Extraintestinal Manifestations of Inflammatory Bowel Disease PDF

E X T R A I N T E S T I N A L M A N I F E S TAT I O N S O F I N F L A M M AT O R Y B O W E L D I S E A S E Punyanganie de Silva, MBBS, MRCP, and Mital Patel, MD Ulcerative colitis (UC) and Crohn disease (CD) are the two is also some evidence to suggest that the manifestation of main...

E X T R A I N T E S T I N A L M A N I F E S TAT I O N S O F I N F L A M M AT O R Y B O W E L D I S E A S E Punyanganie de Silva, MBBS, MRCP, and Mital Patel, MD Ulcerative colitis (UC) and Crohn disease (CD) are the two is also some evidence to suggest that the manifestation of main manifestations of a broad spectrum of chronic inflam- extraintestinal organ involvement may differ depending mation defined as inflammatory bowel disease (IBD). on whether a patient has CD or UC, as demonstrated in a Although the diseases are characterized by chronic Portugese study of 792 individuals followed over 20 years, inflammatory activity of the intestinal mucosa, it is also where it was noted that EIMs were more common among well-recognized that they often involve organs other than patients with a diagnosis of CD.3 Furthermore, within this those of the gastrointestinal tract. These nonintestinal mani- large cohort, it was noted that the presence of one EIM led festations are termed extraintestinal symptoms. to an increased risk of developing another, with over 25% Various classifications of extraintestinal manifestations of individuals having multiple EIMs of IBD. The cumulative (EIMs) have been described in the literature. probability of EIMs also increased from 12% to 30% during For the purpose of this review, the EIMs of IBD can be the 20-year follow-up. Similar findings were noted in a large classified as the following: (a) true EIMs due to reactive Swiss IBD cohort with 43% of CD and 31% of UC patients IBD affecting organ systems, (b) complications secondary demonstrating at least one EIM and 12% having at least two to IBD activity, (c) non–IBD-specific autoimmune disease (CD 15%, UC 8%).4 which occurs in increased frequency in individuals with IBD [see Figure 1]. Etiology/Genetics/Pathogenesis However, it is important to bear in mind that sometimes differentiation of EIMs from extraintestinal complications The etiology of EIMs in IBD remains poorly understood. can be challenging as overlap is frequent, and it is increas- It is increasingly thought that similar to the parent disease ingly evident that multiple organ systems may be involved. of CD or UC, EIMs occur due to a combination of genetic, bacterial and immune-mediated risk factors [see Figure 2].5,6 However, because the EIMs are so broad in their presen- Epidemiology tation and organ involvement, no common factor has been The incidence of EIMs in UC and CD varies depend- isolated.2 ing on the populations studied and has been reported as A number of HLA associations have been described with ranging from between 6 to 47% of all patients with IBD.1,2 EIMs of IBD.8–11 The majority of this data has been derived Risk factors that have been associated include a familial from small studies from one single center and should be predisposition to IBD-EIM or family history of IBD, more interpreted with caution. Associations have been described extensive colonic involvement, and female gender. There with DRB1*0103 8 in type 1 peripheral arthritis, along with Classification of EIM Organ systems involved Complications of IBD Non-IBD autoimmune with reactive IBD activity and treatment disease Joints Anatomical Vitiligo Skin Thromboembolism Thyroid Eyes Bone Type 1 diabetes Hepatobiliary Renal mellitus Pulmonary Amyloidosis Pernicious anemia Neurological Multiple sclerosis Severe iron deficiency Myasthenia gravis anemia Figure 1 Classification of extraintestinal manifestations (EIM) of inflammatory bowel disease (IBD). scientific american gastroenterology, hepatology, and endoscopy © 2015 Decker Intellectual Properties Inc DOI 10.2310/7900.5418 05/15  extraintestinal manifestations of inflammatory bowel disease — 2 α4β7 integrins UC: HLAB8, DR3, DRB1 MAdCAM-1 CD: HLAB*27, VAP-1 B*35, B*44 Cutaneous IBD: TRAF3IP2 Lymphocyte Genetic migration Bacterial HLA-B27/human model β2 microglobulin transgenic model of spondylarthritis Figure 2 The etiology and pathogenesis of extraintestinal manifestations of inflammatory bowel disease (IBD). CD = Crohn disease; UC = ulcerative colitis. HLA B*27 and B*35.9 HLA-B*44 has been associated with Prognosis type II peripheral arthritis.12 Uveitis has been associated Although EIMs can correlate with intestinal disease activ- with DRB1*0103 and HLA-B*27, and erythema nodo- ity,2,6 the Swiss IBD cohort were unable to reproduce these sum with the tumor necrosis factor (TNF) promoter SNP results for CD and UC patients.4 Also, it has been noted that TNF-1031C.10 past IBD-related surgery such as colectomy does not cor- In addition, a recent case control study involving 467 indi- relate with the regression of EIM. Furthermore, these EIMs viduals with either UC or CD demonstrated that TRAF3IP2 have also been reported to occur in patients after restor- variants increase the risk of cutaneous EIMs in IBD.8 Aberrant homing of T-cells may also be involved in the ative proctocolectomy and formation of an ileo-anal pouch, pathogenesis of EIM.13 Under normal conditions, naive lym- despite the absence of pouchitis.18 Conversely, it has also phocytes migrate continuously from the blood into the lym- been noted that individuals with EIM tend to have a greater phoid tissues of the gut in search of their cognate antigens. risk of developing pouchitis after proctocolectomy and for- The lymphocyte recirculation directs naive lymphocytes mation of an ileo-anal pouch.5 into the Peyer patches in a multistep extravasation cascade It has also been noted that apart from PSC, the presence of by recognizing high endothelial venules, regulated by the EIMs does not increase an individual’s risk for dysplasia.4 expression of multiple adhesion molecules and chemokines. When the lymphocyte becomes activated, by exposure to its Organ Systems Involved with Reactive IBD: Musculoskeletal cognate antigen, the cell starts to differentiate and prolifer- Manifestations ate before returning to the systemic circulation via the effer- ent lymphatic system. The activated mucosal lymphocyte epidemiology has the ability to home back to the gut, where it arrives in Musculoskeletal manifestations involve the most common the lamina propria and exerts its effector functions Adhesion molecules that have been implicated in this reg- EIM of IBD and can range from 9 to 53% of IBD popula- ulation include mucosal addressin cellular adhesion mole- tions.4,19–21 The incidence may be underestimated due to the cule 1 (MAdCAM-1), α4β7 integrins, and vascular adhesion use of steroids, which may mitigate mild symptoms. protein 1.14 Although recent data are limited, studies have It can be broadly subclassified into articular involvement demonstrated that the reactive arthritis in IBD is mediated (arthropathies which includes axial and peripheral joint dis- by gut-derived immunoblasts that bind to synovial ves- ease), periarticular involvements (tenosynovitis/dactylitis/ sels.12 It has also been demonstrated that in IBD patients enthesitis), and arthralgias [see Figure 3]. with primary sclerosing cholangitis (PSC), there is an aber- etiology/genetics rant expression of the adhesion molecule MAdCAM-1 in the liver endothelium that enables the recruitment of T cells to Although on average roughly one third of patients with the liver.14,15 IBD suffer from arthropathies, the understanding of the gut- There is also evidence to suggest that macrophage recep- joint axis remains elusive. In ankylosing spondylitis (AS), an tors such as CD-163, which have been linked to EIMs, axial arthropathy, genetics seem