INFLAMMATORY BOWEL DISEASE - PART 8 pot

Cohen © Humana Press Inc., Totowa, NJ Ulcerative colitis UC and Crohn’s disease CD are associated with a wide variety of extraintestinal manifestations EIM that often maketheir managemen

From: Clinical Gastroenterology:

Inflammatory Bowel Disease: Diagnosis and Therapeutics

Edited by: R D Cohen © Humana Press Inc., Totowa, NJ

Ulcerative colitis (UC) and Crohn’s disease (CD) are associated with

a wide variety of extraintestinal manifestations (EIM) that often maketheir management difficult and are significant causes of morbidity andmortality (Fig 1) An EIM can occur before, concomitant with, or after

the diagnosis of the specific type of inflammatory bowel disease (IBD),and in some cases may even follow surgical removal of the diseasedbowel Large case studies have demonstrated that between 25% and

35% of patients with either type of IBD will have at least one EIM (1,2).

Multiple EIMs may occur in the same patient with the triad of skin involvement being the most common

joint-eye-There have been several attempts to classify the EIMs of IBD (Table 1).Greenstein classified them into three groups according to the location ofintestinal inflammation: colon related (joint, eye, skin, and oral mani-festations); small bowel related (malabsorption, nephrolithiasis,cholelithiasis); and nonspecific manifestations (osteoporosis, liver dis-

ease, amyloidosis) (1) An alternative classification based on the

Fig 1 Extraintestinal Manifestations of Inflammatory Bowel Disease

inflammatory bowel activity divided EIMs into three categories: thoserelated to the intestinal disease activity that usually respond to treat-ment of the underlying bowel disease (colitic arthritis, episcleritis,erythema nodosum); those whose course appears to be independent ofthe underlying bowel disease activity (ankylosing spondylitis, pyodermagangrenosum, primary sclerosing cholangitis); and those that are adirect result of the presence of diseased bowel (fistulas, ureteral

obstruction, nutritional deficiencies) (3).

This chapter provides an overview of the clinical aspects of the morecommon extraintestinal manifestations associated with UC and CD

PATHOGENESIS

Little is known about the basis for the different organ distribution andthe characteristic combinations of EIMs in IBD patients While someextracolonic manifestations have clear etiologic factors (e.g., cholelithi-asis, fistulous communications, or side effects of drugs used to treatIBD), the pathophysiology of the main groups of EIM is not clearlyunderstood, and both autoimmunity and genetic susceptibility seem toplay an important role Several observations support the importance ofautoimmunity in the pathogenesis of the EIM in IBD: relationshipbetween EIM and the extent of colonic involvement, association of IBDwith a number of autoimmune diseases (e.g., psoriasis, rheumatoid arthri-tis, thyroid diseases), increased incidence of autoimmune disorders in

c Nonspecific manifestations: osteoporosis, liver disease, amyloidosis

2 According to the inflammatory bowel activityb

a Bowel disease activity related: colitic arthritis, episcleritis, erythemanodosum

b Bowel disease activity unrelated: ankylosing spondylitis, pyodermagangrenosum, primary sclerosing cholangitis

c Direct result of diseased bowel: fistulas, ureteral obstruction, nutritionaldeficiencies

patients with UC compared to the general population, clinical response

of EIM to immunosuppressive therapy, and humoral and cellular malities in patients with IBD (activation of complement, presence ofantineutrophilic cytoplasmic antibodies (ANCAs) in patients with UCand primary sclerosing cholangitis, and autoantibodies against pancreas,

abnor-skin, and intestinal extracts) (4–7) The importance of genetic

suscep-tibility is supported by the observation that the incidence of EIM is

higher in familial IBD (8) Whatever genetic or environmental factors

initiate IBD, the presence of altered mucosal permeability, reduced oraltolerance, cytokine imbalances, and influx of protein sequences allowconstant stimulation of an abnormally regulated inflammatory reaction.Increased permeability of endothelial cells allows the combination ofbacteria, their antigens and metabolic products, proinflammatorycytokines, and activated lymphocytes and neutrophils to get into the gen-eral circulation Distant organs, such as the eyes or the peripheral joints,lose their normal immunologic tolerance and develop an inflammatory

response that corresponds to an extraintestinal manifestation (9).

