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- Review Pathogenesis and clinical perspectives of extraintestinal manifestations in inflammatory bowel diseases
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Jung Min Kim1
, Jae Hee Cheon1,2,3 -
Intestinal Research 2020;18(3):249-264.
DOI: https://doi.org/10.5217/ir.2019.00128
Published online: April 18, 2020
1Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
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Correspondence to Jae Hee Cheon, Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea. Tel: +82-2-2228-1990, Fax: +82-2-393-6884, E-mail: geniushee@yuhs.ac
• Received: October 11, 2019 • Revised: November 25, 2019 • Accepted: March 6, 2020
© Copyright 2020. Korean Association for the Study of Intestinal Diseases. All rights reserved.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
- A considerable number of patients with inflammatory bowel disease (IBD) experience extraintestinal manifestations (EIMs), which can present either before or after IBD diagnosis. Unraveling the pathogenic pathways of EIMs in IBD is challenging because of the lack of reliable criteria for diagnosis and difficulty in distinguishing EIMs from external pathologies caused by drugs or other etiologies. Optimizing treatment can also be difficult. Early diagnosis and management of EIM revolve around multidisciplinary teams, and they should have the resources necessary to make and implement appropriate decisions. In addition, specialists of the affected organs should be trained in IBD treatment. Furthermore, patient awareness regarding the extraintestinal symptoms of IBD is of paramount importance for improving patient understanding of disease and health outcomes. Herein, we review the pathogenesis and clinical perspectives of EIMs in IBD.
INTRODUCTION
WHY ARE EIMs IMPORTANT IN IBD?
PATHOGENESIS OF EIMs
CLINICAL ASPECTS OF EIMs
TREATMENT FOR EIMs INCLUDING BIOLOGICS
KEY RECOMMENDATIONS FOR IMPROVING THE DISEASE COURSE AND PRINCIPLES TO BE APPLIED TO TREATMENT
CONCLUSIONS
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FINANCIAL SUPPORT
The authors received no financial support for the research, authorship, and/or publication of this article.
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CONFLICT OF INTEREST
Cheon JH has been the Editor of MIntestinal Research since 2013. However, he was not involved in the peer reviewer selection, evaluation, or decision of this article. Except for that, no potential conflict of interest relevant to this article was reported.
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AUTHOR CONTRIBUTION
Conceptualization, methodology, writing - original draft preparation: Kim JM. Writing - review and editing: Cheon JH. Supervision project administration: Cheon JH. Approval of final manuscript: all author.
NOTES
Fig. 1.Mechanisms of extraintestinal manifestations (EIMs). (a) Activation and expansion of effector memory T cells can lead to induction of mucosal vascular addressin cell adhesion molecule 1 and C-C motif chemokine ligand 25 (CCL25) expression in the liver. (b) Intercellular adhesion molecule-1, vascular adhesion protein-1, and vascular cell adhesion molecule 1 are associated with T cell trafficking. (c) Microbial antigens and materials translocate to extraintestinal sites and drive EIMs. (d) Circulating antibodies can provoke an autoimmune response and peptide(s) expressing common epitopes shared by colon and extra-colonic organs. (e) Neutrophil priming and alteration of circulating monocytes and macrophages can induce intestinal inflammation and are associated with innate immune responses. (f) Gut dysbiosis drives non-intestinal inflammation and increases mucosal permeability and lipopolysaccharides.
Table 1.Extraintestinal Manifestations and Complications Associated with IBD
Table 2.Diagnosis of Extraintestinal Manifestations
HLA-B27, human leukocyte antigen-B27; ECG, electrocardiography; TTE, transthoracic echocardiography; TEE, transesophageal echocardiography; MRA, magnetic resonance angiography; PSC, primary sclerosing cholangitis; MRCP, magnetic resonance cholangio pancreatography; ERCP, endoscopic retrograde cholangiopancreatography; PTC, percutaneous transhepatic cholangiography; NAFLD, nonalcoholic fatty liver disease; US, ultrasound; MRS, magnetic resonance spectroscopy.
