Pulmonary Manifestations of Inflammatory Bowel Disease

Journal Pre-proof Pulmonary Manifestations of Inflammatory Bowel Disease

Annie Massart, Daniel P. Hunt PII:

S0002-9343(19)30584-4

DOI:

https://doi.org/10.1016/j.amjmed.2019.07.007

Reference:

AJM 15287

To appear in:

The American Journal of Medicine

Please cite this article as: A. Massart and D.P. Hunt, Pulmonary Manifestations of Inflammatory Bowel Disease, The American Journal of Medicine(2019), https://doi.org/ 10.1016/j.amjmed.2019.07.007

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© 2019 Published by Elsevier.

JournalBOWEL Pre-proof PULM MANIFESTATIONS OF INFLAMMATORY DISEASE Title: Pulmonary Manifestations of Inflammatory Bowel Disease Authors: Annie Massart, MDa,b and Daniel P. Hunt, MDa a

Corresponding author contact information: Email address: [email protected] Phone : 404-778-5334 Fax : 404-778-4181

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Emory University School of Medicine Division of Hospital Medicine 1364 Clifton Rd., NE Box M-7 Atlanta, GA 30322

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The authors were both involved in writing this narrative review article.

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Conflicts of interest : None to disclose Funding: None

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Key words: Inflammatory Bowel Disease, extraintestinal manifestations, pulmonary manifestations

Abstract Pulmonary manifestations of inflammatory bowel disease are increasingly recognized in patients with Ulcerative Colitis and Crohn’s disease. Most commonly, incidental abnormalities

JournalBOWEL Pre-proof PULM MANIFESTATIONS OF INFLAMMATORY DISEASE are noted on chest imaging or pulmonary function tests. Although clinically significant pulmonary disease is less common, it can carry significant morbidity for patients. We review the presenting symptoms, workup, and management for several of the more common forms of inflammatory bowel disease related pulmonary disease. Increased awareness of the spectrum of extraintestinal inflammatory bowel disease will help providers more readily recognize this

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phenomena in their own patients and more comprehensively address the protean sequelae of

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inflammatory bowel disease.

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Pulmonary Manifestations of Inflammatory Bowel Disease

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Introduction

The number of patients in the United Status with inflammatory bowel disease (either Crohn’s

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disease or ulcerative colitis) has risen in recent years, from 2 million in 1999 to 3 million in

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2015.1 Both Crohn’s disease and ulcerative colitis have been associated with extraintestinal

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manifestations of disease. As many as 21-41% of inflammatory bowel disease patients will develop extraintestinal manifestations during their lifetime.2,3 Patients who develop one form of extraintestinal manifestations are more likely to develop additional extraintestinal manifestations.4 While these extraintestinal manifestations commonly occur in the skin, joints, and eyes,3 there is increasing recognition of clinically significant pulmonary extraintestinal manifestations that may go unrecognized if providers are not vigilant. In addition, subclinical pulmonary involvement is commonly apparent when assessed by pulmonary function testing or high resolution computed tomography.5,6

JournalBOWEL Pre-proof PULM MANIFESTATIONS OF INFLAMMATORY DISEASE

In this review, we will review the presenting symptoms, workup, and management for several of the more common forms of inflammatory bowel disease related pulmonary disease.

First described in 1976 by Kraft, et al., pulmonary manifestations of inflammatory bowel

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disease present with a diverse array of phenotypes.7 This includes disease of the airways, lung parenchyma, pulmonary vasculature, and rarely the serosa as outlined in Table 1. Most

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commonly, patients with lung involvement do not report pulmonary symptoms, yet as many as

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37-55% of inflammatory bowel disease patients manifest abnormalities in their pulmonary

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function tests (PFTs) and/or abnormalities on chest imaging.5,8 As many as 90% of patients with

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active bowel disease demonstrate abnormal PFTs.9 The most common abnormalities include decreased diffusing capacity for carbon monoxide (DLCO) and forced expiratory volume in one

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second (FEV1).10,11 Imaging abnormalities are variable, including both airways disease

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(bronchitis, bronchiectasis) and parenchymal disease (alveolitis, fibrosis). While imaging is

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abnormal 37-53% of the time,5,6 affected patients present with respiratory symptoms far less frequently, only ~10% of the time in one large retrospective study.5

Although the pathophysiologic mechanisms are not fully understood, evolving data suggests that there is a “lung-gut axis” underpinning these shared disease states. A growing body of literature demonstrates the scope of pulmonary diseases connected to inflammatory bowel disease.9,12,13 Similarly, patients with chronic lung disease have been found to have an increased risk of developing gastrointestinal disease.14,15 There are several hypotheses about

