Extraintestinal manifestations and complications in inflammatory bowel diseases.

Katja S Rothfuss, Eduard F Stange, Klaus R Herrlinger, De-
partment of Gastroenterology, Hepatology and Endocrinology,
Robert-Bosch-Hospital, Stuttgart, Germany
Correspondence to: Katja S Rothfuss, Robert-Bosch-Hospital,
Department of Gastroenterology, Hepatology and Endocrinology,
Auerbachstrasse 110, D-70376 Stuttgart,
Germany. katja.rothfuss@gmx.de
Telephone: +49-711-81013406 Fax: +49-711-81013793
Received: 2006-05-18 Accepted: 2006-06-20
Abstract
Crohn’s disease (CD) and ulcerative colitis (UC) are
chronic inflammatory bowel diseases (IBD) that often
involve organs other than those of the gastrointestinal
tract. These nonintestinal affections are termed
extraintestinal symptoms. Differentiating the true
extraintestinal manifestations of inflammatory bowel
diseases from secondary extraintestinal complications,
caused by malnutrit ion, chronic inflammation or
side effects of therapy, may be difficult. This review
concentrates on frequency, clinical presentation and
therapeutic implications of extraintestinal symptoms in
infl ammatory bowel diseases. If possible, extraintestinal
manifestations are differentiated from extraintestinal
compl icat ions. Specia l attent ion is given to the
more recently described sites of involvement; i.e.
thromboembolic events, osteoporosis, pulmonary
involvement and affection of the central nervous system.
© 2006 The WJG Press. All rights reserved.
Key words: Inflammatory bowel diseases; Crohn’s
disease; Ulcerative colitis; Extraintestinal manifestations;
Complications; Therapy
Rothfuss KS, Stange EF, Herrlinger KR. Extraintestinal mani-
festations and complications in infl ammatory bowel diseas-
es. World J Gastroenterol 2006; 12(30): 4819-4831
http://www.wjgnet.com/1007-9327/12/4819.asp
INTRODUCTION
Crohn’s disease (CD) and ulcerative colitis (UC) are the
main entities of chronic inflammatory bowel diseases
(IBD). Although in most cases the gastrointestinal tract is
mainly affected, both ulcerative colitis and Crohn’s disease
are systemic disorders that often involve other organs.
These nonintestinal affections are termed extraintestinal
symptoms and may not always coincide with the underlying
bowel disease. Extraintestinal disease can involve almost
every organ system. The organs most commonly involved
include the skin, eyes, joints, biliary tract and lungs. Some
symptoms, such as oral lesions, gallstones, pancreatitis,
nephrolithiasis and amyloidosis, are more associated with
CD than with UC. Other symptoms, e.g. skin and eye
manifestations, are equally seen in both CD and UC.
Several factors may be responsible for extraintestinal
organ involvement in IBD and sometimes it can be
diffi cult to differentiate the true extraintestinal manifestations
(EIMs); i.e. primary systemic affection by the disease itself,
from secondary extraintestinal complications of the disease,
caused for example by malnutrition, chronic infl ammation
or side effects of therapy. Some of these EIMs may
not correlate with disease activity (primary sclerosing
cholangitis and ankylosing spondylitis) but in general
EIMs tend to follow the clinical course of IBD and may
have a high impact on quality of life, morbidity and even
mortality in these patients.
The reported frequency of EIMs in patients with
IBD varies from 6%-47%[1-4]. The development of one
EIM appears to increase the susceptibility of developing
other EIMs. An overlap of EIMs is particularly observed
with peripheral arthritis, erythema nodosum, affection
of the biliary tract and the eyes, in concordance with
the hypothesis of a common pathogenic pathway. Some
authors discuss an autoimmune reaction towards an
isoform of tropomyosin (Tropomyosin related peptide),
which is expressed in eye (non-pigmented ci l iar y
epithelium), skin (keratinocytes), joints (chondrocytes),
biliary epithelium and the gut[5,6].