Table 3.Treatments for Extraintestinal Manifestations
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Pathogenesis and clinical perspectives of extraintestinal manifestations in inflammatory bowel diseases
Fig. 1. Mechanisms of extraintestinal manifestations (EIMs). (a) Activation and expansion of effector memory T cells can lead to induction of mucosal vascular addressin cell adhesion molecule 1 and C-C motif chemokine ligand 25 (CCL25) expression in the liver. (b) Intercellular adhesion molecule-1, vascular adhesion protein-1, and vascular cell adhesion molecule 1 are associated with T cell trafficking. (c) Microbial antigens and materials translocate to extraintestinal sites and drive EIMs. (d) Circulating antibodies can provoke an autoimmune response and peptide(s) expressing common epitopes shared by colon and extra-colonic organs. (e) Neutrophil priming and alteration of circulating monocytes and macrophages can induce intestinal inflammation and are associated with innate immune responses. (f) Gut dysbiosis drives non-intestinal inflammation and increases mucosal permeability and lipopolysaccharides.
Fig. 1.
Pathogenesis and clinical perspectives of extraintestinal manifestations in inflammatory bowel diseases
| System | Extraintestinal manifestations (prevalence) |
Complications of IBD |
||
|---|---|---|---|---|
| Directly related to bowel disease activity | Not related to bowel disease activity | Unclear relationship to bowel disease activity | IBD or its treatment | |
| Joints/bone | Peripheral arthropathy (2%–20%) | - | ||
| Type 1 peripheral arthritis | Type 2 peripheral arthritis | Metabolic bone disease | ||
| Pauciarthritis | Ankylosing spondylitis (3%–20%) | Osteoporosis/osteopenia | ||
| Axial arthritis (3%–25%) | ||||
| Skin | Erythema nodosum (1%– 15%) | - | Pyoderma gangrenosum (1%–12%) | Drug-induced skin disease (anti-TNF-induced psoriasis, DIL-E) |
| Drug hypersensitivity | ||||
| Drug-induced skin cancer | ||||
| Eye | Episcleritis (<1%) | Uveitis (3%–11%) | - | Drug-induced cataracts |
| Cardiovascular | - | - | Infective endocarditis (0.2%–2.8%) | Drug-induced myocarditis |
| Takayasu’s arteritis (<1%) | Drug-induced pericarditis | |||
| Pericarditis (<1%) | ||||
| Hepato-pancreato-biliary | - | - | Primary sclerosing cholangitis (0.2%–7.5%) | Drug-induced liver injury |
| Nonalcoholic fatty liver disease (8%–59%) | Drug-induced pancreatitis | |||
| Autoimmune hepatitis (0.6%–1.6%) | GB stones | |||
| Granulomatous hepatitis (<1%) | Portal vein thrombosis | |||
| Coagulopathy | - | - | - | Venous thromboembolism |
| System | Extraintestinal manifestations | Diagnosis | |
|---|---|---|---|
| Musculoskeletal/joint | Spondyloarthritis | Assessment of SpondyloArthritis International Society modified Berlin algorithm | |
| Without radiographic sacroiliitis | |||
| HLA-B27 testing | |||
| Evaluated for sacroiliitis by MRI | |||
| Ankylosing spondylitis | Modified New York Classification criteria (≥1 radiological and ≥1 clinical) | ||
| Clinical criteria | |||
| Back pain and stiffness (≥3 months), improves with exercise, but is not relieved by rest | |||
| Limitation of motion of the lumbar spine in both the sagittal and frontal planes | |||
| Limitation of chest expansion relative to normal values correlated for age and sex | |||
| Radiological criterion | |||
| Image of sacroiliitis (grade ≥2 bilaterally or grade ≥3 unilaterally) | |||
| Skin | Erythema nodosum | Patient history and physical examination | |
| Skin biopsy | |||
| Pyoderma gangrenosum | Diagnostic criteria (≥ 1 major & ≥ 4 minor) | ||
| Biopsy of ulcer edge demonstrating neutrophilic infiltrate | |||
| Biopsy of ulcer edge | |||
| Minor criteria | |||
| Exclusion of infection | |||
| Pathergy | |||
