炎症性肠病肠外表现的发病机制和处理原则
Pathogenesis and management principles of extraintestinal manifestations in inflammatory bowel disease
Received date: 2025-02-18
Online published: 2025-07-08
炎症性肠病（inflammatory bowel disease，IBD）是一类慢性复发性胃肠道炎症性疾病，包括克罗恩病（Crohn disease，CD）和溃疡性结肠炎（ulcerative colitis,UC）。30%~50% IBD患者可出现肠外表现（extraintestinal manifestation,EIM），累及肌肉骨骼、皮肤、眼部和肝胆系统等多个器官。部分EIM的发生与IBD炎症活动平行，而另一些则可独立进展,其发病机制涉及遗传易感性、肠道菌群紊乱及免疫异常等多个因素。EIM的诊疗管理需多学科团队（multidisciplinary team，MDT）协作，与IBD活动相关的EIM可通过控制IBD本身来缓解，而独立进展的EIM则需针对其发病机制采取个体化治疗策略。除传统治疗外，肿瘤坏死因子（tumor necrosis factor，TNF）-α抑制剂是适用于大部分EIM治疗的核心生物制剂。未来，精准诊断、个体化治疗及多学科协作将是EIM研究的重点方向。
曹芝君 , 陆君涛 . 炎症性肠病肠外表现的发病机制和处理原则[J]. 内科理论与实践, 2025 , 20(02) : 112 -119 . DOI: 10.16138/j.1673-6087.2025.02.03
Inflammatory bowel disease (IBD) is a group of chronic relapsing inflammatory gastrointestinal diseases, including Crohn disease (CD) and ulcerative colitis (UC). 30%-50% of IBD patients develop extraintestinal manifestations (EIM), which affect multiple organs such as the musculoskeletal, skin, eyes, and hepatobiliary systems. The occurrence of some EIM parallels the activity of IBD inflammation, while others may progress independently. The pathogenesis of EIM involves multiple factors, including genetic susceptibility, dysbiosis of the gut microbiota, and immune dysregulation. The diagnosis and management of EIM require multidisciplinary team (MDT) collaboration. EIM associated with IBD activity can be alleviated by controlling the underlying IBD, while EIM with independent progression requires individualized treatment strategies according to its pathogenesis. In addition to conventional treatments, tumor necrosis factor (TNF)-α inhibitors are core biological agents suitable for the treatment of most EIM. In the future, precision diagnosis, personalized treatment, and multidisciplinary collaboration will be essential directions in EIM research.
| [1] | Vavricka SR, Schoepfer A, Scharl M, et al. Extraintestinal manifestations of inflammatory bowel disease[J]. Inflamm Bowel Dis, 2015, 21(8): 1982-1992. |
| [2] | Rogler G, Singh A, Kavanaugh A, et al. Extraintestinal manifestations of inflammatory bowel disease: current concepts, treatment, and implications for disease management[J]. Gastroenterology, 2021, 161(4): 1118-1132. |
| [3] | Guillo L, D’Amico F, Serrero M, et al. Assessment of extraintestinal manifestations in inflammatory bowel diseases: a systematic review and a proposed guide for clinical trials[J]. United European Gastroenterol J, 2020, 8(8): 1013-1030. |
| [4] | Gordon H, Burisch J, Ellul P, et al. ECCO guidelines on extraintestinal manifestations in inflammatory bowel disease[J]. J Crohns Colitis, 2024, 18(1): 1-37. |
| [5] | Kilic Y, Kamal S, Jaffar F, et al. Prevalence of extraintestinal manifestations in inflammatory bowel disease: a systematic review and meta-analysis[J]. Inflamm Bowel Dis, 2024, 30(2): 230-239. |
| [6] | Boneschansker L, Burke KE. Beyond the gut: the epidemiology of extraintestinal manifestations in inflammatory bowel disease[J]. Clin Transl Gastroenterol, 2023, 14(12): e00618. |
| [7] | He R, Zhao S, Cui M, et al. Cutaneous manifestations of inflammatory bowel disease: basic characteristics, therapy, and potential pathophysiological associations[J]. Front Immunol, 2023, 14: 1234535. |
| [8] | Maverakis E, Marzano AV, Le ST, et al. Pyoderma gangrenosum[J]. Nat Rev Dis Primers, 2020, 6(1): 81. |
| [9] | Sleiman J, Hitawala AA, Cohen B, et al. Systematic review: Sweet syndrome associated with inflammatory bowel disease[J]. J Crohns Colitis, 2021, 15(12): 1864-1876. |