to play a key role. There is may promote bacterial-induced inflammation in target a strong genetic association between HLA-B27 and patients tissues.16,17 with AS. Approximately 8% of Caucasian Europeans are scientific american gastroenterology, hepatology, and endoscopy 05/15  extraintestinal manifestations of inflammatory bowel disease — 3 Musculoskeletal manifestations Arthropathy Periarticular Arthralgia Tenosynovitis/Dactylitis/ Enthesitis Peripheral arthropathy (PA) Axial arthropathy PA type I PA type II Sacroileitis Inflammatory back pain IBD-ankylosing spondylitis (AS) Swelling and pain > 5 joints. Differentiate from Separate from AS ≤ 5 joints. Symmetrical Inflammation of SI mechanical back pain Less HLA-B27 association No deformities distribution, joint Clinical (Calin) criteria More common affecting upper 3m symptoms Large joints in the Asymptomatic/ for diagnosis limbs predominantly Lumbar: spinal back pain/ lower extremities painful metacarpophalangeals Morning stiffness stiffness Acute and self- Insidious Chronic: less likely to 20–46% of patients limiting Onset < 40 yrs Can precede IBD Correlates with IBD parallel IBD activity Associated with uveitis Duration > 3 months Does not correlate with IBD activity. Improvement with activity Joint symptoms exercise can occur prior to PA can coexist IBD dx. Associated with EN Imaging—sacroiliitis and uveitis Figure 3 Musculoskeletal manifestations of inflammatory bowel disease (IBD). dx = diagnosis; EN = erythema nodosum; SI = sacroiliac. HLA-B27-positive, and more than 90% of patients with AS diagnosis carry HLA-B27.22 Additionally, 25 to 78% of patients with IBD and AS are HLA-B27-positive.23 Interleukin 23 receptor Clinical Manifestations (IL23R) variants and the major histocompatibility complex IBD-related arthropathy This is a seronegative spon- (MHC) have also been shown to be associated with CD and dyloarthropathy and consists of a peripheral asymmetric AS, and have been mapped to a locus on the ORMDL3 gene arthropathy and axial disease involving predominantly the in lymphoblastoid cell which in turn encodes a transmem- spine and hip. brane protein and is likely involved in protein folding.24 Peripheral arthropathy is further classified into type 1 HLA is not however associated with sacroileitis. (acute pauciarticular) with involvement of less than five joints and type II ( polyarticular) with involvement of five pathogenesis or more joints. Macrophages expressing the scavenger receptor CD163 Axial arthropathy is subdivided into isolated sacroileitis, have been shown to be increased in the gut mucosa of patients inflammatory back pain, and AS. with CD, as well as in noninflamed gut mucosa and inflamed synovium of patients with spondylarthropathies.25 The CD-163 Physical Examination molecule acts as a receptor for hemoglobin-haptoglobin Type 1 peripheral arthropathy Involves large weight- complexes and mediates cell-cell interactions between macro- bearing joints, but characteristically, no joint deformities are phages and developing erythroblasts in erythroblastic islands. noted on examination. The disease tends to mimic gut dis- It is also shown to play a role in host defence, functioning as ease activity. a macrophage receptor for bacteria and promoting bacteria- induced proinflammatory cytokine production. 26 Type II peripheral arthropathy This is a polyarticular As mentioned previously, mechansims involving aberrant disease and does not mimic bowel activity. Typically, it homing of gut-primed lymphocytes to the joints have also involves the small joints, usually the metacarpophalangeal been described.27 joints of the hands. scientific american gastroenterology, hepatology, and endoscopy 05/15  extraintestinal manifestations of inflammatory bowel disease — 4 Axial arthropathy patients with IBD. Arthralgia occurs more often in patients Isolated sacroiliitis This usually consists of unilateral or with CD compared to patients with UC.33 It is a noninflam- bilateral inflammation of the sacroiliac joint. matory joint pain, and is diagnosed clinically. Physical exam- Very often, the inflammation can be asymptomatic, ination, which involves palpation of the joints, reveals pain, and it is usually an incidental diagnosis during routine but no swelling or effusion. In IBD, it may be due to several radiological investigations.28 Prevalence depends on the causes such as a delayed hypersensitivity reaction/serum radiological method used and varies from 18% in plain sickness-like reaction following anti-TNF therapy, or chronic radiographs and 32% in computed tomography (CT) widespread pain and fibromyalgia. imaging to 52% on radioisotope scintigraphy.29 Isolated sacroiliitis seems not to be associated with HLA*B27. Blood Tests Asymptomatic HLA*B27-negative patients with normal At present, there are no blood tests that are specifically spinal mobility do not require specific treatment. used to diagnose musculoskeletal manifestations. Labora- tory tests like C-reactive protein (CRP) and white blood cell Inflammatory back pain The major clinical symptom count usually reflect the bowel activity and cannot be used that differentiates inflammatory back pain from mechanical as a diagnostic tool. Depending on the type of manifestation, back pain is that it improves with exercise and not with rest. diagnosis is usually made based on clinical criteria with sup- There is also associated early morning stiffness. The onset of porting radiological information. back pain is usually insidious and tends to occur before the Aspiration of synovial fluid is necessary when an alterna- age of 40 years. In order to confirm diagnosis, symptoms tive diagnosis, such as reactive arthritis, gout, crystal-induced should be present for at least 3 months. arthritis, Lyme disease, or septic arthritis, is suspected. Ankylosing spondylitis AS is a chronic inflammatory Imaging Studies disease of the axial skeleton (sacroiliitis, spondylitis, spon- Plain films are useful when positive but often are impeded dylodiscitis, and/or enthesitis), but it can also affect other by significant inter-observer variability in reading and delay locations, for example, the peripheral joints. Chronic inflam- in the development of radiographic findings compared to mation of the spine causes sclerosis, erosions, syndesmo- the onset of clinical disease. phytes, and bony bridging of one or more intervertebral discs, Ultrasonography examination is very useful in the diag- producing the classical “bamboo spine,” resulting in loss of nosis of enthesitis and dactylitis. Ultrasound and MRI stud- the lumbar lordosis and decreased spinal mobility. Males are ies show the sausage-like appearance in dactylitis which is more frequently affected than females. AS usually starts in due to flexor tenosynovitis and peritendinous soft tissue the sacroiliac joints, and typical presentations include back or swelling in which joint synovitis is often present. buttock pain, which worsens in the morning or after rest and Bone scans are not noted to be specific for disease. MRI is relieved with exercise. A physical examination may reveal is increasingly used as the investigation of choice as it can limited spinal flexion and reduced chest expansion. identify early sacroiliac disease including bone marrow Schober test is commonly used to assess flexion of the edema, synovitis, osteitis, and inflammation of the spine in lumbar spine and extension of the cervical spine is also often axial disease.34 limited [see Table 1]. The prevalence of AS in IBD (1–6%) is higher than in the general population (0.25–1%).30 In con- management trast, the association with HLA*B27 is considerably weaker Education is very important, and physical exercise and than in idiopathic AS, with only 50 to 80% of IBD patients therapy can help maintain function and relieve symptoms. being positive