|
Laszlo
Lakatos, Tunde Pandur, Gyula David, 1st Department of
Medicine, Csolnoky F. Province Hospital, Veszprem
Zsuzsanna Balogh, Department of Medicine, Grof Eszterhazy
Hospital, Papa
Pal Kuronya, Department of Infectious Diseases, Magyar Imre
Hospital, Ajka
Arpad Tollas, Department of Medicine, Municipal Hospital,
Varpalota
Peter Laszlo Lakatos, 1st Department of Medicine,
Semmelweis University, Budapest, Hungary
Correspondence to: Laszlo Lakatos, MD, 1st Department of
Medicine, Csolnoky F. Province Hospital, Korhaz u.1, Veszprem,
H-8200 Hungary. laklaci@hotmail.com
Telephone: +36-20-911-9339
Fax: +36-1-313-0250
Received: 2003-06-21
Accepted: 2003-08-02
Abstract
AIM: IBD is a systemic disease associated with a large number of
extraintestinal manifestations (EIMs). Our aim was to determine the
prevalence of EIMs in a large IBD cohort in Veszprem Province in a
25-year follow-up study.
METHODS:
Eight hundred and seventy-three IBD patients were enrolled
(ulcerative colitis/UC/: 619, m/f: 317/302, mean age at
presentation: 38.3 years, average disease duration: 11.2 years;
Crohn’s disease/CD/: 254, m/f: 125/129, mean age at presentation:
32.5 years, average disease duration: 9.2 years). Intestinal,
extraintestinal signs and laboratory tests were monitored regularly.
Any alteration suggesting an EIMs was investigated by a specialist.
RESULTS:
A total of 21.3 % of patients with IBD had EIM (UC: 15.0 %, CD: 36.6
%). Age at presentation did not affect the likelihood of EIM.
Prevalence of EIMs was higher in women and in CD, ocular
complications and primary sclerosing cholangitis (PSC) were more
frequent in UC. In UC there was an increased tendency of EIM in
patients with a more extensive disease. Joint complications were
more frequent in CD (22.4 % vs UC 10.2 %, P<0.01). In UC
positive family history increased the risk of joint complications
(OR:3.63). In CD the frequency of type-1 peripheral arthritis was
increased in patients with penetrating disease (P=0.028). PSC
was present in 1.6 % in UC and 0.8 % in CD. Dermatological
complications were present in 3.8 % in UC and 10.2 % in CD, the rate
of ocular complications was around 3 % in both diseases. Rare
complications were glomerulonephritis, autoimmune hemolytic anaemia
and celiac disease.
CONCLUSION:
Prevalence of EIM in Hungarian IBD patients is in concordance with
data from Western countries. The high number of EIM supports a role
for complex follow-up in these patients.
Lakatos
L, Pandur T, David G, Balogh Z, Kuronya P, Tollas A, Lakatos PL.
Association of extraintestinal manifestations of inflammatory bowel
disease in a province of western Hungary with disease phenotype:
Results of a 25-year follow-up study. World J Gastroenterol
2003; 9(10):2300-2307
http://www.wjgnet.com/1007-9327/9/2300.asp
INTRODUCTION
Ulcerative colitis (UC) and Crohn’s disease (CD) are chronic
inflammatory diseases of undetermined origin. Inflammatory bowel
disease (IBD) is a multifactorial polygenic disease with probable
genetic heterogeneity. In this hypothesis, the disease may develop
in a genetically predisposed host as a consequence of altered
mucosal barrier and disregulated immune response to environmental,
in particular enteric antigens, resulting in continuous
immune-mediated inflammation[1-4]. IBD predominantly
affects the gastrointestinal system but it is associated with a
large number of extraintestinal manifestations (EIMs)[5].
Some disorders parallel the activity of the bowel disease but for a
number of these conditions, their courses run independently of the
course of the intestinal disease[6,7]. Furthermore, there
has been some variance in the literature as to whether these EIMs
are more associated with CD or UC. In the classical study of
Greenstein et al.[8] EIMs were classified as
colitis associated, small bowel associated and none specific
manifestations.
EIMs
contribute significantly to morbidity and mortality. Defining
specific associations of immune mediated diseases in extraintestinal
sites and IBD may be helpful in the better understanding of the
pathogenesis of IBD.