MUSCULOSKELETAL MANIFESTATIONS

Peripheral arthritis, axial arthropathy, and ankylosing spondylitis arethe three more important patterns of musculoskeletal manifestations inpatients with IBD

Peripheral colitic arthritis is the most common EIM in IBD and occurs

in about 20% of patients A recent clinical classification describes twotypes of peripheral arthropathy that are immunogenetically distinctentities: type 1 (pauciarticular) is related to HLA-B27 and is an acute,self-limiting arthropathy lasting a median of 5 wk, affects less than fivejoints, correlates with relapses of IBD, and is strongly associated withboth erythema nodosum and uveitis; type 2 (polyarticular) is a sym-metrical seronegative polyarthropathy not associated with HLA-B27,that runs a course independent of IBD, affects more than five joints,tends to cause persistent symptoms with a median duration of 3 yr, and

is associated with uveitis but not with other extraintestinal

manifesta-tions (10,11) (Table 2) Both forms are migratory, and nondeforming

arthritis that mostly affect the large joints of the lower extremities Theknees are most commonly affected followed by the hips, ankles, wrists, andelbows, and less often the hands and shoulders The involved joints areswollen, erythematous, warm, and painful The risk for peripheral arthri-tis increases with the amount of involved colon, although episodes

of acute arthritis have been reported in patients with disease limited to

the rectum, or after a colectomy with ileoanal anastomosis (12)

Treat-ment of peripheral arthropathy associated with IBD should be directedtoward decreasing gut inflammation; and total proctocolectomy usuallyresolves it If joint symptoms persist, additional therapies may includenonsteroidal antiinflammatory agents (NSAIDs), intraarticular corti-costeroid injections, and physical therapy NSAIDs should be used with

caution because exacerbation of IBD with NSAID has been reported (13).

Axial arthropathy occurs in 3–5% of IBD patients It frequently sents before identification of IBD and does not parallel bowel diseaseactivity It involves sacroiliac joints (more frequently), spine, hips, andshoulders Asymptomatic sacroiliitis is a common radiographic finding,but this entity may also be a cause of low back pain Most of the patientswith sacroiliitis are HLA-B27 negative and do not progress to ankylosing

pre-spondylitis (14).

Ankylosing spondylitis (AS) affects 3–6% of patients with IBD,

whereas 2%–18% of patients with AS have associated IBD (15) It is

related to HLA-B27 in 50–80% of patients compared to over 90% of

those with non-IBD associated AS (16) Typical symptoms of AS include

insidious onset of back pain and morning stiffness The pain typicallyexacerbates with rest and relieves with exercise Progression of thedisease is variable and does not run parallel to the severity of bowelsymptoms In early cases, radiographs may be normal or show onlyminimal sclerosis, whereas in advanced cases there are squaring ofvertebral bodies, and marginal syndesmophytes leading to bony prolif-eration and ankylosis called “bamboo spine” (Figs 2A,B) Treatmentfor AS with IBD is the same as for idiopathic AS, and includes NSAIDsand physiotherapy, with some reported benefits with other agents includ-

- Strongly associated with extraintestinal manifestations of IBD

Type 2 (polyarticular)

- Five or more joints

- Symptoms usually persist for months to years

- Runs a course independent of IBD

- Associated with uveitis, but not with other extraintestinal manifestationsAdapted from Orchard TR, Wordsworth BP, Jewell DP Peripheral arthropathies in inflammatory bowel disease: their articular distribution and natural history Gut 1998;42:387–39.

Fig 2 (A) and (B) Ankylosing Spondylitis Spine radiographs of a patient with

long-standing ankylosing spondylitis showing squaring of vertebral bodies, marginal and symmetric syndesmophytes, and bilateral sacroiliitis.

ing sulfasalazine, methotrexate, and azathioprine Proctocolectomy

does not affect AS (14) Recent reports suggest marked improvement

with the anti-tumor necrosis factor agents etanercept and infliximab

Numerous other rheumatic conditions have been reported in patients

with IBD (15): osteomalacia and osteoporosis (secondary to vitamin D

and calcium deficiency from impaired dietary intake, malabsorption, orcorticosteroid use), hypertrophic osteoarthropathy, polymyositis, iso-lated atlantoaxial subluxation, and avascular necrosis of the hip second-ary to corticosteroids use

Fig 2 Continued

DERMATOLOGIC MANIFESTATIONS

More than 40 different dermatologic manifestations have been

des-cribed in IBD (17) The incidence of dermatologic manifestations varies

from 9% to 19%, with a higher incidence when the large intestine is

involved (1,18) Conversely, an increased risk of pouchitis after total

colectomy with ileal pouch anal anastomosis has been reported inpatients with extraintestinal manifestations, particularly on the skin and

the eyes (19).