for HLA B*27 compared to 94% in the general The first-line drug treatment for symptomatic patients is population.31 nonsteroidal antiinflammatory drugs. In patients with IBD and AS and with peripheral arthritis, treatment with sul- Enthesitis The prevalence of enthesitis in patients with fasalazine may be considered. Methotrexate, azathioprine, IBD varies from 5 to 10%,32 is predominantly seen in CD, and affects particularly the Achilles tendon or plantar fascia insertion, resulting in plantar fasciitis. Peripheral enthesitis may cause mild-to-severe pain and swelling, resulting in a limitation of mobility. Table 1 Modified New York Criteria for Ankylosing Spondylitis39 Dactylitis Prevalence studies of dactylitis in patients Clinical criteria Low back pain and stiffness for more than with IBD are limited, and suggest a prevalence between 2 3 months, which improves with exercise, to 4%.32 In IBD patients, dactylitis has been observed as a not relieved by rest painful and diffuse swelling of the entire finger or toe which Limitation of motion of the lumbar spine in both the sagittal and frontal planes can be diagnosed clinically with a 100% sensitivity and spec- Restriction of chest expansion relative to ificity compared with magnetic resonance imaging (MRI). normal values corrected for age and sex Radiological Bilateral sacroileitis grade ≥ 2 or unilateral Arthralgia Arthralgia is a common problem in patients criteria sacroiliitis grade 3–4 with IBD resulting in morbidity and disability. Hospital-based Definite ankylosing spondylitis if the radio- and population-based studies have reported a prevalence logical criterion is associated with at least ranging from 8 to 30% of clinically-investigated arthralgia in one clinical criterion scientific american gastroenterology, hepatology, and endoscopy 05/15  extraintestinal manifestations of inflammatory bowel disease — 5 and leflunomide are also commonly used for treatment of peripheral arthropathy. Table 2 Pulmonary Manifestations of TNF-a inhibitors are increasingly used and have demon- Inflammatory Bowel (IBD) Disease and strated to be the only effective drugs for axial disease.35–37 IBD-related Treatment Furthermore, infliximab improves the severity of pain and Large airway disease Subglottic stenosis duration of morning stiffness of joint symptoms in CD.35 Chronic suppurative airway disease Although the fusion protein etanercept is effective in AS, it Small airway disease Chronic bronchitis is not effective in IBD, and there have been reported cases of Bronchiectasis paradoxical IBD development following etanercept use.38,39 Chronic bronchiolitis Granulomatous bronchiolitis complications Interstitial lung Secondary organizing pneumonia Musculoskeletal involvement often leads to significantly disease (bronchiolitis obliterans with organizing pneumonia) impaired mobility and can result in reduced quality of life. Nonspecific interstitial infiltrates with In axial disease, there is also the risk of developing pseu- lymphocytes or eosinophils doarthroses and spine instability with resulting neurological Necrobiotic pulmo- Cavitating sequelae. nary nodules Noncavitating Serositis Pleuritis Organ Systems Involved with Reactive IBD: Pulmonary Pericarditis Pleuropericarditis Manifestations Myopericarditis epidemiology Pulmonary vasculitis — Symptomatic pulmonary involvement is a relatively rare Common pulmonary Hypersensitivity pneumonitis manifestation of IBD but is well-recognized. It is known to manifestations of Eosinophilic lung disease side effects of IBD Inflammatory interstitial lung disease affect any part of the pulmonary tree, and seems to be more treatment Secondary organizing pneumonia common in UC.40 These manifestations can be broadly clas- Granulomatous lung disease sified into large airway inflammatory disease, small airway Pulmonary fibrosis inflammatory disease, interstitial lung disease, necrobiotic Serositis Infection related to immune suppression parenchymal nodules, serositis, and side effects related to medications used for the management of IBD [see Table 2]. Pulmonary embolism — Pulmonary function test abnormalities have also been noted in various studies and range from 18 to 45%.40 The majority of patients were, however, asymptomatic from a respiratory reported, along with inflammation involving every part of standpoint. the pulmonary tree in patients with IBD.43 The inflammation Patient demographics, IBD duration before presentation, results in airway narrowing and can progress to bronchiec- and overall type and severity of pulmonary involvement tasis or bronchiolitis obliterans. In reports of IBD-associated varies.41 Pulmonary EIMs of IBD usually follow the devel- pulmonary interstitial disease, pulmonary infiltrates with opment of classic gastrointestinal IBD. However, pulmonary eosinophilia and necrobiotic nodules resembling pyoderma disease can develop concomitantly with IBD or precede the gangrenosum (PG) have been described. development of classic gastrointestinal IBD. Thoracic serositis includes the development of pleu- ritis, pericarditis, pleuropericarditis, or myopericarditis etiology/genetics [see Figure 4].44 This EIM is the least reported among the pul- The etiology varies according to the pulmonary manifes- monary complications of IBD, and due to its rare occurrence, tation. Given the relative paucity of pulmonary IBD cases in it is difficult to attribute specific risk factors or disease mech- anisms. IBD patients can develop pleural effusions that can the literature, published data on genetic variants are limited. be directly or indirectly related to the disease activity, such However, for CD and sarcoidosis, a common susceptibility as sympathetic pleural effusions related to the subdiaphrag- locus has been identified through genome-wide association matic activity and complications of IBD (e.g., abscess or analysis on chromosome 10p12.2.42 Pulmonary EIM of IBD bowel perforation), or parapneumonic effusions related to may also be related to the common embryological origin of the development of pneumonia in the immunosuppressed the gastrointestinal tract and pulmonary epithelium from patient. the primitive foregut. Both tracts are lined by epithelial layers, mucosal glands, and goblet cells, and contain sub- diagnosis mucosal lymphoid tissue, which are constantly challenged by inhaled or ingested antigens. It is unclear whether the Clinical Manifestations pathophysiology of IBD or its pulmonary EIM represents an Symptoms involving airways disease are consistent with overactive systemic inflammatory response or a decreased the location of respiratory tree involvement. local regulation of the immune response. Upper airway and medium-sized bronchiolar involve- ment result frequently in cough and copious amounts of pathogenesis sputum. Epiglottis and tracheobronchitis present with Pathogenesis can vary depending on the site affected. shortness of breath and dysphonia. Bronchiolitis and inter- Anatomical abnormalities leading to fistulas have been stitial disease result in dyspnea and cough. Colobronchial, scientific american gastroenterology, hepatology, and endoscopy 05/15  extraintestinal manifestations of inflammatory bowel disease — 6 a b c d Figure 4 Pulmonary manifestation of inflammatory bowel disease. (a) Lingula mass consistent with granulomatous disease prior to commence- ment of anti-tumor necrosis factor (anti-TNF) therapy. (b) Resolution of lingula mass following commencement of anti-TNF therapy. (c) Biopsy of mass, high power. Histology showing evidence of granulomatous infiltration. (d) Biopsy of mass, low power. esophagobronchial, and ileobronchial fistulae have also management been reported and should be considered in patients with The treatment of CD-related airway diseases depends on CD affected by frequent episodes of pneumonitis or in the the