The high concordance in EIMs in siblings and first
degree relatives with IBD[7] suggests a common genetic
background. Crohn’s disease and ulcerative colitis are
polygenic disorders and certain susceptibility genes in
the major histocompatibility complex (MHC) region on
chromosome 6 seem to be linked to EIMs in IBD. In
CD, extraintestinal co-morbidities are more commonly
observed in patients with HLA-A2, -DR1 and DQw5,
whereas in ulcerative colit is, the genotypes HLA-
DRB1*0103, B*27 and B*58 are linked with EIMs
involving the joints, skin and eyes[8-10]. Fifty to eighty
percent of IBD patients with ankylosing spondylitis are
TOPIC HIGHLIGHTS
Extraintestinal manifestations and complications in
infl ammatory bowel diseases
Katja S Rothfuss, Eduard F Stange, Klaus R Herrlinger
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Paolo Gionchetti, MD, Series Editor

HLA*B27 positive[11]. Furthermore, in UC the haplotype
HLA B8/DR3 is associated with primary sclerosing
cholangitis (PSC) and may also be l inked to other
autoimmune diseases (e.g. celiac disease, autoimmune
hepatitis, myasthenia gravis)[12]. Interestingly, the NOD2
gene in CD seems to be associated not only with ileal
disease in CD but also with sacroileitis[13].
In the following, an overview of the involvement
of the different organ systems in IBD will concentrate
on frequency, clinical presentation and therapeutic
impl icat ions. In some cases, a different iat ion of
extraintestinal manifestations and extraintestinal complications
wil l be given. Besides the classical extraintestinal
manifestat ions, such as skin, joints, eyes and the
hepatobiliary system, special attention will be given to
the rarer, more recently described involvements, such as
thromboembolic events, osteopenia and osteoporosis,
pulmonary involvement and affection of the central
nervous system.
MUSCULOSCELETAL MANIFESTATIONS
Joint manifestations are the most common EIMs in IBD
and occur in approximately 20%-30% of patients[3,14].
Males and females are equally affected. Symptoms may
range from arthralgia only to acute arthritis with painful
swollen joints. Both peripheral arthritis and axial arthritis
can occur.
Peripheral arthritis
Peripheral ar thri t is in IBD is quite dist inct from
specifi c forms of arthritis since there is little or no joint
destruction, and tests for rheumatoid factor, antinuclear
antibody and LE factor are negative. The prevalence of
all forms of peripheral arthritis is reported to be between
5%-10% in UC and 10%-20% in CD, respectively[6,15],
not considering asymptomatic patients under medical
treatment. There are two types of peripheral arthritis
in IBD[15] that should be distinguished from unspecific
myalgia or arthralgia:
Type 1 (pauciarticular) arthritis affects less than five
large joints (predominantly of the lower limbs) and the
swelling is acute and often self-limiting. Type I arthritis is
related to disease activity of the underlying bowel disease.
The mean duration is 5 weeks; some 25%-40% of patients
will have recurring arthritis. Type 2 (polyarticular) arthritis
is a symmetrical polyarthritis, frequently involving fi ve or
more of the small joints (e.g. knuckle joints). Its course is
independent of disease activity and may last for several
months.
The etiology of peripheral arthritis in IBD is thought to
be a combination of genetic predisposition and exposition
to luminal (bacterial) bowel contents. Type 1 IBD arthritis
is associated with HLA-DRB1*0103, HLA-B*27 and
HLA-B*35, whereas type 2 IBD arthritis is associated with
HLA-B*44 and MHC class I chain-like gene A, which
is a non classical HLA gene located near the HLA-B on
chromosome 6[8,10,16]. The site of intestinal infl ammation is
of particular interest concerning the pathogenesis of joint
infl ammation since CD patients with colonic involvement
are at higher risk of developing arthritis than those with
isolated small bowel disease. Furthermore the incidence
of new joint complications significantly decreases after
ileocecal resection (even when corrected for the time
spent in remission after surgery), suggesting that bacterial
overgrowth proximal to the ileocecal valve plays an
important role in the pathogenesis of extraintestinal joint
infl ammation[6].
The diagnosis of peripheral arthritis in IBD is made
clinically since radiographic fi ndings do not show erosions
or deformities. In persisting disease, a positive rheumatic
factor should be excluded. In acute swelling, septic
arthritis, fistulating arthritis or gout may be excluded by
joint aspiration.