Erythema nodosum (EN) and pyoderma gangrenosum (PG) are themost common dermatologic conditions observed EN appears in up to

9% of patients with UC and 15% of patients with CD (17) It usually

reflects increasing bowel activity, but not severity or extent of the boweldisease EN presents as one or several hot, red, tender, and symmetri-cally distributed subcutaneous nodules, generally on the extensor sur-faces of the lower legs but occurring also on the ankles, calves, thighs,and arms (Fig 3) Approximately 75% of patients developing EN alsopresent with peripheral arthritis Most lesions usually respond to medi-cal or surgical treatment of the bowel disease; however, recurrences are

common and may be seen after colectomy (20).

PG has been associated classically with UC with a reported incidence

of 5% of patients with UC, although it can also occur in CD, particularly

in Crohn’s colitis PG develops commonly during earlier stages of IBD,but does not show any relation to the clinical activity of the boweldisease PG begins as pustules or fluctuant nodules that increase rapidlyinvolving adjacent areas of healthy skin Lesions then ulcerate showingviolaceous edges delimited by a margin of erythema (Fig 4) Lesionscan be single or multiple and vary in size and location, although theyoccur more frequently on extensor surfaces of the lower limbs or othersites susceptible to trauma (surgical scars, and skin adjacent to ileo-stomy can often be the site for PG) Up to 50% of patients with PG haveassociated manifestations involving joints and/or eyes Total colectomy,dapsone, cyclosporine A, and more recently thalidomide and infliximab

have been found to be effective for the treatment of PG (20–22).

Aphthous stomatitis appears in 20% of CD patients and in 5% of

UC patients Oral lesions occur spontaneously, with or without tion to the bowel disease activity and, in general, cause minimal dis-comfort, although some patients may complain of debilitating pain.Treatment regimens have included systemic or topical steroids,immunosuppressives, clofazimine, dapsone, and cyanoacrylate adhe-sive Thalidomide, chloroquine, and infliximab can be tried for patients

rela-with refractory lesions (22).

Metastatic Crohn’s disease (MCD) is a rare cutaneous manifestationdefined as the presence of granulomatous dermatitis occurring distantfrom, or non-contiguous with, the bowel lesions in CD Clinical presen-tation may be diverse and includes genitalia ulcerations, papules andnodules of trunk and extremities, ulcerating and nonulcerating plaques,

and hidradenitis or erysipelas-like facial eruption (23) (Figs 5A,B).

Therapy for MCD includes corticosteroids, dapsone, sulfasalazine, thioprine, 6-mercaptopurine, metronidazole, and in resistant cases,

aza-hyperbaric oxygen (17) Most recently, the chimeric monoclonal

anti-body anti-TNF α, infliximab, showed efficacy in two cases of

therapy-resistant perineal MCD (24).

Other skin manifestations include vesiculopustular eruption andpyoderma vegetans that occur mainly in UC; aphthous ulcers, necrotiz-ing vesiculitis, and cutaneous polyarteritis nodosa which are more com-mon in CD; and other autoimmune diseases such as psoriasis, vitiligo,and epidermolysis bullosa acquisita Other cutaneous changes arecaused by nutritional deficiencies Acrodermatitis enteropathica, as a

Fig 3 Erythema Nodosum The lesions of erythema nodosum are ized as raised, red, tender subcutaneous nodules characteristically located on the anterior tibial surfaces of the lower extremities (Adapted with permission from: Callen, Greer, Hood, Paller, Swinyier Color Atlas of Dermatology W.B Saunders, Philadelphia, PA, 1993.)

character-Image Not Available

result of zinc deficiency, is common in patients with draining fistulas

and patients with long-term total parenteral nutrition (25).

HEPATOBILIARY MANIFESTATIONS

Hepatobiliary complications are the most serious EIMs that occur inpatients with IBD and include small duct and large duct primary scle-rosing cholangitis (PSC), hepatitis (chronic active, viral, drug induced,granulomatous), cirrhosis, cholangiocarcinoma, steatosis, amyloidosis,hepatic abscess, and cholelithiasis

The incidence of steatosis among patients with IBD has been reported

as occurring in up to 80% of patients (26) Fat deposition is of

macro-vesicular type, nonspecific, and usually reversible The pathogenesis islikely to be multifactorial with malabsorption, protein loss, bacterialmetabolites, drug injuries including corticosteroids and methotrexate,

Fig 4 Pyoderma gangrenosum in the anterior tibial surface, showing a deep ulceration with a necrotic center, an undermined border, and violaceous skin surrounding the lesion (Adapted with permission from: Callen, Greer, Hood, Paller, Swinyier Color Atlas of Dermatology W.B Saunders, Philadelphia,

PA, 1993.)

