Kwak et al.

BMC Gastroenterology 2014, 14:85

http://www.biomedcentral.com/1471-230X/14/85

RESEARCH ARTICLE Open Access

Efficacy of early immunomodulator therapy on

the outcomes of Crohn’s disease
Min Seob Kwak1, Duk Hwan Kim1, Soo Jung Park1,2, Tae Il Kim1,2, Sung Pil Hong1,2, Won Ho Kim1,2
and Jae Hee Cheon1,2,3*

Abstract
Background: The natural course of Crohn’s disease (CD), with continuing relapses and remissions, leads to
irreversible intestinal damage. Early adoption of immunomodulator therapy has been proposed in order to address
this; however, it is still uncertain whether early immunomodulator therapy could affect the natural course of the
disease in real practice. We evaluated the efficacy of such therapy on the prognosis of newly diagnosed patients
with CD.
Methods: This retrospective study included 168 patients who were newly diagnosed with CD and who started
treatment at Severance Hospital, Seoul, Korea between January 2006 and March 2013. The short- and long-term
outcomes were compared between patients treated with early immunomodulator therapy and those treated with
conventional therapy.
Results: A Kaplan-Meier analysis identified that administration of immunomodulators within 6 months after diagnosis
of CD was superior to conventional therapy in terms of clinical remission and corticosteroid-free remission rates
(P=0.043 and P=0.035). However, there was no statistical significance in the disease relapse rate between the two
groups (P=0.827). Patients with a baseline elevated CRP level were more likely to relapse (P<0.005). Drug-related
adverse events were more frequent in the early immunomodulator therapy group than in the conventional therapy
group (P=0.029).
Conclusions: Early immunomodulator therapy was more effective than conventional therapy in inducing remission,
but not in preventing relapse. Baseline high CRP level was a significant indicator of relapse.
Keywords: Crohn’s disease, Azathioprine, 6-mercaptopurine, Immunomodulator

Background agents [1]. A step-up strategy, i.e., a progressively intensi-

Crohn’s disease (CD) is a chronic inflammatory disease fied method of treatment, is being recommended in
with unknown etiology that can affect any part of the current guidelines for medical therapy of CD [2,3].
gastrointestinal tract. Patients with CD have a host of For mild disease, less toxic but often less efficacious
symptoms, including diarrhea, hematochezia, abdominal drugs are recommended, while on the other hand, more
pain, weight loss, and fever. The last few decades have efficacious yet potentially more toxic drugs are typically
seen a gradual increase in the number of drugs available administered to patients with severe disease or those
for use in the treatment of CD. From a time when only who are not responsive to first-line therapy. The purpose
sulfasalazine/5-aminosalicylic acids, corticosteroids, and of this strategy is to ensure therapeutic endpoints such as
antibiotics were used, we now have immunomodulators induction and maintenance of clinical relief, withdrawal
such as thiopurines and methotrexate, as well as biological from steroids, and prevention of post-operative relapse.
However, conventional treatment has not been successful
* Correspondence: [email protected] in reducing complications or the need for surgery [4].
1
Department of Internal Medicine, Graduate School, Yonsei University According to several recent studies, more aggressive
College of Medicine, Seoul, Korea
2
Department of Internal Medicine and Institute of Gastroenterology, Yonsei
treatment early in the disease may result in betterre-
University College of Medicine, Seoul, Korea sponse and remission rates [2,5,6]. However, one cohort
Full list of author information is available at the end of the article