Treatment: Type 1 arthritis is related to disease activity
and therefore therapy of the underlying IBD is the
treatment of choice. Especially in patients with relapsing
arthritis (HLA-DRB*0103), 5-ASA treatment should be
switched to sulfasalazine, thereby taking advantage of the
antiarthritic effect of sulfapyridine to minimize the risk
of relapse. In addition, symptomatic treatment is often
sufficient. For analgetic therapy, NSAID’s and COX-2
selective inhibitors should be avoided, if possible, due
to their potential to activate the underlying IBD[17]. In
severe cases, symptoms relief can be achieved by intra-
articular steroid injection. Type 2 IBD arthritis generally
requires long-term treatment. In persisting disease,
sulfasalazine should be initiated at an initial dose of 2
× 500 mg per day, increasing the daily dose by 1000 mg
every two weeks towards the maximum dose of 3 × 1500
mg or until symptoms improve. If not effective despite
12 wk of continuing treatment, immunosuppression
with methotrexate (7.5 mg po once weekly) should be
started. The dose can be increased by 2.5 mg steps in
monthly intervals up to the maximum dose of 25 mg per
week. Concomitant folic acid (5 mg po 24 h following
methotrexate) is recommended to reduce side effects.
Systemic corticosteroids may be necessary to control
symptoms.
Axial arthropathies
The axial arthropathies are not associated with disease
activity of IBD. Spondylitis occurs in 1%-26% of patients
with IBD and males are more often affected than females.
Both progressive ankylosing spondylitis and sacroiliitis
(sometimes asymptomatic) may occur. Plain radiographs
of the sacroiliac joints show uni- or bilateral sclerosis
and/or erosions. The diagnostic gold standard is magnetic
resonance imaging (MRI) with a high sensitivity in
detecting sacroiliitis even in the absence of symptoms.
Ankylosing spondylitis
Ankylosing spondylitis (AS) affects the vertebral column
by progressive ankylosis of the vertebral facet joints
and the sacroiliac joint (Figure 1). The prevalence
of AS in IBD (1%-6%) is higher than in the general
population (0.25%-1%)[18]. In contrast, the association
with HLA*B27 is considerably weaker than in idiopathic
AS with only 50%-80% of IBD patients being positive
for HLA B*27 compared to 94% in the g enera l
population[11]. Again, bacteria and gut infl ammation seem
to play an important role in the pathogenesis of AS.
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Interestingly, ileocolonoscopy in patients with idiopathic
spondylarthropathies reveals ileal inflammation in more
than two thirds of patients[19].
The cl inical course of AS in IBD is s imilar to
idiopathic AS, and disease progression leads to increasing
immobility of the spine resulting in ankylosis (bamboo
spine). Secondary to reduced chest expansion, poor lung
expansion with fi brosis and dilatation of the aortic root
can occur. AS is associated with peripheral arthritis in
about 30% of patients and with uveitis in 25% of patients.
Treatment: There is no causative treatment and therefore
physical therapy is of particular importance to maintain
mobility of the spine. In the absence of active IBD,
NSAID are the drugs of choice, otherwise acetaminophen
or tramadol are preferred. Steroid injection (MRI-guided)
into the sacroiliac joint may be an option in patients with
severe low back pain[20]. Sulfasalazine may be used, but is
more effective in associated peripheral arthritis. The fi rst
line immunosuppressant in patients with AS and IBD is
methotrexate. Anti-TNF-strategies should be reserved for
severe cases. Experience is limited to small case series, but
improvement of both spondylarthropathy and active bowel
disease has been reported in CD with infliximab[21-23].
Etanercept is effective in spondylarthropathies[24,25] but the
effi cacy in CD has not yet been demonstrated.
Isolated sacroiliitis
It may occur in patients with IBD but most patients
are asymptomatic and the disease is non-progressive.
Prevalence depends on the radiological method used and
varies from 18% in plain radiographs and 32% in CT
imaging to 52% in radioisotope scintigraphy. Isolated
sacroiliitis seems not to be associated with HLA*B27[6].
Asymptomatic HLA*B27 negative patients with normal
spinal mobility do not require specifi c treatment.