Image Not Available

Fig 5 (A) and (B) Metastatic Crohn’s Disease Patient with diffuse swelling

on the left side of the mouth with superficial skin corrugations, diffuse erythema, and a textural change to the surface of the skin.

and in rare cases total parenteral nutrition associated cholestasis, ascontributing factors Patients tend to be asymptomatic unless they mayhave hepatomegaly, which may cause discomfort

Cholelithiasis is a frequent complication in patients with IBD (30%).

It usually occurs in patients with CD involving the terminal ileum or

following ileal resection, and is secondary to bile salt malabsorption (27).

Primary sclerosing cholangitis (PSC) is the most specific biliary complication of IBD and it has been reported in up to 4% ofpatients with IBD In 70–90% of patients with PSC, especially young

hepato-males, the disorder is associated with UC (28) PSC is a chronic

cholestatic syndrome characterized by fibrosing inflammation of thebiliary system resulting in bile duct obliteration, biliary cirrhosis, andhepatic failure Clinically, PSC presents most commonly with progres-sive fatigue, weight loss, pruritus, jaundice, and a cholestatic biochemi-cal profile with marked elevations of the serum alkaline phosphatase.Visualization of irregularities, strictures, and dilatations in the biliarytree is essential to confirm the diagnosis (Fig 6) Endoscopic retrogradecholangiopancreatography is the diagnostic method of choice Althoughthere is a strong association of UC with PSC, there is no relation to theonset, duration, extent, or activity of colitis, and indeed, the colitis isusually total but symptomatically mild and characterized by prolonged

remissions (29) Total colectomy does not alter the course of PSC, and

liver disease may develop after years a total colectomy has been

per-formed (30) Patients with UC and PSC are at increased risk of oping pouchitis following ileoanal anastomosis (31).

devel-Although only 5% of UC patients have associated PSC, the majority

of PSC patients will develop IBD Therefore, patients with newly nosed PSC should undergo colonoscopy even if no symptoms of boweldisease are present; similarly, patients with IBD and increased concen-trations of serum alkaline phosphatase should have an examination ofthe bile ducts

diag-Patients with PSC, with or without concomitant IBD, are at higher risk

of developing cholangiocarcinoma (1–15% of patients) (32) Malignancy

should be suspected in patients with a rapid clinical deterioration and thepresence of a dominant stricture or mass effect on imaging studies Theprognosis for cholangiocarcinoma is poor, with most patients dying within

1 yr of diagnosis The occurrence of PSC also appears to be an additionalrisk factor for the development of dysplasia and carcinoma in patients

with long-standing UC (33) There is now general consensus that annual

surveillance colonoscopy is indicated in these patients

At present, there are no medical or endoscopic treatments with provenbenefit for PSC Immunosuppressive agents such as prednisone, aza-thioprine, methotrexate, and penicillamine have failed to demonstrate

efficacy (34–38) A study from the Mayo Clinic using ursodeoxycholic

acid showed no clinical benefit in retarding disease progression but

demonstrated an improvement in cholestatic biochemistry markers (39).

Several authors have reported favorable results with endoscopic

dilata-tion of symptomatic dominant strictures (40) Addidilata-tional studies

com-paring the efficacy and safety of various endoscopic treatmentapproaches are needed Orthotopic liver transplantation is presently, theultimate therapy for end-stage PSC and should be considered in patientswith signs of decompensating liver cirrhosis, recurrent cholangitis, or

intractable pruritus (41).

OCULAR MANIFESTATIONS

A wide variety of ocular manifestations may be seen in patients withIBD including episcleritis, uveitis, marginal keratitis, conjunctivitis,scleritis, orbital inflammatory disease, optic neuritis, ischemic opticneuropathy, and retinal vasculitis Some ocular problems may run acourse independent of the activity of the underlying bowel disease (e.g.,

uveitis, scleritis) or may reflect bowel activity (e.g., episcleritis) (42).