specific pattern of involvement, and if left untreated, the presence of intestinal anaerobic flora in the sputum. patient will be put at risk of developing irreversible destruc- In addition to the above symptoms, serositis can also tion. In the majority of patients with airway diseases, marked present with febrile episodes. Drug-induced pulmonary and long-lasting responses are seen following systemic or reactions can occur, particularly related to sulfasalazine and inhaled steroids. Bronchial lavages with methylpredniso- mesalamine, and are seen between 2 and 6 months of drug lone are also effective in some patients with severe airway administration. inflammation. In mesalamine- and sulfasalazine-induced pulmonary dis- Physical Examination ease, resolution usually occurs with discontinuing the drug. Findings on clinical examination will correspond to the Supportive steroids are not universally required, yet they location of disease involvement. Airways disease often have been shown to hasten recovery in severely ill patients. shows reduced air entry with no additional sounds, whereas Definitive diagnosis of drug reaction can be diagnosed by bilateral fine crepitations are noted on auscultation in inter- rechallenge with the inciting agent, although this is not nec- essary, but symptoms do resolve in most cases within a few stitial lung disease. Patients with serositis may demonstrate days to weeks after withdrawal of the offending agent. In the clinical signs consistent with a pleural effusion. published literature, biologic agents such as anti-TNFs have Investigations been shown to increase the risk of infection and reactivation of tuberculosis. Management consists of withdrawing the A combination of radiological investigations and pulmo- immunosuppressant and treating with appropriate antimi- nary function tests are used to diagnose pulmonary IBD. crobial/antifungal coverage. Reports of fistulae treated with In addition, as in the case of granulomatous disease, bron- conservative bowel rest and steroids have been published, chioalveolar lavage and biopsy may be useful in order to although the majority required wedge resection of the lung. differentiate extraintestinal CD from other chronic inflamma- Most cases of patients with concomitant granulomatous dis- tory conditions such as sarcoidosis or granulomatosis with ease of the gastrointestinal tract and lung are treated with polyangiitis. [see Table 3]. steroids, but the use of anti-TNFs has also been reported. scientific american gastroenterology, hepatology, and endoscopy 05/15  extraintestinal manifestations of inflammatory bowel disease — 7 Table 3 Diagnostic Techniques in Lung Disorders Associated with Inflammatory Bowel Disease Drug-Induced Diagnostic Test Airways Disease Interstitial Disease Granulomatous Disease Serositis Disease Chest x-ray and Clear Patchy focal opacities/ Patchy opacities and Pleural effusion Bilateral infiltrates CT imaging diffuse infiltrates/air increased mediastinal or opacities bronchograms shadow Bilateral lung infiltrates/ hilar lymphadenop- athies Bronchoscopy/ Inflammation and — — — Eosinophils Bronchioalveolar narrowing of the Lymphocytic lavage tracheal and/or alveolitis, bronchial lumen reversed CD4/ CD8 ratio Sputum Intestinal anaerobic — — — — bacteria when fistulas present Histology Metaplastic epithelial Acute alveolitis, gran- Granulomas, macro- Nonspecific Interstitial changes, granulo- ulomatous lympho- phages in alveolar inflammatory pneumonitis, matous infiltra- cytic infiltration of spaces, neutrophilic changes granuloma tion, ulceration the interstitium, infiltrates in blood formation and arteriolar walls, and capillaries bronchiolitis interstitial fibrosis Pulmonary Obstructive pattern Restrictive pattern — — Reduced diffusion function test capacity Thoracocentesis — — — Predominantly — neutrophils CT = computed tomography. complications identified, along with EN and PTGER4, ITGAL, SOCS, Respiratory compromise can occur secondary to infection CD207, ITGB3, and rs6828740.47 and reduced respiratory reserve. Prompt treatment with pathogenesis appropriate antibiotic or steroid therapy and drug with- The dermatologic manifestations of IBD can be broadly drawal where appropriate usually results in good progno- classified into four main categories each having their own sis. Enteropulmonary/colopulmonary fistulae have been underlying pathogenesis [see Table 4, Table 5, Table 6, Table 7, reported to result in life-threatening septicemia and in such Table 8, Table 9, Figure 5, Figure 6, Figure 7, Figure 8, Figure 9]: cases, surgical resection is necessary. 1. Specific cutaneous manifestations or granulomatous cutaneous lesions with the same histological features as Organ Systems Involved with Reactive IBD: the underlying bowel disease Dermatological Manifestations 2. Reactive cutaneous manifestation of IBD with immu- nological mechanisms triggered by common antigens epidemiology shared by gut bacteria and skin Cutaneous manifestations make up common EIMs of 3. Cutaneous disorders or dermatosis associated with IBD, IBD, affecting 22 to 75% of patients with CD and 5 to 11% of which share genetic predispositions as well as specific patients with UC. The most common cutaneous manifesta- immune response patterns and common inflammatory tions are erythema nodosum (EN), PG, aphthous stomatitis, pathways and perianal fissures and fistulae.45,46 In addition, nutritional 4. Secondary cutaneous manifestations either due to com- deficiencies secondary to IBD as well as IBD therapies can plications of IBD or adverse effects of IBD treatments lead to secondary skin manifestations. Importantly, skin It has been proposed that classes 1 and 2 may be a result of findings can parallel or in some instances precede intesti- immune dysregulation, resulting in a lymphocyte-mediated nal activity, emphasizing the need to better identify these destructive process.27 findings. Several cutaneous manifestations, including perianal dis- ease, orofacial disease, EN, aphthous ulcers, Sweet syndrome etiology/genetics (SS), and leukocytoclastic vasculitis can closely parallel the Studies regarding the etiology and genetics of cutane- course of intestinal disease, providing important informa- ous CD- and IBD-associated dermatological manifestations tion on the overall disease state. Conditions such as PG and remain limited. Recently, genetic associations with PG and metastatic CD can have a clinical course independent of the the IBD loci IL8RA, PRDM1, USP15 and TIMP3 have been intestinal disease. Additionally, conditions such as Sweet scientific american gastroenterology, hepatology, and endoscopy 05/15  extraintestinal manifestations of inflammatory bowel disease — 8 Table 4 Dermatologic Manifestations of recognize cutaneous manifestations that reflect underlying luminal disease activity and those that are a direct result of Inflammatory Bowel Disease (IBD) Based on IBD therapy or IBD complications are important caveats. Classifications A diagnosis of dermatologic manifestations of IBD is Disease specific cutaneous Perianal, orofacial, metastatic established based on history, clinical features, and physical manifestations [see Crohn disease examination. In some instances, laboratory tests, skin biopsy Table 5] for histopathologic correlation, and imaging can aid con- Reactive cutaneous mani- Erythema nodosum, pyoderma firming a diagnosis. The main dermatologic manifestations festations [see Table 6] gangrenosum, pyostomatitis of each of the four classifications discussed above are further vegetans, oral aphthous ulcers, Sweet syndrome, leukocytoclastic elaborated below [see Tables 5, Tables 6, Tables 7, Tables 8, vasculitis, bowel-associated Tables 9]. dermatosis-arthritis syndrome management Associated cutaneous dis- Psoriasis, hidradenitis suppura- orders [see Table 7] tiva, acquired