The
pathogenesis of EIMs is also multifactorial. The role of genetic
factors is supported by family and candidate (e.g. certain HLA) gene
studies[9-11]. The role of humoral immunity is supported
by the higher prevalence of autoantibodies in the presence of EIMs,
especially pANCA in primary sclerosing cholangitis (PSC). The
immunological and clinical connections between these diseases and
IBD have never been fully elucidated.
In
this study we aimed to define the prevalence of EIMs in a 25-year
follow up study in Hungarian IBD patients. We sought to determine if
any of the EIMs was more likely associated with CD or UC, with male
or female gender in a follow-up study. Possible associations between
EIMs and location and disease behaviour were also investigated.
MATERIALS
AND METHODS
Eight hundred and seventy-three IBD patients followed-up at the
Out- and Inpatient Gastroenterology Units of the Csolnoky F.
Province Hospital in Veszprem Province were enrolled. This hospital
is the secondary referral center for IBD patients in the province.
The
data of the 619 UC patients (male/female: 317/302) are summarized in
Table 1. The age at presentation varied between 9 and 80 years
(average: 38.3 years). Average disease duration was 11.2 years (1-56
years). The location of UC according to the known greatest extent
was proctitis in 117, left sided colitis in 304 (including 171
patients with proctosigmoiditis), subtotal (98) and pancolitis (100)
in 198 cases. Two hundred and fifty-four CD patients were included
(125 males, 129 females). Average age at presentation was 32.5 years
(12-80 years). According to the Vienna classification 192 patients
were classified as A1, while 62 as A2. Disease duration was 9.2
years (1-40 years). Location of CD was ileal (L1) in 60, colonic
(L2) in 81 and ileocolonic (L3) in 113 cases. Patients with upper GI
manifestation had lower GI disease as well and they were classified
according to their lower GI disease. According to the disease
behavior 83 of our CD patients were defined as non-stricturing
non-penetrating, 62 as stricturing and 105 as penetrating.
Fifty-eight patients of the 95 penetrating cases had parallel
strictures. Patients with indeterminate colitis were excluded.
Table
1 Clinical data of
IBD patients
| |
Ulcerative
colitis |
Crohn’s
disease |
| Number
of patients |
619 |
254 |
| Male/female |
317/302 |
125/129 |
| Mean
age at diagnosis |
38.3
yrs (9-80 yrs) |
32.5
yrs (12-80 yrs) |
| Location |
Proctitis:
117 |
L1:
60 |
| |
Left
sided colitis: 304 |
L2:
81 |
| |
Pancolitis:
198 |
L3:
113 |
| Behaviour
of CD |
- |
B1:
87 |
| |
|
B2:
62 |
| |
|
B3:
105 |
In
Crohn’s disease (CD). Location: L1: terminal ileum, L2: colonic,
L3: ileocolonic, behaviour: B1: non stricturing-non penetrating, B2:
stricturing, B3: penetrating.
Patients in remission were followed-up twice per year.
Patients who relapsed were followed-up or hospitalised according to
the actual disease activity. Special interest was dedicated to the
presence of EIM. Screening of EIMs was not performed, therefore the
number of EIMs may have been underestimated. Routine follow-up
consisted of assessment of patient’s complaints, physical
examination and laboratory testing.
Any
alteration suggesting an EIMs was investigated by a specialist. In
this study we did not assess the association between disease
activity and the presence of EIM. Major EIMs studied in this report
were axial and peripheral arthropathies (including ankylosing
spondylitis), aseptic femoral head necrosis, primary sclerosing
cholangitis (PSC), small duct cholangitis, autoimmune hepatitis,
erythema nodosum, pyoderma gangrenosum, chronic urticaria, acute
anterior uveitis, iritis, episcleritis, conjunctivitis, autoimmune
hemolytic anaemia (AIHA), immune thrombocytopenic purpura (ITP),
celiac disease, myositis, and glomerulonephritis.
Joint
involvements were classified as peripheral and/or axial
arthropathies. Peripheral arthropathies were divided into two
subgroups according to the classification of Orchard et al[13].