Osteoporosis
Patients with IBD have an increased risk of developing
osteoporosis, associated with fragility fractures and
morbidity. The overall prevalence of osteoporosis in IBD
is approximately 15% but is more prevalent with older
age; the overall relative risk of fractures is 40% greater
when compared to the general population[26,27]. Vertebral
fractures often occur spontaneously or after minimal
trauma and it is estimated that only one-third of vertebral
fractures come to clinical attention[28]. X-ray images of
the spine most commonly show wedge or compression
deformities. A variety of studies have demonstrated both
decreased bone mineral density (BMD) in patients with
IBD[29-39], and increased rates of bone loss when followed
longitudinally[35,40,41] in comparison to healthy controls. The
current Gold standard for measuring bone mass is dual-
energy X-ray absorptiometry (DEXA)[42].
The pa thogenes i s of os teoporos i s in IBD i s
multifactorial. Important pathogenetic factors in IBD
include the cumulative steroid dose, hypogonadism
induced by IBD (absence of menstrual period in women),
malabsorption of calcium and vitamin D, low body
mass index and disease activity/elevated inflammatory
cytokines[43]. Other risk factors are previous fragility
fracture, a positive family history, concomitant liver/
endocrine disease (hyperthyroidism, hyperparathyroidism),
immobilization and life style risk factors (smoking,
excessive alcohol intake, physical inactivity) . The
multifactorial pathogenesis of bone loss in IBD makes
it difficult to assess the importance of each single
contributing factor. The results of a study from Norway
indicate that disease activity and corticosteroid therapy are
the most important factors involved in bone loss in CD
patients[44]. However, it remains unclear whether the bone
loss is related to the disease or to its treatment.
B iochemica l markers of bone turnover (e.g. ,
osteocalc in , bone specif ic a lka l ine phosphatase,
carboxyterminal propeptide procollagen type 1, urinary
deoxypyridinoline, pyridinoline, carboxytelopeptide of
type I collagen, N-telopeptide cross-linked type I collagen)
do not correlate suffi ciently with current BMD for routine
use[33,34,36,45-47] and should be confi ned to research studies[26].
Treatment: Few IBD patients are receiving optimal bone-
sparing therapy, highlighting the importance of increasing
awareness of osteoprosis in managing these patients[39].
Preventing bone loss should begin with an attempt to
limit corticosteroid-induced bone loss. This can be done
by minimizing the corticosteroid dosage, substituting with
budesonide when appropriate[48,49], administering other
steroid-sparing immunomodulators once corticosteroid
dependence becomes evident, or by prescribing additional
agents that enhance bone health. The administration of
calcium and vitamin D[50] appears to maintain or enhance
bone mass[26]. Bisphosphonates are of unclear additional
benefi t to the majority of patients who are at low fracture
risk. In a small trial in Denmark, one year of daily
alendronate treatment p.o. improved BMD in the spine[51].
Bisphosphonates (etidronate, risedronate, alendronate) are
effective in preventing bone loss in steroid treated patients,
but only few patients with IBD have been included in these
trials[52-55]. Nasal or s.c. calcitonin can be considered as an
alternative treatment approach when bisphosphonates
are contraindicated or poorly tolerated. Testosterone
replacement should be considered in hypogonadal men[26],
estrogen replacement in postmenopausal women[56].
Osteomalacia
Osteomalacia is a rare complication of IBD, most likely
occurring in patients with severe CD and multiple
Rothfuss KS et al. Extraintestinal manifestations in IBD 4821
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Figure 1 X-ray thoracic spine demonstrating ankylosing spondylitis (Bechterew's
disease) with syndesmophytes/ bamboo spine in a patient with CD.
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1/1
Img 1
5 cm
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intestinal resections[57], resulting from prolonged and
severe vitamin D deficiency. Though both osteoporosis
and osteomalacia result in low BMD, apart from elevated
bone alkaline phosphatase levels, osteomalacia can only be
distinguished from osteoporosis by bone biopsy.
Joint complications in IBD
Complications involving the joints should always be
considered and have to be distinguished from sterile
joint inflammation, since steroid treatment can cause
osteonecrosis (avascular necrosis of the bone). Patients on
immunosuppressive therapy are at increased risk of septic
arthritis. In CD, fi stulization may cause bacterial infection
of the iliosacral joint. Rarely a psoas abscess can cause
septic hip arthritis.