epidermolysis The treatment approach varies depending on the individ- bullosa, vitiligo ual cutaneous manifestation [see Table 10]. Secondary cutaneous Zinc deficiency, iron deficiency manifestations due to anemia, essential fatty acid complications complications of IBD [see deficiency IBD-related cutaneous manifestations generally respond Table 8 and Table 9] well to therapy. However, perianal CD can be very difficult Secondary cutaneous mani- Nonmelanoma skin cancers, to treat, requiring medical and surgical therapy and sig- festations due to adverse melanoma, psoriasis effects of IBD therapy nificantly impacting patients’ quality of life. PG can have a [see Table 8 and Table 9] severe refractory course, and often control of the underlying IBD does not lead to improvement of the PG. Lesions of PG can become superinfected, requiring antibiotics, and heal with permanent cribriform scarring. Major apthous ulcers syndrome and leukocytoclastic vasculitis can occur in con- can also be quite deep and painful, making it difficult to junction with intestinal disease but also as a side effect of maintain oral intake and can lead to significant scarring of the IBD medications. the oral mucosa. Malignant skin complications secondary to anti-TNF-a and diagnosis immunosuppressive therapy are a growing complication in It is important that the gastroenterologist be aware of the patients with IBD.49,50 Patients should be advised to comply varying manifestations and refer appropriately for confirmation with recommendations for sun protection, which include of diagnosis and management. Furthermore, the ability to the use of sun protective clothing as well as use of high sun Table 5 Specific Cutaneous Manifestations or Granulomatous Cutaneous Lesions with the Same Histological Features as the Underlying Bowel Disease Laboratory and Diagnosis: Clinical Manifestations and Physical Examination Incidence Imaging Contiguous Mucocutaneous Lesions: Perianal Multiple morphologies: perianal fissures, abscesses, fistulas; CD: 25–80% 27 Clinical impression, include: anal ulcers, skin tags, and anal stenosis sigmoidoscopy may Most common: perianal fissures, abscesses and fistulas be needed to assess Perianal fissures are typically found posteriorly and are often abscesses and fistulas painless Perianal abscesses are frequently multiple, complex, and very painful Perianal fistulas can be internal or enterocutaneous27,80 Orofacial Multiple morphologies: linear fissures, ulcers, swelling of the CD: 8–9% 80 Clinical impression and labial and buccal mucosa, angular chelitis, cobblestone appear- (seldom) skin/mucosal ance of the buccal mucosa and vestibule biopsy Most common: linear fissures and/or ulcers of the vestibule Fibrosis and adhesions can occur as sequelae of these lesions27,80 Noncontiguous Mucocutaneous Lesions: Metastatic Crohn Two forms: Genital and extragenital Rare Clinical impression and disease [see Figure 5] Genital: Labial or scrotal erythema and swelling, more common skin biopsy in children Extragenital: erythematous plaques and subcutaneous nodules, which can form nonhealing ulcerations, most commonly on the lower legs and abdomen80,81 scientific american gastroenterology, hepatology, and endoscopy 05/15  extraintestinal manifestations of inflammatory bowel disease — 9 Table 6 Reactive Cutaneous Manifestation of Inflammatory Bowel Disease (IBD) with Immunological Mechanisms Triggered by Common Antigens Shared by Gut Bacteria and Skin Diagnosis Clinical Manifestation and Physical Examination Incidence Laboratory and Imaging Erythema nodosum Crops of tender erythematous nodules Up to 15% Clinical impression Most common location: bilateral shins in IBD rarely requires skin Rarely: on the thighs, arms, abdomen, and face biopsy Does not ulcerate and typically heals without scarring Reactive process which can be: idiopathic, secondary to medications, postinfectious or sarcoidosis27,80 Pyoderma gangrenosum Chronic recurrent ulcerative process CD: 1–2% Sterile skin biopsy of (PG) [see Figure 6] Four clinical forms: ulcerative, bullous, pustular, and superficial UC: up to active lesion granulomatous 12% Tissue culture (bacte- Pustular form most frequent in IBD rial, mycobacterial, Initial lesions: tender papulopustule, nodule, or bulla with fungal, and viral) surrounding erythema, which undergo necrosis and ulcerate Ulcers: well demarcated with a necrotic purulent base and an undermined gunmetal-gray colored border Occur as single or multiple lesions and vary in size Most common location in IBD patients: lower legs and peristomal region Can occur as a single lesion or as multiple lesions and vary greatly in size Exhibit pathergy27,80,82 Oral aphthous ulcers Two main forms: minor and major Common Clinical impression; [see Figure 7] Minor aphthae: more common, round shallow, painful, sharply seldom requires a demarcated ulcers covered by a creamy-white to grey with an skin biopsy for erythematous border that are usually < 5 mm in diameter confirmation Major aphthae: larger and deeper ulcerations, > 1 cm, that may heal with scarring Most common location: buccal and labial mucosa, lateral and ventral tongue, soft palate, and oropharynx27,80 Pyostomatitis vegetans Multiple, small, pinpoint pustules arranged linearly on an Rare Clinical impression erythematous background and skin biopsy for Pustules are easily ruptured, leaving multiple erosions and superficial confirmation ulcerations Most common location: labial, gingival, and buccal mucosa80 Sweet syndrome (SS) Acute febrile neutrophilic dermatosis Rare Clinical impression [see Figure 8] Fever and tender edematous erythematous to violaceous papules and CD > UC and skin biopsy for nodules which enlarge or coalesce to form plaques with an uneven confirmation surface CBC: leukocytosis with Edema within lesions give them pseudovesicular or pseudopustular neutrophilia appearance; however, some patients can develop true vesiculation, bullae, or pustules Lesions classically occur on the head and neck, back and dorsal surface of the hands Constitutional symptoms: malaise, headaches, and arthralgias Rarely, extracutaneous manifestations involving the eyes, muscles, bones, lungs, kidneys, liver, pancreas, and central nervous system Reactive process can also be idiopathic, paraneoplastic, or associated with infections, autoimmune disorders, pregnancy, and drugs27 Leukocytoclastic Neutrophilic dermatosis with palpable purpura, which can develop Rare Clinical diagnosis; skin vasculitis [see into necrotic ulcers biopsy for confirma- Figure 9] Most common location: lower extremities and ankles27 tion may be needed Hypersensitivity reaction that can be idiopathic, paraneoplastic, or secondary to infections, autoimmune conditions, or drugs Bowel-associated Neutrophilic dermatosis with fever, diarrhea, arthritis of small Rare Clinical impression dermatosis-arthritis peripheral joints, and a cutaneous eruption and skin biopsy for syndrome Erythematous macules, which progress to papules and purpuric confirmation vesicopustules; they are clinically and PG-like in nature Electrolytes should be Recurrent tender erythematous subcutaneous nodules are also seen, monitored because of may be associated with fever, which can mimic SS risk of diarrhea Most commonly seen following bowel bypass surgery, but can be Liver function seen in patients with IBD Likely caused by bacterial overgrowth in a blind loop of bowel, leading to immune complex deposition within the skin and synovium27,80,82 CBC = complete blood count; CD = Crohn disease; UC = ulcerative colitis. scientific american gastroenterology, hepatology, and endoscopy 05/15  extraintestinal manifestations of inflammatory bowel disease — 10 Table 7 Cutaneous Disorders or Dermatosis Associated with Inflammatory Bowel Disease Cutaneous Disorder Skin Lesions Psoriasis 1. Well-demarcated