Type-1 arthritis is an acute self-limiting pauciarticular (less than
5 joints) arthropathy typically affecting large joints. It is
associated with other EIMs and its course parallels with the
activity of the bowel disease. In contrast, type 2 arthritis is a
chronic bilateral, symmetrical polyarticular arthropathy affecting
five or more small joints. Its course runs independently of the
course of the intestinal disease. Axial arthropathies are divided
into sacroileitis and ankylosing spondylitis (SPA). Its incidence is
20-times higher than that in the normal population[14].
Rheumatologists investigated sacroileitis and ankylosing spondylitis
cases. Laboratory testing (rheumatoid factor), X-ray and since 1997
MRI examinations were done.
Patients
with elevated liver function tests (LFT, aminotransferases,
cholestatic enzymes) were followed-up more cautiously. In patients
with chronic or progressive elevation of enzyme levels liver biopsy
and/or endoscopic retrograde cholangiopancreatography (ERCP)
examination was done if patient gave informed consent. The diagnosis
of PSC was based on elevated liver function tests, ERCP and
consistent histology findings. Small duct PSC was diagnosed if
histology suggested PSC, but ERCP could not verify the diagnosis[15,16].
Cholelithiasis, cirrhosis and focal nodular hyperplasia (FNH) were
excluded from hepatobiliary manifestations.
In
patients with verified thrombosis, blood samples were examined for
hypercoagulability including in almost all cases analysis of
plasminogen, proteins C and S activity and factor V Leiden mutation.
Patients with glomerulonephritis were followed-up by
nephrologists as well. Diagnosis was based on clinical and chemical
data and congruent histology findings. Ureteral obstruction was
diagnosed by cystoscopy and urography, CT or MRI. If the alteration
suggested fistulae in the urinary tract, cytography was also
performed.
Statistical
analysis
For statistical comparison of the data, Statistica 6.0 (Statsoft
Inc, USA) was used. Normality was tested by Shapiro-Wilk’s W test.
x2 test with Yates correction was used to compare groups
and odds ratios were calculated.
RESULTS
The prevalence of major (joint, hepatobiliary, ocular and
cutaneous) and all EIMs determined in this study are shown in Table
2. Major EIMs were apparent more frequently in CD than in UC (36.6 %
vs 15.0 %, P<0.001). EIMs were more frequent in patients
with a disease duration for more than 10 years in both CD (22.1 % vs
48.9 %, P=0.003) and UC (22.1 % vs 10.4 %, P<0.001).
Table
2 Prevalence of
extraintestinal manifestations (EIM) in IBD
|
Total
n (%) |
Disease
duration |
|
≤
10 yrs n (%) |
≤
10 yrs n (%) |
| IBD |
873 |
511 |
352 |
| Major
EIMs |
186
(21.3) |
86
(16.8) |
102
(30.0) |
| All
EIM signs |
547
(62.7) |
278
(54.4) |
269
(76.4) |
| Ulcerative
colitis |
619 |
357 |
262 |
| Major
EIMs |
93
(15.0) |
37
(10.4) |
58
(22.1) |
| All
EIM signs |
360
(58.2) |
167
(46.8) |
193
(73.7) |
| Crohn’s
disease |
254 |
164 |
90 |
| Major
EIMs |
93
(36.6) |
49
(29.9) |
44
(48.9) |
| All
EIM signs |
187
(73.6) |
111
(67.7) |
76
(84.4) |
The prevalence of EIMs was higher in CD except ocular
complications and PSC (P<0.001 for joint, hepatobiliary
and cutaneous manifestations, Tables 3 and 4). In general, EIMs were
more frequent in women except hepatobiliary manifestations and
arthropathies in UC patients.
All
major EIMs were more prevalent in more extensive UC (Table 5). There
was a tendency of increased frequency of joint manifestations in CD
patients with colonic involvement (L2 and L3: 23.7 %) compared to
patients with only ileal disease (18.3 %, P=NS, Table 5). The
prevalences of hepatobiliary, ocular and cutaneous manifestations
were not different according to disease location.