© 2014 Kwak et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain
Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,
unless otherwise stated.
Kwak et al. BMC Gastroenterology 2014, 14:85 Page 2 of 6
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study showed that although immunomodulators have Definition of treatment response and disease relapse
been used more frequently over the last 25 years, there Clinical remission was defined as a CDAI < 150 and clin-
was no significant decrease in the need for surgery in ical response was defined by a 100 point decrease from
patients with CD [4]. Therefore, it remains uncertain the baseline CDAI score [9]. Steroid-free remission was
whether early immunomodulator therapy could affect defined as maintaining remission for up to 4 weeks after
the natural course of disease in real practice. Few studies complete withdrawal of corticosteroids. The definition of
have focused on the effect of early immunomodulator disease relapse was a CDAI >150 points plus a 100-point
therapy on the natural course of CD. Accordingly, we increase from CDAI baseline [9].
evaluated the efficacy of early immunomodulator ther-
apy on the prognosis of patients newly diagnosed with Primary and secondary outcome measures
CD in a clinical setting. The primary outcome measure was the proportion of
patients responsive to treatment at each time point during
a 12-month period. The following secondary outcome
Methods
measures were considered: (1) clinical remission rate of
Patients
each group, (2) steroid-free clinical remission rate of each
We enrolled a total of 168 patients who were newly diag-
group, (3) disease relapse rate of each group, (4) disease-
nosed with CD and who started treatment at Severance
related hospitalization rate of each group, and (5) surgical
Hospital, Seoul, Korea between January 2006 and March
resection rate of each group.
2013. The diagnosis of CD was made according to previ-
ously established international criteria based on clinical,
Statistics
endoscopic, histopathological, and radiological findings
Statistical analyses were performed with SPSS software
[7]. The disease extent was determined through endo-
(version 18.0 for Windows; SPSS, Inc., Chicago, IL,
scopic and/or radiological work-up. Patients who were
USA). Continuous variables were compared using a two-
diagnosed with or suspected to have indeterminate colitis,
tailed Student’s t-test and categorical data were compared
coexistence of infectious or ischemic colitis, coexistence
using a two-tailed χ2 test or Fisher’ exact test. The clinical
of other localized or systemic infections, any malignant
response and disease relapse rates after treatment were
disease, major systemic illness, connective tissue disease,
illustrated using Kaplan Meier survival curves for the
or inflammatory arthritis were excluded. Patients in the
grouped factors over the intervention period. Moreover,
early therapy arm initiated immunomodulator therapy
we analyzed factors associated with relapse by logistic
(azathioprine or 6-mercaptopurine) within 6 months of
regression analysis. P -values <0.05 were considered to
diagnosis. The conventional therapy arm was comprised
indicate statistical significance.
of patients with CD who initiated immunomodulatory
therapy more than 6 months after being diagnosed, or
Results
who did not receive immunomodulators during the
Baseline patient characteristics
course of their disease. The Institutional Review Board of
The baseline characteristics of the 168 patients with CD
the Severance Hospital approved this study.
are listed in Table 1. Of them, 102 patients (81 males,
The Crohn’s Disease Activity Index (CDAI) [8], erythro-
median age ± SD, and 26.5 ± 11.0 years) were treated
cyte sedimentation rate (ESR, normal value <15 mm⁄hr),
with early immunomodulator therapy and the other 66
C-reactive protein level (CRP, normal value < 8 mg⁄L), and
patients (57 males, median age ± SD, 30.0 ± 12.3 years)
hematocrit level (Hct, normal value:40.4-52%) were regu-
were treated with conventional therapy. The baseline
larly monitored during the follow-up period.
characteristics of the patients such as age, sex, location
of disease, disease behavior, and laboratory findings ex-
Thiopurine dosing and follow-up protocol cept for medications used were not significantly different
The initial azathioprine dose (0.5-1.0 mg/kg) was between the two groups.
increased to 2.0 to 2.5 mg/kg over one- to four-week
intervals unless there were adverse effects. The initial 6- Primary and secondary outcome measures
mercaptopurine (6-MP) dose (0.25-0.5 mg/kg) was The median length of follow-up for patients was
increased in the same fashion to 1.0 to 1.5 mg/kg. Dur- 27 months (Range, 35 or IQR, 21). The clinical remis-
ing AZA/6-MP therapy, 5-ASA was administered at a sion rates at 6 months were 85.0% in the early immuno-
conventional dose (mesalazine 3.0 g/day). Outpatient modulator group and 76.4% in the conventional therapy
visits were scheduled at one- to two-week intervals for group, respectively (Figure 1A). There was a statistically
the first month, a visit at two months, and visits every significant difference in the overall remission rate be-