| Personal history and history of papule, pustule, or vesicle | |||
| Peripheral erythema, undermining border, and tenderness at site of ulceration | |||
| Multiple ulcerations (≥ 1 anterior lower leg) | |||
| Cribriform or “wrinkled paper” scar(s) | |||
| Decrease in ulcer size within 1 month of initiating immunosuppressive medications | |||
| Psoriasis | History and physical examination (Koebner phenomenon) | ||
| Skin biopsy (punch biopsy) | |||
| Eczema | Diagnostic criteria | ||
| Evidence of pruritic skin, including the report by a parent of a child rubbing or scratching | |||
| In addition to itchy skin, 3 or more of the following are needed to make the diagnosis: | |||
| History of skin, asthma or hay fever | |||
| Dry skin within the past year | |||
| Symptoms beginning in a child (<2 years of age) | |||
| Visible dermatitis involving flexural surfaces | |||
| Eye | Episcleritis/scleritis | History and physical examination | |
| Slit-lamp biomicroscopy (ophthalmologist) | |||
| Uveitis (anterior or posterior) | History and physical examination | ||
| Slit-lamp biomicroscopy (ophthalmologist) | |||
| Cardiovascular | Infective endocarditis | Fever±relevant cardiac risk factors or other predisposing conditions | |
| Modified Duke criteria | |||
| ECG, CT, TTE, TEE, or chest X-ray | |||
| Takayasu's arteritis | Clinical findings | ||
| MRA or CT angiography | |||
| Pericarditis | ECG, echocardiography or chest X-ray | ||
| Hepato-pancreato-biliary | PSC | MRCP, ERCP, PTC | |
| NAFLD | History and rule out other disorders | ||
| US, vibration controlled transient elastography | |||
| CT, MRI or MRS | |||
| Liver biopsy | |||
| Coagulopathy | Thromboembolism | Compression ultrasonography with Doppler | |
| CT | |||
| System | Extraintestinal manifestations | NSAIDs | Corticosteroids | 5-ASA | MTX/AZA | Immunomodulators | Anti-TNFs |
|---|---|---|---|---|---|---|---|
| Musculoskeletal/joint | Spondyloarthritis | ○ | - | ○ | - | - | ○ |
| Ankylosing spondylitis | ○ | - | △ | △ | - | ○ | |
| Peripheral arthritis | ○ | ○ | ◎ | ○ | - | ○ | |
| Skin | Erythema nodosum | ○ | ◎ | - | - | - | ○ |
| Pyoderma gangrenosum | - | ◎ | - | - | ○ | ○ | |
| Eye | Episcleritis/scleritis | ○ | ○ | - | △ | - | △ |
| Uveitis | - | ○ | - | △ | △ | △ | |
| Hepatobiliary | PSC | Ursodeoxycholic acid, ERCP and liver transplantation | |||||
| Autoimmune hepatitis | Prednisolone alone or in combination with azathioprine | ||||||
| Granulomatous hepatitis | - | ○ | - | - | ○ | ○ | |
| Coagulopathy | Deep vein thrombosis | Low-molecular-weight heparin, low-dose unfractionated heparin or fondaparinux | |||||
| Pulmonary embolism | Vitamin K antagonist (acenocoumarol, warfarin, fluindione) | ||||||
| Thromboembolism | Non-vitamin K antagonist oral anticoagulants (dabigatran, rivaroxaban, apixaban, and edoxaban) | ||||||
Table 1. Extraintestinal Manifestations and Complications Associated with IBD
DIL-E, drug-induced lupus erythematosus; GB, gallbladder.
Table 2. Diagnosis of Extraintestinal Manifestations
HLA-B27, human leukocyte antigen-B27; ECG, electrocardiography; TTE, transthoracic echocardiography; TEE, transesophageal echocardiography; MRA, magnetic resonance angiography; PSC, primary sclerosing cholangitis; MRCP, magnetic resonance cholangio pancreatography; ERCP, endoscopic retrograde cholangiopancreatography; PTC, percutaneous transhepatic cholangiography; NAFLD, nonalcoholic fatty liver disease; US, ultrasound; MRS, magnetic resonance spectroscopy.
Table 3. Treatments for Extraintestinal Manifestations
5-ASA, 5-aminosalicylic acid; MTX, methotrexate; AZA, azathioprine; PSC, primary sclerosing cholangitis; ERCP, endoscopic retrograde cholangiopancreatography; ◎, recommended; ○, available; △, controversial.