JournalBOWEL Pre-proof PULM MANIFESTATIONS OF INFLAMMATORY DISEASE connections within the “lung-gut axis”. The lungs and the intestines are derived from the same embryonic cell line, the foregut region of the endoderm.16 They share a common epithelium with its columnar cell lining, goblet cells, and submucosal lymphoid tissue. The lymphoid tissue is a key component of host mucosal defense.17 The lung and gut may develop similar inflammatory reactions because of these shared anatomical features. A second possibility, the shared antigen theory, notes that gut and lung epithelia are exposed to the same antigens and

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this shared exposure may induce similar inflammation in both systems.18 Experimental models

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demonstrated changes in cytokine levels and epithelial breakdown when intestinal epithelium

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is exposed to airway antigens that are similar to changes in the lung epithelia when they are

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exposed to that same antigen.19

Other theories focus on the systemic impacts of inflammation in inflammatory bowel disease

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and how the lung may be involved. During activation of the cellular immune system,

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lymphocytes follow a chemokine and receptor-based homing system to migrate to the

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appropriate tissue.20 In patients with inflammatory bowel disease, this homing system becomes less specific and lymphocytes may invade the gut as well as other organs such as the lungs. 21 The aberrant migration of inflammatory cells to other organs may explain the basis for extraintestinal manifestations in general.

While the focus of hospitalizations for patients with inflammatory bowel disease is often related to their gastrointestinal symptoms, patients may report dyspnea or cough. Although

JournalBOWEL Pre-proof PULM MANIFESTATIONS OF INFLAMMATORY DISEASE these are nonspecific and ubiquitous symptoms that might be dismissed, they may also be the first presentation of lung disease.

Medication-related lung disease Although it is not a direct effect of inflammatory bowel disease, medication-related lung injury is the most common non-infectious cause of lung disease in inflammatory bowel disease

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patients.22 The development of new respiratory symptoms or unexplained abnormalities on

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chest imaging may be caused by medications and drug cessation may be sufficient to address

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the insult. Several medications used to treat inflammatory bowel disease may cause lung injury:

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sulfasalazine, mesalamine, azathioprine, 6-mercaptopurine, methotrexate, as well as the anti-

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TNF monoclonal antibodies. Given the potential for life-threatening respiratory failure, treating physicians must have a high index of suspicion for this complication and immediately stop the

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medication if drug-related lung injury is suspected.

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Differentiating between inflammatory bowel disease related lung disease vs medication induced lung disease can be very difficult. See Table 2. The former is more likely to affect the airways while the latter is more likely to affect the parenchyma but that does not preclude the opposite from being true for a given patient. After infection is ruled out, imaging and bronchoscopy facilitate further evaluation. For many patients, tissue sampling may be necessary for definitive diagnosis.

JournalBOWEL Pre-proof PULM MANIFESTATIONS OF INFLAMMATORY DISEASE There are numerous case reports of mesalamine and sulfasalazine causing acute lung injury. In general, the onset of symptoms can begin 5 days to several years after initiating the medication.23 Patients typically present with dyspnea, fever, and non-productive cough.24 There is often associated hypoxemia which can range from mild to severe.23 Imaging will often reveal bilateral infiltrates while eosinophilia in the serum and/or in BAL fluid is common.24 Lung histopathology may demonstrate a wide variety of findings, including bronchiolitis obliterans,

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interstitial lymphocytic infiltrates, lymphocytic alveolitis, non-necrotizing granulomas,24

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eosinophilic pneumonia25 , and hypereosinophilic obliterative bronchiolitis.26 Most patients

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have rapid improvement after stopping the medication, while others require systemic

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steroids.23 The majority of patients experience a full recovery after cessation of the offending

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agent.23

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The purine analogs, azathioprine and 6-mercaptopurine (6MP), are another class of

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medications commonly used to treat inflammatory bowel disease. Case reports implicate these

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medications, primarily azathioprine, in drug-induced lung injury. Patients usually present with fever, dry cough, dyspnea, and hypoxemia.27 Symptoms often occur within 1-4 months of medication initiation, but may develop as late as two years after starting the drug.27 Patients may present with interstitial pneumonitis, bronchiolitis obliterans with organizing pneumonia, 27 or diffuse alveolar damage.28 Patients may experience a rapid and severe deterioration, with multiple cases reporting the need for mechanical ventilation.27 Treatment includes stopping the medication, often combined with systemic steroids.27 Some patients make a full recovery while others are left with chronic lung damage.27 Given the risk of severe respiratory failure, treating

JournalBOWEL Pre-proof PULM MANIFESTATIONS OF INFLAMMATORY DISEASE physicians must have a low-threshold to consider this phenomenon as a potential explanation for new, progressive pulmonary dysfunction in patients who were recently started on azathioprine or 6MP.