Fig 6 Endoscopic retrograde cholangiopancreatography (ERCP) showing the typical irregularities, strictures, and dilatations in the biliary tree in a patient with primary sclerosing cholangitis.

There is a clear association between eye lesions and other EIM cially those involving the joints.

espe-Episcleritis is the most common ocular complication and develops in5% of patients with active IBD Clinically it appears as a painless hype-remia of the sclera and conjunctiva and does not affect the visual acuity.Episcleritis responds to antiinflammatory therapy, and local corticos-teroids are usually effective

Uveitis is a general term used to describe any inflammatory conditioninvolving the uveal tract that is composed by the iris, ciliary body, andchoroid, whereas the term iritis describes inflammation limited to theiris Uveitis/iritis appear in 1–3% of patients and manifest with eye pain,blurred vision, photophobia, headache, iridospasm, and abnormal pup-illary response to light In patients positive for HLA-B27, uveitis isusually sudden in onset, anterior, and unilateral, whereas in patientsnegative for HLA-B27 uveitis is often insidious, posterior, and bilateral

(43) Diagnosis is confirmed by slit-lamp examination and treatment

consists of pupillary dilatation, covering the eye to reduce pain andphotophobia, and topical or systemic corticosteroids Refractory cases

of uveitis, usually in HLA-B27 positive patients, may require suppressive therapy Treatment is important to prevent iris atrophy andsynechial formation The incidence of asymptomatic uveitis in pediatricIBD patients (6%) may warrant periodic ocular screening in this age

immuno-group (44).

RENAL/UROLOGIC MANIFESTATIONS

Renal and urologic complications are not unusual in patients withIBD and have been reported in 4–23% of patients The most commonmanifestations are kidney stones, enterovesical fistulas, and ureteral

obstruction (45).

Patients with IBD have a risk of nephrolithiasis that is 10–100 timesgreater than that for the general hospital patients, ranging from 1% to

25% (46) Classically described risk factors for renal stone development

include presence of ileostomy, extensive ileal disease, and extensiveileal resection Other potential lithogenic factors include dehydration,diminished water absorption, urinary tract obstruction, abnormal urateexcretion, alterations in oxalate absorption and excretion, steroids, andprolonged bedrest Renal stones in IBD patients are mainly composed

of calcium oxalate or uric acid During an episode of nephrolithiasis,aggressive hydration, adequate analgesia, and occasionally lithotripsymay be required Patients with an ileostomy should be encouraged todrink adequate fluids

choice (47) Other diagnostic techniques include magnetic resonance

imaging, cystoscopy, and cystography Spontaneous resolution ofenterovesical fistulas can occur but is uncommon Surgical resection of

the fistula and involved bowel is the definitive treatment (48) If resection

is not possible, a diverting colostomy may be performed In addition,

cyclosporine (49) and 6-mercaptopurine (50) have been successfully used.

Ureteral obstruction is not secondary to stones in 50–70% of patients

with IBD (51) In CD, it is usually caused by retroperitoneal

inflamma-tion, whereas in UC patients, obstruction is often secondary to surgicalcomplications (e.g., suture in or near the ureter) or to colon cancer Most

of the nonstone-related ureteral obstructions associated with IBDimprove with conservative therapy alone If this does not occur, bowelsurgery is recommended

Glomerulonephritis, tubulointerstitial abnormalities, and sis have also been reported in the setting of IBD

amyloido-PANCREATIC MANIFESTATIONS

Pancreatitis may occur in patients with CD or UC Many of thesecases are either acute pancreatitis related to choledocholithiasis, or drug-induced pancreatitis from 5-ASA, sulfasalazine, corticosteroids, aza-

thioprine or 6-mercaptopurine (52) In addition, clinically significant

and nondrug-related pancreatitis has been reported in two subgroups ofinflammatory bowel disease patients First, patients with duodenal CDmay have reflux of duodenal contents into pancreatic ducts through anincompetent ampulla, or direct ampullary involvement with stenosis,resulting in pancreatitis Second, pancreatitis may occur in patients with