MUCOCUTANEOUS MANIFESTATIONS
Erythema nodosum, pyoderma gangraenosum and oral
ulceration are the most common cutaneous manifestations
in IBD and are usually related to disease activity but
sometimes may take an independent course. All patients
presenting with IBD should be examined for cutaneous
manifestations.
Erythema nodosum
It is the most common skin manifestation in IBD
affecting up to 15% of CD patients, with a female
predominance[1,6,14]. Erythema nodosum (EN) affects
the subcutaneous fat (septal panniculitis), causing tender
erythematous nodules usually located on the shins
(Figure 2). EN normally heals without ulceration and
the prognosis is good. The clinical picture is typical and
biopsy rarely is required for diagnosis. The etiology of
EN is unknown, however there is a genetic association
with a distinct HLA region on chromosome 6 (HLA-B)[9].
EN characteristically parallels intestinal disease activity.
There is an association with other EIMs such as arthritis
and uveitis[14,15]. Treatment of the underlying bowel disease
usually results in improving EN lesions and at least 25% of
EN will heal spontaneously. There is no specifi c treatment
for EN, but symptomatic therapy should comprise pain
medication and oral steroids may be given in severe cases.
Immunosuppressive treatment is not necessary. In the
absence of active bowel disease, other causes of EN, such
as sarcoidosis or post-streptococcal infection, should be
taken into consideration.
Pyoderma gangrenosum (PG)
Pyoderma gangrenosum occurs in 0.5%-2% of both
pat ients with UC and CD and may take a course
independent of disease activity (Figure 3). Conversely,
36%-50% of patients with PG suffer from IBD. PG
appears as a tender erythematous papule evolving into
a livid pustule with central necrosis and subsequent
ulceration, occurring in single or multiple lesions. The ulcer
often has a irregular outline and is sharply demarcated
with a heaped-up mushy violaceous border, surrounded
by a erythematous zone (Figure 1). Often minor trauma,
needle stitches or biopsy can induce new PG lesions
(pathergy phenomenon). PG lesions have a predilection
for the lower limbs but may occur in any area of the skin,
sometimes even as peristomal ulcers[58]. The diagnosis of
PG is made clinically; nevertheless skin biopsy of the border
of the ulcer may be performed to rule out vasculitis or
infection. There are no pathognomonic histologic features,
generally revealing only diffuse neutrophilic infi ltration and
dermolysis.
PG is the most severe skin manifestation in IBD. PG
is painful and often persisting despite adequate therapy.
Without treatment, PG can last for years and ulcers
may spread. Therefore, aggressive and early treatment is
required. Local wound care consists of dressings, mild
débridement of necrotic material and eschar (continuous
wet saline compressions, topical enzymatic ointment,
hydrocolloid dressings similar to common ulcer treatment).
Topical tacrolimus has also emerged as potentially
useful therapy[59]. First line systemic treatment in PG is
high dose prednisolone. Intravenous pulse therapy over
three days is highly effective. Careful tapering should be
started with clinical improvement. In steroid dependent
or steroid refractory (no improvement within 5 d) cases,
immunosuppressive therapy should be initiated. In mild
cases a combination of steroids with dapsone has been
successfully used with an initial dosage of dapsone 100
mg po/d, gradually increasing to 200-300 mg/d[60]. In
more severe cases cyclosporine or tacrolimus are effective.
Steroid dependent patients require immunosuppressive
treatment with azathioprine/6-mercaptopurine. A variety
of other treatments (thalidomide, topical cromoglycate,
Figure 2 Erythema nodosum in a patient
with CD.
Figure 3 Pyoderma gangrenosum in a patient with CD.
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clofazimine, plasmapheresis, granulocyte apheresis,
hyperbaric oxygen) have been reported anecdotally.
Surgical intervention should be avoided, if possible, since
it may induce pathergy. In resistant cases infliximab at
a dose of 5 mg/kg has been used successfully[60,61]. PG
often takes a prolonged course, but in general will be
controllable with medical therapy. About 35% of patients
will experience relapsing PG.
Oral ulcerations
Oral aphthous ulcers occur in at least 10% of patients
with UC and 20%-30% with CD and rapidly resolve once
remission is achieved. Stomatitis, as an adverse event of
methotrexate therapy, should be taken into account.