erythematous plaques with silvery scale; commonly on the elbows, knees , back, 1. Chronic plaque and scalp 2. Palmoplantar 2. Erythematous scaly plaques with deep-seeded pustules on the palms and soles 3. Inverse 3. Well-demarcated brightly erythematous plaques with or without scale involving the skin folds: axilla, inframammary, inguinal folds, abdominal folds, intergluteal cleft Hidradenitis suppurativa Painful inflamed nodules and sterile abscesses associated with drainage which develop into deep sinus tracts, fistulae, and hypertrophic scars seen in the skin folds Acquired epidermolysis acquisita Noninflammatory subepidermal tense blisters secondary to autoantibodies to collagen type IV/V Most commonly affects areas of trauma such as the hands and feet; mucosa can also be involved Vitiligo Irregularly shaped depigmented patches commonly on the face, hands, feet, elbow, knees, and genitals protection factor barrier. Yearly full-skin examinations with Organ Systems Involved with Reactive IBD: Ophthalmic a dermatologist can help with early recognition of nonmela- Manifestations noma skin cancer (NMSC) and melanoma, which will reduce epidemiology the risk of invasive disease. However, it is important to remember that a preceding history of skin cancer may be a True ocular manifestations are relatively infrequent and relative contraindication to commencing thiopurine therapy, presumed to involve 2 to 10% of all IBD cases.53 The vast given the relatively higher risk of this complication.51,52 majority of cases have been limited to case reports and series. Prevalence and incidence remain topics of some prognosis debate as some tertiary center surveys indicate that ocular findings in IBD patients may be significantly more prevalent In general, the prognosis for cutaneous manifestations of (as high as 60%) when a thorough evaluation by an oph- IBD is quite favorable. thalmologist is performed,54 whereas other studies contra- The specific cutaneous manifestations of IBD typically dict these findings. A recent study suggested that although respond well to standard IBD treatments. Reactive lesions ocular symptoms may be frequent in IBD, they are nonspe- such as EN and SS are self-limited conditions that respond cific, and rarely associated with true ocular inflammation.55 well to standard therapy and can self resolve. Patients with metastatic CD and PG often require long-term multimodal etiology/genetics therapies and this can lead to significant morbidity. Although the etiology of orbital inflammatory disease in In the case of drug-induced psoriasis, withdrawal of the patients with IBD is unknown, it is generally thought that offending agent can lead to resolution.50 Early referral and immune-mediated processes are involved. For example, management of IBD therapy–induced NMSC has a good an immune-complex-type hypersensitivity reaction to a prognosis with favorable response to standard therapies. colonic antigen has been suggested. This view is supported Table 8 Secondary Cutaneous Manifestations due to Complications of Inflammatory Bowel Disease (IBD) IBD-related Complication Skin Lesions Zinc deficiency (acrodermatitis enteropathica) Sharply demarcated, erythematous plaques with scale-crust; occasionally form intact vesicles/bullae commonly head and neck, hands, feet, genitalia Iron deficiency anemia Angular chelitis, pale skin, koilonychia Essential fatty acid deficiency Xeroderma/eczema Table 9 Secondary Cutaneous Manifestations due to Adverse Effects of Inflammatory Bowel Disease (IBD) Treatment IBD Treatment Adverse Effects of Treatment Immunosuppressive therapy Immunosuppressive medications increase risk for squamous cell carcinoma, basal cell carcinoma, and to a lesser extent, melanoma.52 Yearly full skin examinations are recommended for patients on these therapies. Oral corticosteroids Acne, striae Anti-TNF-a; agents [see Figure 10] Induced psoriasis and lupus erythematosus53 TNF = tumor necrosis factor. scientific american gastroenterology, hepatology, and endoscopy 05/15  extraintestinal manifestations of inflammatory bowel disease — 11 Figure 7 Oral apthous ulcers. Figure 5 Metastatic Crohn disease of the intergluteal cleft. a Figure 8 Sweet syndrome. b Figure 9 Leucocytoclastic vasculitis. pathogenesis The ocular manifestations of IBD can be broadly classified into four main categories, each with a differing underlying Figure 6 (a) Early pyoderma gangrenosum. (b) Advanced pyoderma pathogenesis. gangrenosum. 1. Ocular manifestations of IBD. These are the most common ophthalmic manifestations of IBD and consist chiefly of uveitis [see Figure 11] and episcleritis [see Figure 12]. 2. Orbital complications secondary to IBD. These are rare by the observation that IBD patients with colitis or ileo- but potentially blinding EIMs of IBD that involve the colitis are more likely to have ocular inflammation than extraocular muscles, lacrimal gland, or posterior sclera. those with only small bowel disease.56 IBD susceptibility 3. Optic nerve complications in patients with IBD. This can loci such as HOXA11S, HOXA13, HORMAD2, IL27 have occur due to damage of the optic nerve tissue per se as also demonstrated an increased association with ocular a result of inflammat ion and/or ischemia, intracranial manifestations.57 hypertension, or secondary to anti-TNF agents. Although scientific american gastroenterology, hepatology, and endoscopy 05/15  extraintestinal manifestations of inflammatory bowel disease — 12 Table 10 Treatment of Dermatological Manifestations of Inflammatory Bowel Disease (IBD) Cutaneous Condition Treatment Options Contiguous mucocutaneous lesions: orofacial Treatment of underlying intestinal disease and perianal Crohn disease (CD) Metastatic CD Oral metronidazole (250 mg three times daily) combined with topical or intralesional corticosteroids Systemic corticosteroids, sulfasalazine, azathioprine, 6-mercaptopurine, infliximab, and adalimumab Surgical excision for refractory genital lesions Erythema nodosum (EN) Treatment of the bowel disease will lead to resolution of EN Symptomatic treatment for pain as needed Pyoderma gangrenosum Treatment can be challenging: Diligent wound care Mainstay treatment: systemic steroids Evidence to support the use of other agents including: azathioprine, dapsone, sulfasala- zine, mycophenolate mofetil, methotrexate, etanercept, infliximab, and adalimumab Multimodal therapy to heal ulceration is often needed Aphthous ulcers Local anesthetics Potent topical corticosteroids, intralesional, or inhaled corticosteroid Topical tacrolimus Colchicine, dapsone, thalidomide Pyostomatitis vegetans Treatment of the underlying intestinal disease Sweet syndrome Few lesions: potent topical or intralesional corticosteroids Most effective: systemic steroids for 4–6 weeks Alternative (or maintenance): potassium iodide, dapsone, and colchicine Leukocytoclastic vasculitis Minor: treatment of underlying intestinal disease Chronic: dapsone, colchicine Ulcerative: systemic corticosteroids Bowel-associated dermatosis-arthritis Mild disease: oral antibiotics (tetracycline, minocycline, doxycycline, clindamycin, metro- syndrome nidazole), colchicine, dapsone, thalidomide Severe disease: prednisone, cyclosporine, azathioprine, mycophenolate mofetil, TNF-a; inhibitors Surgically, revision of the bowel bypass or surgical resection of the blind loop of bowel is curative TNF = tumor necrosis factor. the pathomechanism responsible for neuroretinitis, papil- neuropathy is related to occlusion of the vascular bed litis, and retrobulbar neuritis is related to direct involve- supplying the optic nerve secondary to inflammation or ment of neural tissue by peripapillary or retrobulbar hypercoagulability. inflammation, the pathomechanism of ischemic optic 4. Damage secondary to intracranial hypertension. a b Figure 10 (a and b) Anti-tumor necrosis