UC and primary sclerosing cholangitis or pericholangitis Finally, cases

of pancreatitis have been reported in IBD patients with none of the

previous mentioned risk factors (53) Whether these patients have

idio-pathic pancreatitis or can be considered as a rare EIM of IBD is unclear

PULMONARY MANIFESTATIONS

Symptomatic bronchopulmonary manifestations have been describedonly rarely in patients with CD or UC However, several recent studieshave reported a significantly higher rate of findings compatible with

interstitial lung disease in pulmonary function tests in asymptomatic

IBD patients compared to controls (54) Pulmonary manifestations in

patients with IBD can be divided as sulfasalazine related or unrelated.Sulfasalazine-associated lung problems usually occur after 2 mo oftherapy and include eosinophilic pneumonia, fibrosing alveolitis, and

interstitial pneumonitis (55) Nonsulfasalazine-related disorders include

pulmonary vasculitis, chronic bronchitis and bronchiectasis, and

inter-stitial pulmonary disease (56) Whether or not there is truly a

relation-ship or only a coincidental association between these entities and IBD

is unknown

CARDIAC MANIFESTATIONS

Myopericarditis and pleuropericarditis have been reported in patientswith both UC and CD although the incidence is <1% in patients with

IBD (57) The clinical course can range from mild to pericardial

tam-ponade requiring drainage Treatment with corticosteroids is effective.Aortic insufficiency and conduction defects are often associated withidiopathic ankylosing spondylitis and can be seen also in patients with

IBD with or without ankylosing spondylitis (58).

NEUROLOGIC MANIFESTATIONS

Association of IBD with neurologic involvement is rare and oftencontroversial Cerebrovascular thromboembolic disease can occur at

any age and tend to correlate with bowel disease activity (59) Direct

extension of inflammatory masses or abscesses into neural structureshas been reported in patients with CD and may lead to meningitis or

epidural abscesses (60) Peripheral neuropathy occurs relatively quently with metronidazole therapy (61) About 50% of patients will

fre-present with paresthesias after 6 mo or more of receiving metronidazole(mean dose 15–20mg/kg/d) and 80% develop a sensory peripheral neu-ropathy Multiple sclerosis has also been associated with IBD The twodiseases coexist at three times the expected frequency, and familialaggregation occur at about nine times more often than would be

expected by chance (62) An idiopathic chronic inflammatory nating polyneuropathy may also occur (63).

demyeli-HEMATOLOGIC MANIFESTATIONS

Anemia is seen in 50% of patients with IBD and is usually caused byiron deficiency Other causes include folic acid deficiency, vitamin B12deficiency, malnutrition, hemolysis (drug-induced, e.g., sulfasalazine

Patients with IBD may have abnormalities in the coagulation profilethat predispose to thromboembolic complications These include: throm-bocytosis, increased plasma levels of fibrinogen, and factors V and VIII,decreased levels of antithrombin III, spontaneous platelet aggregation,

impaired fibrinolytic capability, and mutation of factor V Leiden (65).

Venous thrombosis involving the lower extremities is the most monly described, but thrombosis may also appear in brain, lung, and liver.Budd-Chiari syndrome and portal vein thrombosis have been described inthe setting of UC Deep vein thrombosis leading to pulmonary embolism

com-is the third most frequent cause of death in patients with UC, followingperitonitis and cancer Thus, a high index of suspicion for venous throm-bosis must be maintained in patients with IBD

METABOLIC AND ENDOCRINE MANIFESTATIONS

Growth retardation accompanied by a delay in sexual maturation ismore common in children with CD, but may be seen also in UC About50% of children have weight-for-age measurements less than 90% ofexpected, with absolute height deficits seen in 10–40% of children with

IBD (66) Nonspecific endocrine abnormalities have been documented in

these IBD children Chronic undernutrition is considered the primaryetiologic factor in the pathogenesis of growth impairment and is consid-ered to be secondary to diminished intake, malabsorption of nutrients, andprotein loss enteropathy A significant iatrogenic cause of growth failure

is the chronic administration of high-dose daily corticosteroid therapy.Alternate-day treatment with corticosteroids may have less effect on

growth retardation (67) Thus, the suppression of gastrointestinal

symp-toms using high doses of corticosteroids with the concomitant mise of growth is not considered a successful medical therapy in children

compro-In these patients, surgical therapy should be considered (68).

SUMMARY

About one-third of patients with IBD will develop one or moreextraintestinal manifestations that can involve virtually all the organs ofthe body EIMs may precede or follow the diagnosis of IBD and mayoccur with exacerbations of bowel symptoms or independently Identi-

fied pathogenetic mechanisms include genetic susceptibility, and mally regulated autoimmune and inflammatory reactions Systematicassessment, early recognition, and adequate therapy are essential aims

abnor-in the management of patients with abnor-inflammatory bowel disease andextraintestinal manifestations to prevent severe complications andimprove their quality of life

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