| [10] | Richardson H, Yoon G, Moussa G, et al. Ocular manifestations of IBD: pathophysiology, epidemiology, and iatrogenic associations of emerging treatment strategies[J]. Biomedicines, 2024, 12(12): 2856. |
| [11] | Migliorisi G, Vella G, Dal Buono A, et al. Ophthalmological manifestations in inflammatory bowel diseases: keep an eye on it[J]. Cells, 2024, 13(2): 142. |
| [12] | Wang MH, Friton JJ, Rebert N, et al. Novel genetic risk variants and clinical predictors associated with primary sclerosing cholangitis in patients with ulcerative colitis[J]. Clin Transl Gastroenterol, 2023, 14(9): e00615. |
| [13] | Beheshti Maal A, Shahrbaf MA, Sadri B, et al. Prevalence of hepatobiliary manifestations in inflammatory bowel disease: a GRADE assessed systematic review and meta-analysis of more than 1.7 million patients[J]. J Crohns Colitis, 2024, 18(3): 360-374. |
| [14] | van Sommeren S, Janse M, Karjalainen J, et al. Extraintestinal manifestations and complications in inflammatory bowel disease: from shared genetics to shared biological pathways[J]. Inflamm Bowel Dis, 2014, 20(6): 987-994. |
| [15] | Khrom M, Long M, Dube S, et al. Comprehensive association analyses of extraintestinal manifestations in inflammatory bowel disease[J]. Gastroenterology, 2024, 167(2): 315-332. |
| [16] | Taurog JD, Richardson JA, Croft JT, et al. The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats[J]. J Exp Med, 1994, 180(6): 2359-2364. |
| [17] | Horai R, Zárate-Bladés CR, Dillenburg-Pilla P, et al. Microbiota-dependent activation of an autoreactive T cell receptor provokes autoimmunity in an immunologically privileged site[J]. Immunity, 2015, 43(2): 343-353. |
| [18] | Tie Y, Huang Y, Chen R, et al. Current insights on the roles of gut microbiota in inflammatory bowel disease-associated extra-intestinal manifestations: pathophysiology and therapeutic targets[J]. Gut Microbes, 2023, 15(2): 2265028. |
| [19] | Hedin CRH, Vavricka SR, Stagg AJ, et al. The pathogenesis of extraintestinal manifestations: implications for IBD research, diagnosis, and therapy[J]. J Crohns Colitis, 2019, 13(5): 541-554. |
| [20] | McCarthy DA, Rampton DS, Liu YC. Peripheral blood neutrophils in inflammatory bowel disease: morphological evidence of in vivo activation in active disease[J]. Clin Exp Immunol, 1991, 86(3): 489-493. |
| [21] | Nikolaus S, Bauditz J, Gionchetti P, et al. Increased secretion of pro-inflammatory cytokines by circulating polymorphonuclear neutrophils and regulation by interleukin 10 during intestinal inflammation[J]. Gut, 1998, 42(4): 470-476. |
| [22] | Smith AM, Rahman FZ, Hayee B, et al. Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn’s disease[J]. J Exp Med, 2009, 206(8): 1883-1897. |
| [23] | Sanders TJ, McCarthy NE, Giles EM, et al. Increased production of retinoic acid by intestinal macrophages contributes to their inflammatory phenotype in patients with Crohn’s disease[J]. Gastroenterology, 2014, 146(5): 1278-1288. |
| [24] | Yan JB, Luo MM, Chen ZY, et al. The function and role of the Th17/Treg cell balance in inflammatory bowel disease[J]. J Immunol Res, 2020, 2020: 8813558. |
| [25] | Mortier C, Gracey E, Coudenys J, et al. RORγt inhibition ameliorates IL-23 driven experimental psoriatic arthritis by predominantly modulating γδ-T cells[J]. Rheumatology, 2023, 62(10): 3169-3178. |
| [26] | Wang Y, Yang C, Hou Y, et al. Dimethyl itaconate inhibits antigen-specific Th17 cell responses and autoimmune inflammation via modulating NRF2/STAT3 signaling[J]. FASEB J, 2024, 38(5): e23607. |