Miscellaneous skin lesions
Many other skin affections have been described in
patients with IBD, such as Sweet’s syndrome (neutrophilic
dermatosis)[62] (Figure 4), leukocytoclastic vasculitis,
psoriasis, epidermolysis bullosa acquisita, and cutaneous
polyarteriitis nodosa. Since these diseases have been
mainly reported as single case reports, they probably occur
coincidentially rather than as a true EIM. Angular cheilitis
in nearly 8% of patients with CD often is a sign of iron
defi ciency.
EYE MANIFESTATIONS
Two to five percent of patients with IBD experience
ocular manifestations[63]. The manifestations range from
conjunctivitis to more signifi cant infl ammation, including
iritis, episcleritis, scleritis and anterior uveitis. Mild cases
of conjunctivitis may be diagnosed clinically, but in other
cases early referral to an ophthalmologist is important for
accurate diagnosis.
Episcleritis
Episcleritis is less common in UC than in CD, presents
as an infection of the ciliary vessels and an infl ammation
of the episcleral tissues and does not affect visual acuity.
Infl ammation episodes tend to occur in association with
active bowel disease. Successful treatment consists of both
topical corticosteroids and treatment of the underlying
bowel disease. Scleritis affects deeper layers of the eye and
can cause lasting damage if untreated.
Uveitis
Uveitis is less common than episcleritis and occurs in
0.5%-3% of patients. It does not affect visual acuity unless it
involves the posterior segment. Uveitis frequently presents
bilaterally, is insidious in onset and chronic in duration. It
is more common in females and may not parallel bowel
disease activity. On slit-lamp examination uveitis presents
as a perilimbic edema and “infl ammatory fl are” in the an-
terior chamber. Conjunctival vessel injection and corneal
clouding may also be seen. An acute episode of uveitis
can lead to permanent damage of the eye with iris atro-
phy, lens deposits or synechiae. More aggressive therapy
may be necessary, especially when the posterior chamber
is affected. Prompt diagnosis and therapy with topical
and systemic steroids is crucial and sometimes intraocular
injections of corticosteroids may be necessary. Steroid
treatment should be continued for four weeks before ta-
pering if uveitis is under control. Iridospasm is relieved by
topical mydriatic eyedrops. Successful treatment for IBD-
associated uveitis with infl iximab was fi rst described in one
CD patient having a suitable extraintestinal constellation
(uveitis and sacroileitis)[64]. In rheumatoid arthritis with se-
vere refractory uveitis, infl iximab was effective but with an
unexpected high rate of side effects[65].
Ocular complications in IBD include keratopathy and
night blindness resulting from malabsorption of vitamin
A. Cataract development is a severe side effect of steroid
therapy, therefore regular ophthalmologic examination
should be considered. Rare eye manifestations are retinal
vascular disease (central vein occlusion or vasculitis),
peripheral corneal ulcers, corneal infiltrates and central
serous chorioretinopathy with bullous retinal detachment.
HEPATOBILIARY MANIFESTATIONS
Primary sclerosing cholangitis
In UC, the main hepatic EIM is primary sclerosing
cholangitis (PSC), a chronic infl ammatory disease of the
biliary tree, occurring in approximately 3% of all patients
(Figure 5). The diagnosis is made by endoscopic or
magnetic resonance cholangiography, showing beading,
irregularity, and stricturing of intrahepatic and extrahepatic
ducts. Histology ranges from obliterating concentric
fibrosis of the bile ducts to chronic inf lammatory
infi ltrates in the portal tracts resulting in interface hepatitis.
Low titres of autoantibodies against smooth muscle,
parietal cells, and nuclear antigens are common, and high
titres of autoantibodies to neutrophils (p-ANCAs)[66],
showing a perinuclear pattern of staining, have been
described. The majority (70%) of patients have the HLA-
DR3, B8 haplotype.
Treatment
Ursodeoxycholic acid has been suggested to delay disease
progression[67]. Although not avoiding the progression of
liver disease, ursodeoxycholic acid has been demonstrated
Figure 4 Sweet syndrome:
papulosquamous exanthema
in a patient with UC.
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