Methotrexate pneumonitis is a well-established adverse effect in a variety of different patient populations (with most of the data coming from rheumatology patients). It can present as acute,

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subacute, or more rarely chronic pneumonitis.29 Symptoms usually include fever, dyspnea, and

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dry cough.29 Although it may occur at any point during treatment, it is often within several

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months of starting.29 Imaging often shows diffuse infiltrates that may be interstitial, alveolar, or

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both.29 Bronchoalveolar fluid often reveals lymphocytosis with an increase in CD4 or CD8

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lymphocytes.29 Histopathology may reveal cellular interstitial infiltrates or diffuse alveolar damage.29 Most patients respond rapidly to withdrawal of methotrexate while some also find

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benefit from systemic steroids.29

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As the anti-TNFα medications (infliximab, adalimumab, certolizumab) are increasingly utilized for inflammatory bowel disease patients, potential adverse effects have emerged. Patients most commonly present with dyspnea, fever, and cough.30 Imaging often reveals bilateral consolidations and/or ground glass opacities.30 Lung injury occurs within the first few doses of the medication.30 Most patients experience significant improvement over weeks to months after the medication is stopped and often with the addition of systemic steroids. 30

Airway disease

JournalBOWEL Pre-proof PULM MANIFESTATIONS OF INFLAMMATORY DISEASE Inflammation of the airways is the most common manifestation of inflammatory bowel disease in the lungs.16 Airway involvement most often develops months to years after the initial presentation of the inflammatory bowel disease and often presents when GI disease is quiescent.31 Disease in the large airways is more common than the small airways.17 It is generally more common in patients with ulcerative colitis than Crohn’s disease and has a female predominance.17 Some patients may develop chronic symptoms, especially those who

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develop irreversible processes like bronchiectasis.17 In addition to evaluating for infections,

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clinicians should have a low threshold to evaluate for noninfectious inflammatory processes.

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Most patients with large airway disease present with dyspnea, wheezing, productive cough, or

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chest pain.31 This inflammation can target any segment of the bronchial tree. Of patients with large airway disease, about 2/3 will have bronchiectasis while the second most common

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manifestation is chronic bronchitis.17 Although rare, patients may present with stridor from

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subglottic stenosis after developing tracheitis.32 This can progress to airway compromise and

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requires urgent evaluation and management. First presentations of large airway disease are commonly associated with quiescent GI disease and, interestingly, patients may have recently undergone colectomy.31 There is a hypothesis that the inflammatory process that had previously targeted the colon can transfer its effects to the lungs after colectomy. 33

Clinically significant small airways disease is uncommon among inflammatory bowel disease patients.17 While large airway disease generally occurs well after inflammatory bowel disease diagnosis, small airways disease presents before the inflammatory bowel disease has

JournalBOWEL Pre-proof PULM MANIFESTATIONS OF INFLAMMATORY DISEASE manifested in 29% of cases.17 Small airway disease usually manifests as bronchiolitis and histologically may have any of several disease patterns including bronchiolitis obliterans, granulomatous bronchiolitis, or diffuse panbronchiolitis.34 More commonly, incidental findings are discovered in asymptomatic patients and include CT scans demonstrating centrilobular micronodules, “tree in bud” changes, and/or air trapping.34 Inflammatory bowel disease

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patients are also more likely to have asymptomatic abnormalities in their pulmonary function tests suggestive of small airways disease, including decreased FEV1, FEV1/forced vital capacity

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ratio, forced expiratory flow 25-75%, and/or a decrease in the DLCO.16

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When investigating potential airway involvement, initial diagnostics include imaging which may

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reveal peribronchial thickening, bronchiectasis, and air trapping.16 Bronchoscopy may demonstrate erythematous, inflamed airways that resemble the endoscopic changes seen on

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colonoscopy in inflammatory bowel disease patients.35 Otherwise, bronchoscopy can allow for

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culture collection, tissue sampling, and checking cell counts on the BAL which are often

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elevated and often demonstrate lymphocytosis and frequently neutrophilia.31