| [27] | Graham JJ, Mukherjee S, Yuksel M, et al. Aberrant hepatic trafficking of gut-derived T cells is not specific to primary sclerosing cholangitis[J]. Hepatology, 2022, 75(3): 518-530. |
| [28] | Chen YH, Eskandarpour M, Zhang X, et al. Small-molecule antagonist of VLA-4 (GW559090) attenuated neuro-inflammation by targeting Th17 cell trafficking across the blood-retinal barrier in experimental autoimmune uveitis[J]. J Neuroinflammation, 2021, 18(1): 49. |
| [29] | Qaiyum Z, Gracey E, Yao Y, et al. Integrin and transcriptomic profiles identify a distinctive synovial CD8+ T cell subpopulation in spondyloarthritis[J]. Ann Rheum Dis, 2019, 78(11): 1566-1575. |
| [30] | Nardone OM, Calabrese G, La Mantia A, et al. Reducing diagnostic delays of extraintestinal manifestations in inflammatory bowel disease: a comparative study of a multidisciplinary outpatient clinic versus conventional referral specialists[J]. Therap Adv Gastroenterol, 2025, 18: 17562848251323529. |
| [31] | Sayers S, Lam D, Shah Q, et al. Impact on patient outcomes of spondyloarthritis-inflammatory bowel disease multi-disciplinary meetings[J]. Rheumatology (Oxford), 2025, 64(2): 815-820. |
| [32] | Krauss O, Holzer K, Schuler A, et al. Challenges and approaches to make multidisciplinary team meetings interoperable[J]. Stud Health Technol Inform, 2017, 236: 63-69. |
| [33] | Khumalo AC, Kane BT. Perspectives on record-keeping practices in MDT meetings and meeting record utility[J]. Int J Med Inform, 2022, 161: 104711. |
| [34] | Guillo L, Savoye G, Amiot A, et al. Prevalence of and factors associated with extraintestinal manifestations and their remission in inflammatory bowel disease: the EXTRA-intestinal manifestation prospective study from the Groupe d’Etude Thérapeutique des Affections Inflammatoires du Tube Digestif[J]. Clin Transl Gastroenterol, 2023, 14(12): e00607. |
| [35] | Greuter T, Rieder F, Kucharzik T, et al. Emerging treatment options for extraintestinal manifestations in IBD[J]. Gut, 2021, 70(4): 796-802. |
| [36] | De Galan C, Truyens M, Peeters H, et al. The impact of vedolizumab and ustekinumab on articular extra-intestinal manifestations in inflammatory bowel disease patients: a real-life multicentre cohort study[J]. J Crohns Colitis, 2022, 16(11): 1676-1686. |
| [37] | Tímár áE, Párniczky A, Budai KA, et al. Beyond the gut: a systematic review and meta-analysis of advanced therapies for inflammatory bowel disease-associated extraintestinal manifestations[J]. J Crohns Colitis, 2024, 18(6): 851-863. |
| [38] | Narula N, Aruljothy A, Wong ECL, et al. The impact of ustekinumab on extraintestinal manifestations of Crohn’s disease: a post hoc analysis of the UNITI studies[J]. United European Gastroenterol J, 2021, 9(5): 581-589. |
| [39] | Jansen FM, Vavricka SR, den Broeder AA, et al. Clinical management of the most common extra-intestinal manifestations in patients with inflammatory bowel disease focused on the joints, skin and eyes[J]. United European Gastroenterol J, 2020, 8(9): 1031-1044. |
| [40] | Greuter T, Navarini A, Vavricka SR. Skin manifestations of inflammatory bowel disease[J]. Clin Rev Allergy Immunol, 2017, 53(3): 413-427. |
| [41] | Licona Vera E, Betancur Vasquez C, Peinado Acevedo JS, et al. Ocular manifestations of inflammatory bowel disease[J]. Cureus, 2023, 15(6): e40299. |
| [42] | Danve A, Deodhar A. Treatment of axial spondyloarthritis: an update[J]. Nat Rev Rheumatol, 2022, 18(4): 205-216. |
| [43] | Webers C, Ortolan A, Sepriano A, et al. Efficacy and safety of biological DMARDs: a systematic literature review informing the 2022 update of the ASAS-EULAR recommendations for the management of axial spondyloarthritis[J]. Ann Rheum Dis, 2023, 82(1): 130-141. |