factor–induced psoriasis. scientific american gastroenterology, hepatology, and endoscopy 05/15  extraintestinal manifestations of inflammatory bowel disease — 13 and visual field testing should not be neglected during follow-up. In addition, some manifestations such as episcleritis usu- ally resolve with IBD treatment. complications The main complication of ocular manifestations of IBD is potential irreversible damage to visual acuity as described above, and in the case of prior anti-TNF therapy, the associ- ation with multiple sclerosis. prognosis Recurrences of retrobulbar neuritis are not uncommon. In the case of orbital pseudotumors and myositis, recurrences are common on withdrawing steroids. Given the association of anti-TNF and demyelinating optic neuropathy, which is potentially irreversible, close monitoring of anti-TNF-a- treated patients for the occurrence of ophthalmic or neuro- logical symptoms and signs is necessary. In such an event, Figure 11 Uveitis. discontinuation of the anti-TNF-a agent and commence- ment of steroid treatment are mandatory. diagnosis Organ Systems Involved with Reactive IBD: Diagnosis of ophthalmic manifestations of IBD varies Hepatobiliary Manifestations depending on pathogenesis and is explained in greater detail in Table 11. epidemiology Up to 30% of IBD patients may have abnormal liver func- management tion tests.58 Although liver and biliary tract diseases are Episcleritis usually resolves with IBD treatment. The common EIMs for both CD and UC, they do not typically management of patients with ocular manifestations mainly correlate with intestinal activity. consists of steroid administration per eye or intravenously. The typical dose involves prednisone at a dose of 1 mg/kg/ Primary Sclerosing Cholangitis day. In most patients, the response is favorable with rapid PSC is the most common hepatobiliary manifestation and control of symptoms. Anti-TNF-a agents such as infliximab is more prevalent in UC. Of all UC patients 2.2 to 7.5% and and adalimumab have also been shown to be useful in case 0.7 to 3.4% of all CD patients will develop PSC. Sixty to 75% reports and short series of patients. In extreme cases, surgi- of PSC patients have coexisting UC, whereas it is approxi- cal orbital decompression may be required. Because orbital mately 5% in CD patients. UC patients with pancolitis are inflammatory disease can pose a significant danger to the more at risk than those with disease limited to the left side. optic nerve if severe and/or long-standing, visual acuity Prevalence rates for PSC in North America and Europe range from six to 16 cases per 100,000 population with an incidence of one per 100,000 persons. Lower estimates have been reported from Asia and Southern Europe.59 There is also a 2:1 male prevalence. The disease is usually diagnosed by the age of 40 years. Other hepatobiliary manifestations include autoimmune hepatitis (AIH), immunoglobulin (Ig)G4-associated chol- angiopathy, primary biliary cirrhosis, hepatic amyloidosis, granulomatous hepatitis, cholelithiasis, portal vein throm- bosis, liver abscess, and hepatitis B reactivation secondary to immunosuppressive therapy [see Table 12]. In addition, it is well-recognized that IBD therapies are associated with liver disease. Methotrexate-induced hepatotoxicity has been described in 14% of patients with IBD, in a dose-dependent manner. Cases of infliximab-induced hepatotoxicity have also been reported. Thiopurines are associated with hepa- totoxicity, veno-occlusive disease, and regenerative nodular hyperplasia. etiology/genetics PSC etiology remains unclear. It is believed that a combi- Figure 12 Episcleritis. nation of genetic, immunological, and environmental factors scientific american gastroenterology, hepatology, and endoscopy 05/15  extraintestinal manifestations of inflammatory bowel disease — 14 Table 11 Diagnosis of Ophthalmological Manifestations of Inflammatory Bowel Disease (IBD) Laboratory and Diagnosis: Clinical Manifestations and Physical Examination Incidence Imaging Ocular Manifestations of IBD 1. Episcleritis Painless hyperemia of the conjunctiva and sclera 25–80% of all ocular Split lamp imaging No visual changes manifestations in Parallels IBD luminal disease course IBD 2. Uveitis Inflammation of the middle chamber of the eye 2–10% of all IBD Split lamp imaging Commonly presents with pain, photophobia, red eye, patients 17% of all blurry vision, or floaters ocular manifesta- Permanent visual deficits may occur tions in IBD Can occur independent of IBD activity Associated with IBD-related spondylarthropathy Orbital Complications Secondary to IBD 1. Orbital pseudotumor Enlargement of retrobulbar anatomical elements Rare , but more Split lamp imaging. occurs due to inflammation common in CD. MRI/CT imaging Symptoms and signs often resemble retrobulbar Not associated with tumours intestinal disease Retro-orbital pain (often worse at night and/or activity. with eye movements), diplopia, ophthalmoplegia, proptosis, eyelid swelling, decreased vision, conjunctival chemosis, and infection are common 2. Orbital myositis One or more of the extraocular muscles are affected Not known CT scans of eyes show Characteristically, patients will experience symptoms indistinct swelling that are acute in onset, with severe pain inside, around one or more behind, or around the eye. muscles with no Pain on eye movement; occasional diplopia and specific pattern of conjunctival chemosis have been reported which muscle is enlarged 3. Scleritis Painful disease of the sclera (either anterior or poste- Associated with both Clinical impression and rior segment) CD and UC ultrasonography for Prognosis better with anterior scleritis; may lead posterior scleritis to significant visual impairment if not treated promptly 4. Dacryoadenitis Tender swelling of the upper eyelids with discomfort Very rare Slit lamp examination and lacrimation Associated with CD Usually parallels IBD activity Optic Nerve Complications in Patients with Inflammatory Bowel Disease 1. Damage due to 1a. Symptoms include painless blurring of vision and Associated with both 1a. Fundoscopy/fluorescent inflammatory and/or variable decline of visual acuity UC and CD, and angiography can reveal ischemic insults No association with intestinal activity anti-TNF use. Usu- inflammation of the optic ally arises several nerve and retina. 1.a neuroretinitis, 1b. Blurry and/or decreased vision over a period of months after anti- 1b. Fundoscopy is often papillitis, ischemic few hours to several days, but is often accompa- TNF initiation normal. Pallor is noted optic neuropathy nied by retrobulbar pain, sometimes worsening May be related to after recurrent episodes. with eye movements and at night time anti-TNF dose and MRI reveals optic nerve 1.b optic (demyelinat- 1c. Sudden painless visual acuity decline, frequently duration demyelination. ing/ retrobulbar ) accompanied by an altitudinal visual field defect 1c. Fundoscopy often neuritis reveals optic disc 1.c ischemic optic swelling with tiny neuropathy splinter hemorrhages and indistinct optic disc margins MRI/CT Damage Due to Intracranial Hypertension Intracranial hypertension Headache, nausea, vomiting, tinnitus, neck or back Rare Fundoscopy and MRI/CT pain, blurred or dimmed vision, visual field Limited to case imaging scotomas, and short episodes of vision loss or reports flashing lights Known to be associated with high dose steroid use, and cerebral vein/sinus thrombosis secondary to hypercoaguable state in IBD Case reports have been noted with patients taking mesalamines and sulfasalazines CD = Crohn disease; CT = computed tomography; MRI = magnetic resonance imaging; TNF = tumor necrosis factor; UC = ulcerative colitis. scientific american gastroenterology, hepatology, and endoscopy 05/15  extraintestinal manifestations of inflammatory