Table
3 Age at
presentation and prevalence of major extraintestinal manifestations
in patients with IBD
|
A1
n (%) |
A2
n (%) |
| UC
(n: 619) |
369 |
250 |
| Joint |
32
(8.7) |
20
(8.0) |
| Hepatobiliary |
49
(13.3) |
28
(11.2) |
| Cutaneous |
17
(4.6) |
7
(2.8) |
| Ocular |
11
(3.0) |
8
(3.0) |
| CD
(n: 254) |
192 |
62 |
| Joint |
48
(25.0) |
9
(14.5) |
| Hepatobiliary |
48
(25.0) |
9
(14.5) |
| Cutaneous |
20
(10.4) |
6
(9.7) |
| Ocular |
5
(2.6) |
3
(4.8) |
A1:
age at presentation <40 yrs, A2: age at presentation ≥40 yrs.
Table
4A Familial IBD and
association with extraintestinal manifestations
|
Total |
First
degree relative |
Second
degree relative |
| Ulcerative
colitis |
24/619 |
18
(14 UC+4 CD) |
6 (5 UC+1 CD) |
|
(3.9
%) |
(2.9
%) |
(1.0%) |
| Crohn’s
disease |
31/254 |
20
(3 UC+17 CD) |
11
(2 UC+9 CD) |
|
(12.2
%) |
(7.9%) |
(4.3%) |
Table
4B Familial IBD and
association with extraintestinal manifestations
|
Ulcerative
colitis |
Familial
IBD |
| Number
of patients |
619 |
24 |
| Joint |
52
(8.4 %) |
6
(25.0 %) |
| Hepatobiliary |
77
(12.4 %) |
3
(12.5 %) |
| Cutaneous |
24
(3.9 %) |
1
(4.2 %) |
| Ocular |
19
(3.0 %) |
2
(8.3 %) |
|
Crohn’s
disease |
Familial
IBD |
| Number
of patients |
254 |
31 |
| Joint |
57
(22.4 %) |
11
(35.5 %) |
| Hepatobiliary |
57
(22.4 %) |
4
(12.9 %) |
| Cutaneous |
26
(10.2 %) |
2
(6.5 %) |
| Ocular |
8
(3.1%) |
0 |
Table
5 Prevalence of
extraintestinal manifestations in ulcerative colitis and Crohn’s
disease according to location and disease behaviour
|
Joint
n (%) |
Hepatobiliary
n (%) |
Cutaneous
n (%) |
Ocular
n (%) |
| Location |
|
Ulcerative
colitis |
|
|
| Proctitis
(n=117) |
5
(4.3) |
9
(7.7) |
1
(0.9) |
1
(0.9) |
| Left
sided colitis (n=304) |
14
(4.6) |
32 (15.7) |
8
(2.6) |
7
(2.3) |
| Pancolitis
(n=198) |
33
(16.7) |
36 (18.2) |
15
(7.6) |
12
(6.1) |
| Location |
|
Crohn’s
disease |
|
|
| L1
(n=60) |
11
(18.3) |
14
(23.3) |
6
(10.0) |
2
(3.3) |
| L2
(n=81) |
17
(21.0) |
17
(21.0) |
10
(12.3) |
3
(3.7) |
| L3
(n=113) |
29
(25.7) |
26
(23.0) |
10
(8.8) |
3
(2.7) |
| Behaviour |
|
|
|
|
| B1
(n=87) |
13
(14.9) |
22
(25.3) |
11
(12.6) |
1
(1.1) |
| B2
(n=62) |
16
(25.8) |
11
(17.7) |
5
(8.1) |
0 |
| B3
(n=105) |
28
(27.6) |
24
(22.9) |
10
(9.5) |
7
(6.7) |
Age at presentation (A1: <40 years, A2: =40 years) did
slightly affect the prevalence of EIMs (Table 3). Joint
manifestations were more prevalent in CD patients with earlier
disease onset (OR: 1.96, 95 % CI: 1.01-4.21). The same tendency was
observed for cutaneous manifestations.
Familial
disease was seen in 3.9 % of patients with UC and 12.2 % of patients
with CD (Tables 4A-B). Joint manifestations were more frequent in UC
patients with familial disease (OR: 3.63, 95 % CI: 1.43-9.31) than
without. The same tendency was seen in UC patients (OR: 1.9, 95 %
CI: 0.87-4.14) and ocular
manifestations were found in familial UC cases.