| [44] | Abdel-Aty A, Gupta A, Del Priore L, et al. Management of noninfectious scleritis[J]. Ther Adv Ophthalmol, 2022, 14: 25158414211070879. |
| [45] | Maronese CA, Pimentel MA, Li MM, et al. Pyoderma gangrenosum: an updated literature review on established and emerging pharmacological treatments[J]. Am J Clin Dermatol, 2022, 23(5): 615-634. |
| [46] | Sadeghi S, Goodarzi A. Various application of tofacitinib and ruxolitinib (Janus kinase inhibitors) in dermatology and rheumatology: a review of current evidence and future perspective[J]. Dermatol Pract Concept, 2022, 12(4): e2022178. |
| [47] | Assis DN, Bowlus CL. Recent advances in the management of primary sclerosing cholangitis[J]. Clin Gastroenterol Hepatol, 2023, 21(8): 2065-2075. |
| [48] | Shah A, Jones MP, Callaghan G, et al. Efficacy and safety of biologics in primary sclerosing cholangitis with inflammatory bowel disease: a systematic review and meta-analysis[J]. Hepatol Commun, 2024, 8(1): e0347. |
| [49] | European Association for the Study of the Liver. EASL clinical practice guidelines: autoimmune hepatitis[J]. J Hepatol, 2015, 63(3): 971-1004. |
| [50] | Hertz S, Anderson JM, Nielsen HL, et al. Fecal microbiota is associated with extraintestinal manifestations in inflammatory bowel disease[J]. Ann Med, 2024, 56(1): 2338244. |
| [51] | Glassner KL, Abraham BP, Quigley EMM. The microbiome and inflammatory bowel disease[J]. J Allergy Clin Immunol, 2020, 145(1): 16-27. |
| [52] | Fan Z, Ross RP, Stanton C, et al. Lactobacillus casei CCFM1074 alleviates collagen-induced arthritis in rats via balancing Treg/Th17 and modulating the metabolites and gut microbiota[J]. Front Immunol, 2021, 12: 680073. |
| [53] | Dusek O, Fajstova A, Klimova A, et al. Severity of experimental autoimmune uveitis is reduced by pretreatment with live probiotic Escherichia coli Nissle 1917[J]. Cells, 2020, 10(1): 23. |
| [54] | Gibson GR, Hutkins R, Sanders ME, et al. Expert consensus document: the International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics[J]. Nat Rev Gastroenterol Hepatol, 2017, 14(8): 491-502. |
| [55] | Hoentjen F, Welling GW, Harmsen HJM, et al. Reduction of colitis by prebiotics in HLA-B27 transgenic rats is associated with microflora changes and immunomodulation[J]. Inflamm Bowel Dis, 2005, 11(11): 977-985. |
| [56] | Allegretti JR, Kassam Z, Carrellas M, et al. Fecal microbiota transplantation in patients with primary sclerosing cholangitis: a pilot clinical trial[J]. Am J Gastroenterol, 2019, 114(7): 1071-1079. |
| [57] | Al-Shakhshir S, Quraishi MN, Mullish B, et al. FAecal micRobiota transplantation in primary sclerosinG chOlangitis (FARGO): study protocol for a randomised, multicentre, phase Ⅱa, placebo-controlled trial[J]. BMJ Open, 2025, 15(1): e095392. |
| [58] | Eiro N, Fraile M, González-Jubete A, et al. Mesenchymal (stem) stromal cells based as new therapeutic alternative in inflammatory bowel disease: basic mechanisms, experimental and clinical evidence, and challenges[J]. Int J Mol Sci, 2022, 23(16): 8905. |
| [59] | Wang P, Li Y, Huang L, et al. Effects and safety of allogenic mesenchymal stem cell intravenous infusion in active ankylosing spondylitis patients who failed NSAIDs: a 20-week clinical trial[J]. Cell Transplant, 2014, 23(10): 1293-1303. |
| [60] | Clua-Ferré L, Suau R, Va?ó-Segarra I, et al. Therapeutic potential of mesenchymal stem cell-derived extracellular vesicles: a focus on inflammatory bowel disease[J]. Clin Transl Med, 2024, 14(11): e70075. |
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