suggests that PFCD arises from complex immune-stromal cell interactions, involving cellular senescence, epigenetic alterations, and population heterogeneity. Diagnostic advances include metabolic profiling and urinary Raman spectroscopy, alongside established biomarkers such as granulomas, faecal calprotectin, and NGAL.

Conclusions

This review highlights several promising biomarkers involved in the pathogenesis and diagnosis of PFCD; however, heterogeneity across studies limits their immediate translation into clinical guidelines. Larger, well-designed studies are needed to validate these biomarkers and support personalised treatment strategies.

Graphical abstract