Table
6A Joint
manifestations in IBD patients
| |
Total
n (%) |
Axial
arthritis
n (%) |
Type-1
arthritis
n (%) |
Type-2
arthritis
n (%) |
| Ulcerative
colitis |
|
|
|
|
| Total
(n=619) |
52
(8.4) |
20
(3.2) |
17
(2.7) |
13
(2.1) |
| Male
(n=317) |
24
(7.6) |
10
(3.2) |
7
(2.2) |
7
(2.2) |
| Female
(n=302) |
28
(9.3)* |
10 (3.4) |
10
(3.3) |
6
(2.0) |
| Crohn’s
disease |
|
|
|
|
| Total
(n=254) |
57
(22.4) |
26
(10.2) |
29
(11.4) |
8
(3.1) |
| Male
(n=125) |
23
(18.4) |
11
(8.8) |
12
(9.6) |
3
(2.4) |
| Female
(n=129) |
34
(26.4) |
15 (11.6) |
17
(13.2) |
5
(3.9) |
*Two
female patients with ulcerative colitis had rheumatoid arthritis.
Table
6B Joint
manifestations in IBD according to location and disease behaviour
|
Total
n (%) |
Axial
arthritis n
(%) |
Type-1
arthritis n
(%) |
Type-2 arthritis
n (%) |
| Location |
|
Ulcerative
colitis |
|
|
| Proctitis
(n=117) |
5 (4.3)* |
1
(0.9) |
2 (1.8) |
1
(0.9) |
| Left
sided colitis(n=304) |
14
(4.6) |
4
(1.3) |
5 (1.6) |
5
(1.6) |
| Pancolitis
(n=198) |
33
(16.7)* |
15
(7.6) |
10 (5.0) |
7
(3.5) |
| Location |
|
Crohn’s
disease |
|
|
| L1
(n=60) |
11
(18.3) |
5
(8.3) |
4
(6.7) |
2
(3.3) |
| L2
(n=81) |
17
(21.0) |
7
(8.6) |
10
(12.3) |
3 (3.7) |
| L3
(n=113) |
29
(25.7) |
14
(12.4) |
15
(13.3) |
3 (2.7) |
| Behaviour |
|
|
|
|
| B1
(n=87) |
13
(14.9) |
8
(9.2) |
5
(5.7) |
2
(2.3) |
| B2
(n=62) |
16
(25.8) |
8
(12.9) |
6
(9.7) |
3 (4.8) |
| B3
(n=105) |
28
(27.6) |
10
(9.5) |
18
(17.1) |
3 (2.9) |
*One
patient with proctitis and one with pancolitis had rheumatoid
athritis.
Joint manifestations were more frequent in CD than in UC (P<0.001,
Tables 6A-B.). There was a tendency of increased frequency of joint
manifestations in women with CD (26.4 % vs 18.4 %, OR: 1.58, 95 %
CI: 0.87-2.87). Axial arthritis (10.2 % vs 3.2 %, P=0.0001)
and type 1(11.4 % vs 2.7 %, P=0.0001) arthritis were more
frequent in CD, with equal prevalence of type-2 arthritis. In UC
joint manifestations were almost three-fold more frequent in
patients with pancolitis compared to proctitis and left sided
colitis cases (P<0.002 for both, Table 5). In CD a
tendency of increased frequency of joint manifestations was observed
in patients with colonic involvement (L2 and L3: 23.7 %) or
stricturing/penetrating disease (26.3 %) compared to patients with
ileal only disease (18.3 %) or non-stricturing non-penetrating
disease behavior (14.9 %, Table 6B). An increased frequency of type
1 arthritis was observed in patients with penetrating compared to
non-stricturing non-penetrating disease (P=0.028), the same
tendency was observed in patients with or without colonic
involvement. Type-1 arthritis affected more frequently the joints of
the lower extremities (most frequently the knee and ankle), while
type-2 arthritis was more common in the joints of the upper
extremities.
Hepatobiliary
manifestations are summerised in Table 7. PSC was diagnosed in 10
patients with UC and only 2 patients with CD. Small duct PSC was
diagnosed in 8 and 6 cases, respectively. Non-alcoholic fatty liver
disease (NAFLD) or non-alcoholic steatohepatitis (NASH) was
diagnosed in 9.4 % of UC patients and 19.3 % of CD patients (P<0.0001).