Once infection has been ruled out, management involves steroids. Inhaled steroids may be used for mild symptoms from large airway disease while systemic steroids are first line for severe symptoms.31 In general, patients with large airway involvement are more responsive to steroids, regardless of their route of administration, than those patients with small airways disease who tend to have a more refractory course.33

JournalBOWEL Pre-proof PULM MANIFESTATIONS OF INFLAMMATORY DISEASE Parenchymal disease Parenchymal abnormalities are uncommon manifestations of inflammatory bowel disease although a variety of patterns have been noted. Evaluating for this disease manifestation is complicated by the potential drug-induced lung injury discussed earlier, which often involves the parenchyma. Patients with parenchymal involvement are more likely to have ulcerative

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colitis than Crohn’s disease and there is a slight female predominance.17 Patients typically present with a combination of exertional dyspnea, cough (dry or productive), fever, and/or

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pleuritic chest pain.34 About half of patients have cryptogenic organizing pneumonia, 17 while

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rare cases have been reported of eosinophilic pneumonia, nonspecific interstitial pneumonia,

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fibrosis, and necrobiotic nodules.34 Treatment begins with systemic steroids and most patients

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respond well.31 Other immunosuppressant agents have been used in more severe cases, including cyclophosphamide36 and anti-TNFα agents.31 Rarely, patients develop fibrosis that is

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Clinical approach

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not steroid responsive resulting in a poor prognosis.31

For patients with inflammatory bowel disease who present with respiratory symptoms (cough, dyspnea, fever, chest discomfort) and abnormal chest imaging, the work-up should initially consider the possibility of infection. Depending on patient characteristics, clinical presentation, and degree of immunosuppression, the work-up may consider bacterial, fungal, mycobacterial etiologies. For patients presenting with predominant dyspnea and/or chest discomfort, consideration should be given to the possibility of pulmonary embolism given the increased risk of venous thromboembolism in patients with inflammatory bowel disease.37 Next, the

JournalBOWEL Pre-proof PULM MANIFESTATIONS OF INFLAMMATORY DISEASE evaluating clinician should give careful scrutiny to medications in view of known pulmonary adverse effects. Potentially causative medications should be discontinued. If there are no apparent medication etiologies, the patient deteriorates despite medication elimination, or the pulmonary process is severe, the evaluation should consider whether the pulmonary process is directly related to the underlying inflammatory bowel disease. Diagnostic studies might include

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high resolution lung CT, bronchoscopy, and/or video-assisted thoracoscopic surgery for biopsy. Effective management of patients with inflammatory bowel disease and pulmonary illness

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requires a multi-disciplinary approach that may include the general internist/hospitalist,

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gastroenterologist, infectious disease specialist, and pulmonologist.

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Summary

The lung-gut axis remains poorly understood, but the growing numbers of documented cases

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highlight the clinical relevance for our patients. Acute hospitalizations are often associated with

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active bowel disease, medication adjustments, and immobility that can serve as risk factors for

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a variety of pulmonary pathologies. When treating patients with known or suspected inflammatory bowel disease, clinicians should have a low threshold for aggressively evaluating respiratory symptoms as they may be the first sign of an evolving lung disease.

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Table 138 Lung Involvement in IBD Bronchiectasis Chronic bronchitis Interstitial lung disease Organizing pneumonia Chronic suppurative bronchitis Subglottic stenosis Necrobiotic nodules Chronic bronchiolitis Pulmonary infiltrates and eosinophilia Fibrosing alveolitis Tracheobronchitis Pleuritis Epiglottitis

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Table 2 Features of Medication induced lung injury vs IBD related lung disease Features Medication induced lung injury IBD related lung disease Triggers New medication in recent weeksActive IBD, or no triggers months Symptoms Dyspnea, fever, cough, chest pain Dyspnea, fever, cough, chest pain Involved areas Parenchyma > Airways Airways > Parenchyma Management Hold medication, consider steroids Steroids (inhaled vs systemic) Prognosis Risk for permanent lung damage Chronic pulmonary dysfunction (azathioprine, 6-mercaptopurine, common, significant chronic methotrexate >> mesalamine, symptoms are uncommon sulfasalazine, TNF antagonists)

Clinical Significance  Inflammatory bowel disease frequently impacts lung function and can lead to clinically significant pulmonary disease. 

Pulmonary manifestations of inflammatory bowel disease present with diverse phenotypes and may cause severe symptoms and disease.



Several medications used to treat inflammatory bowel disease can cause lung injury which is often difficult to tease out.



Increased awareness of the pulmonary sequelae of inflammatory bowel disease will help providers recognize, evaluate and manage them effectively.