bowel disease — 15 Table 12 Other Hepatobiliary Manifestations of Inflammatory Bowel Disease (IBD) Clinical Manifestations and Laboratory and Diagnosis Physical Examination Incidence Imaging Management Autoimmune Features of AIH and PSC are More common in UC Elevated liver autoim- Corticosteroid therapy, alone hepatitis/ present in the same patient mune antibodies or in conjunction with PSC overlap Histological features of UDCA syndrome both PSC and AIH Cyclosporine, mycophenolate (AIH/PSC) mofetil, and budesonide have been beneficial in selected patients IgG4-associated Early obstructive jaundice 9–36% of patients with MRCP: similar appear- Corticosteroid therapy; good cholangio­ Systemic organ involvement; PSC ance to PSC prognosis with treatment pathy (IAC) elevated serum IgG4 levels Histopathology: dense Azathioprines also of benefit (135 mg/dL) lymphoplasmacytic infiltration; storiform fibrosis; mild-to-mod- erate eosinophil infiltration; rich in IgG4-positive plasma cells Cholelithiasis Abdominal pain, jaundice, fever More common in CD Ultrasound scan imaging Antibiotics, surgical resection Presumed to be due to abnormal Especially ileitis and malabsorption of bile acids, postileal resection reduced gallbladder motil- (13–34%) ity, and increased gallstone Doubled risk of cholesterol concentrations cholelithiasis in IBD patients compared to healthy controls Granulomatous Increase in cholestatic enzymes Rare Granulomas noted on Corticosteroid therapy hepatitis such as alkaline phosphatase Associated with CD liver biopsy Associated with sulfasalazines, infections, CD metastasis Drug-induced Drug-induced hepatitis 30% of all IBD patients Liver tests may show Routine liver biochemical liver injury Azathioprine will demonstrate transaminitis tests are recommended in 6-mercaptopurine some abnormality on In cases of persistent all patients on methotrex- Methotrexate liver function testing elevated transami- ate, thiopurine, or biologic Cyclosporin Abnormal liver tests nases, consider liver therapy, especially during Infliximab noted in 2% of all biopsy the first month of treat- IBD patients on Transient elastography ment Reactivation of hepatitis B mesalamine, 25% on to assess fibrosis 6–12 monthly liver tests for Anti-TNF therapy methotrexate, 3–10% patients on biologics Corticosteroids on thiopurines Withdraw/ reduce dose of Azathioprine culprit drug Drug-induced pancreatitis Azathioprine 6-mercaptopurine Methotrexate Hepatosplenic T cell lymphoma Combination anti-TNF and immunosuppressive therapy CD = Crohn disease; IgG = immunoglobulin G; MRCP = magnetic resonance cholangiography; PSC = primary sclerosing cholangitis; TNF = tumor necrosis factor; UC = ulcerative colitis; UDCA = ursodeoxycholic acid. contribute to disease activity. Multiple genetic factors asso- pathogenesis ciated with susceptibility have been described, and include In addition to a genetic predisposition, translocation of HLA-B8, HLADRB1* 0301 (DR3), HLADRB3*0101 (DRw52a), microbial flora across an inflamed, permeable gut with sub- and HLA-DRB1*0401 (DR4). In addition, UC susceptibility sequent activation of the immune system and inflammation loci on CARD9, REL, and IL2 have been associated with PSC. of the biliary tree has been hypothesized. Atypical p-ANCA In addition to genetic risk factors, the presence of autoanti- appears to cross-react with human b-tubulin isotype 5 and bodies have been noted in patients: antiinuclear antibodies the bacterial protein FtsZ, which is expressed by intestinal in 24 to 53%, smooth muscle antibodies in 13 to 20%, and flora.60 The interaction between the adhesion molecules vascular antiperinuclear cytoplasmic antibodies (p-ANCA) in 65 to cell adhesion molecule-1 and MAdCAM-1 along with lym- 88% of patients. phocyte recruitment to the liver via chemokines such as CCL scientific american gastroenterology, hepatology, and endoscopy 05/15  extraintestinal manifestations of inflammatory bowel disease — 16 25, CCL28, CXCL12, and CXCL 16 are emerging important concepts in PSC pathogenesis. diagnosis Clinical Manifestations PSC in IBD has unique characteristics, and the clinical fea- tures of this unique presentation have remained stable over time. A shift in the timing of diagnosis of the two diseases has occurred in recent years, with PSC being more often diagnosed first. The majority of patients have mild pancoli- tis, whereas rectal sparing and backwash ileitis has been noted in one third and one fourth of patients, respectively. Patients are often diagnosed incidentally, and nearly 50% are asymptomatic. However, PSC patients have shorter aver- Figure 13 Primary sclerosing cholangitis: characteristic beading age times of survival compared to matched controls from appearance of intrahepatic ducts. the general population. Five years after diagnosis, approxi- mately 22% show clinical symptoms, and after 6 years, up to 76% have some evidence of disease progression.59 Nearly 6% of patients with abnormal liver function tests Pathology and IBD, but normal imaging have concurrent small-duct PSC. Individuals with small-duct PSC have symptoms and Liver biopsy is useful in staging the disease and deter- laboratory results similar to those of subjects with clas- mining prognosis. Features characteristically seen include sic PSC but survive longer and have a lower cumulative fibrous obliteration of small bile ducts, with periductal con- risk for cholangiocarcinoma than patients with large-duct centric fibrosis in an “onion skin” pattern. Other abnormali- involvement. ties are nonspecific and similar to those in primary biliary cirrhosis. Physical Examination management Fatigue, abdominal pain, jaundice, and fever have been noted in approximately one third of patients with PSC. All randomized controlled trials of agents designed to pre- vent PSC progression have produced negative results, despite Laboratory Tests promising results from open-label precursor studies. The most The most common biochemical abnormality detected is an commonly studied agent is ursodeoxycholic acid (UDCA), which significantly slows progression of other chronic bil- increased serum level of alkaline phosphatase, although this iary diseases, such as primary biliary cirrhosis. However, can vary throughout the disease course and may be normal, UDCA has not demonstrated an increase in survival times of or even reduced to three- to fourfold below the upper patients with PSC compared to placebo.62 Although there is no limit of normal.61 Higher values may suggest acute biliary clear role for UDCA therapy at this time, the safety profile of obstruction or even an overlap syndrome with AIH. Total moderate-dose UDCA (17.23 mg/kg/day) indicates that it bilirubin is increased only among patients with significant could be worth further examination in prospective trials. The stricturing. Serum levels of albumin, international normal- American Association for the Study of Liver Diseases recom- ized ratios, and platelet counts are typically normal unless mends against UDCA therapy for PSC, whereas the European cirrhosis and portal hypertension have developed. Unlike Association for the Study of Liver Diseases does not provide primary biliary cirrhosis, there is no diagnostic serologic test recommendations for or against treatment with UDCA, based that is specifically associated with PSC. Serologic tests might on the limited data available.63 be useful for patients suspected of having PSC and AIH, or IgG4-associated cholangitis in association with autoimmune complications pancreatitis. PSC-IBD is a progressive disease and ultimately as with Imaging Studies non–IBD-associated PSC, results in portal hypertension, cir- rhosis, and hepatic failure. Survival is significantly worse Diagnosis is established by the demonstration of diffuse, in symptomatic patients at the time of diagnosis, and PSC- multifo