These patients had unexplained abnormal liver function tests (viral
hepatitis, autoimmune, drug or alcohol induced disease, extrahepatic
obstruction excluded). Liver biopsy was performed in 22/107 cases,
which identified NAFLD or NASH in almost all cases. US proved
hepatomegaly in 13/107 (12.1 %). Progression to cirrhosis was not
observed in these patients during follow-up.
Table
7 Hepatobiliary
manifestations in IBD patients
|
Total
n (%) |
PSC
n (%) |
Small duct PSC
n (%) |
NAFLD/ NASH n (%) |
| Ulcerative
colitis |
|
|
|
|
| Total
(n=619) |
77*
(12.4) |
10
(1.6) |
8
(1.3) |
58
(9.4) |
| Male
(n=317) |
39
(12.3) |
3
(1.0) |
6 (1.9) |
30
(9.5) |
| Female
(n=302) |
38*
(12.6) |
7
(2.3) |
2 (0.7) |
28
(9.3) |
| Crohn’s
disease |
|
|
|
|
| Total
(n=254) |
57
(22.4) |
2
(0.8) |
6 (2.4) |
49
(19.3) |
| Male
(n=125) |
27
(21.6) |
2
(1.6) |
6 (4.8) |
19
(15.2) |
| Female
(n=129) |
30
(23.3) |
0 |
0 |
30
(23.3) |
*One
female patient had autoimmune hepatitis. NAFLD: non-alcoholic fatty
liver disease, NASH: non-alcoholic steatohepatitis.
Cutaneous manifestations were seen in 10.2 % of the patients
with CD and 3.9 % of the patients with UC (Tables 8A-B). Cutaneous
manifestations were more common in women in both UC (male/female:
5.0 %/2.8 %) and CD (13.2 %/7.2 %, OR: 1.95, 95 % CI: 0.85-4.48).
Erythema nodosum and pyoderma gangrenosum were the most frequent
manifestations. In UC cutaneous manifestations were more frequent in
more extensive disease (7.6 % in pancolitis vs 2.1 % in proctitis or
left sided colitis, P=0.002).
Ocular
manifestations were apparent in approximately 3.0 % of UC and CD
patients (Table 9). The prevalence was more frequent in women in
both UC (P=0.009, OR: 4.37, 95 % CI: 1.51-12.6) and CD
(OR:3.0, 95 % CI=0.67-8). Conjunctivitis, acute anterior uveitis and
scleritis were the most frequent manifestations. Ocular
manifestations developed mostly during the early years of the
disease. In UC more than half of the patients with ocular
complication had pancolitis (6.1 % in pancolitis vs 1.9 % in left
sided colitis or proctitis, P=0.01).
Iron
deficiency anaemia was seen in 35.8 % of CD patients and in one
fourth of UC patients (Tables 10A-C). It was more frequent in women
in UC (32.1 % vs 19.6 %, P<0.001, OR=1.95, 95 % CI:
1.35-2.81). Chronic anaemia was more frequent in patients with CD
(9.6 % vs 17.7 %, P<0.001). The prevalence of macrocytic
anaemia was around 4 % in both diseases. It was also observed more
frequently in patients with ileocolonic disease than without it (P=0.03).
The same tendency was observed according to disease behaviour;
chronic anaemia tended to be more frequent in patients with
stricturing or penetrating disease (P=0.06, Table 10C). AIHA
developed in four UC patients.
Table
8A Cutaneous
manifestations in patients with ulcerative colitis (n=619)
| |
Total
n (%) |
Male
n (%) |
Female
n (%) |
| Erythema
nodosum |
8
(1.3) |
2 (0.6) |
6
(2.0) |
| Pyoderma
gangrenosum |
3
(0.5) |
1 (0.3) |
2
(0.6) |
| Chronic
urticaria |
6
(1.0) |
2
(0.6) |
4
(1.3) |
| Psoriasis |
3
(0.5) |
2
(0.6) |
1
(0.3) |
| Aphthous
stomatitis |
3 (0.5) |
1
(0.3) |
2
(0.6) |
| Herpes
zoster |
2
(0.3) |
1
(0.3) |
1
(0.3) |
| Cellulitis |
2
(0.3) |
0 |
2
(0.6) |
| Recurrent
dermatitis |
2
(0.3) |
1
(0.3) |
1
(0.3) |
| Lichen
ruber planus |
1
(0.2) |
| |