2–3 months thereafter, according to the patient’s clinical tween the two groups (Log Rank test P =0.043). In
condition. addition, corticosteroid-free clinical remission rates at 6
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Table 1 Clinical characteristics of patients with Crohn’s increased to 22.3% at 24 months and to 60.9% at
disease (N = 168) 36 months (Figure 2A). In patients treated with conven-
Characteristics Early immuno- Conventional P-value tional therapy the relapse rates at months 12, 24, and 36
modulator therapy therapy were 3.6%, 18.2%, and 68.6%, respectively. There was no
Age, yr, median (IQR) 26.5 (11.0) 30 (12.3) 0.137 statistical significance in relapse rates between the two
Sex, (%) 0.305 groups (Log Rank test P=0.827) (Figure 2A).
Male 81 (79.4) 57 (86.4) After 12, 24, and 36 months of treatment, surgical resec-
Female 21 (20.6) 9 (13.6)
tion was performed in 7.8%, 15.0%, and 37.4% of patients
on early immunomodulator therapy, and in 1.6%, 4.7%,
Activity status at start 0.474
medication, (%) and 31.8% of patients on conventional therapy, respect-
ively, which was not a statistically significant difference
Remission 7 (6.9) 5 (7.6)
(Log Rank test P=0.326) (Figure 2B).
Mild 24 (23.5) 17 (25.8)
There was no difference in the risk of disease-related
Moderate 70 (68.6) 41 (62.1) hospitalization between the two groups at 12, 24, and
Severe 1 (1.0) 3 (4.5) 36 months, respectively (13.5%, 21.0%, and 50.0% vs. 1.1%,
Location, (%) 0.191 6.8%, and 45.7%, Log Rank test P=0.228) (Figure 2C).
L1 (ileal) 9 (8.8) 2 (3.0)
Predictive factors related to disease relapse
L2 (colonic) 13 (12.7) 7 (10.6)
According to univariate analysis, age, gender, body mass
L3 (ileocolonic) 16 (15.7) 13 (19.7)
index (BMI), and disease activity as assessed by CDAI
L4 (only upper GI) 0 (0) 3 (4.5) were not significant predictors of relapse (Table 2). In
NA 64 (62.8) 41 (62.2) the analysis of ESR, CRP, and hematocrit, we selected
Behavior at 0.651 cut-off points of 15, 8.0, and 40.4, respectively. Patients
diagnosis, (%) who had higher CRP levels relapsed more frequently
B1 (non-stricturing, 20 (19.6) 14 (21.2) compared with those who had lower CRP levels (odds ra-
non-penetrating) tio, 3.000; 95% confidence interval, 1.504–5.983; P< 0.005)
B2 (stricturing) 10 (9.8) 3 (4.6) (Table 2). However, there were no significant associations
Perianal disease 8 (7.8) 8 (12.1) between disease relapse and ESR or hematocrit (Table 2).
NA 64 (62.8) 41 (62.1)
Adverse events and side effects
Initial medication, (%) <0.001
Eleven patients treated with early immunomodulator ther-
Only 5-ASA 54 (52.9) 56 (84.8)
apy experienced adverse events such as abdominal pain,
5-ASA with steroids 9 (8.8) 10 (15.2) bone marrow suppression, diarrhea, nausea, edema, and
Only 3 (2.9) 0 (0) dermatitis (Table 3). Medication tolerance was very good
immunomodulators overall in the patients on conventional therapy (Table 3).
Immunomodulators 36 (35.3) 0 (0) Early immunomodulator therapy was significantly associ-
with 5-ASA
ated with the development of an adverse event (P=0.029).
CDAI, median (IQR) 263.0 (119.5) 249.2 (117.9) 0.643
BMI, median (IQR) 19.8 (4.7) 18.9 (3.7) 0.141 Discussion
CRP, median (IQR) 8.1 (39.2) 8.9 (24.8) 0.052 For a considerable number of patients, the natural course
ESR, median (IQR) 54.0 (59.0) 55.0 (52.0) 0.462 of CD has a poor prognosis. Nearly all patients suffer from
symptomatic flares and subsequent complications over a
Hct, median (IQR) 38.4 (8.6) 37.3 (7.2) 0.905
ten-year period [10]. Traditionally, symptom control was
IQR, inter-quartile range; CDAI, Crohn’s disease activity index; BMI, body mass
index; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; Hct, the principal goal of treatment. The conventional thera-
hematocrit; NA, not applicable. peutic strategy for CD dictates that medications are
chosen based on the severity of symptoms.
In recent years, however, a change in the treatment
and 12 months were noted in 44.8% and 62.1% of patients goals for patients with CD has come under intense
in the early immunomodulator group, respectively, and in discussion. To maintain a good quality of life, and to
22.7% and 38.6% in the conventional group. This also keep the patient from suffering any irreversible conse-
reached statistical significance (Log Rank test P =0.035) quences, very early intensive therapy (immunomodulators
(Figure 1B). and/or biologics) has been suggested as a top-down treat-
In the patients treated with early immunomodulator ment strategy [11]. The rationale for such an approach
therapy, 7.0% relapsed at 12 months. This percentage comes from rheumatology, where early intervention with
Kwak et al. BMC Gastroenterology 2014, 14:85 Page 4 of 6
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A B

Cumulative clinical remission rate (%)

100 100 Early immunomodulator therapy

Cumulative clinical steroid-free

Conventional therapy
80 80
P=0.035

remission rate (%)

60 60

40 40
P=0.043
20 20

Early immunomodulator therapy

0 Conventional therapy 0
0 2 4 6 0 2 4 6 8 10 12
Time to remission Time to steroid-free remission

Figure 1 The cumulative probabilities of patients who achieved clinical remission (A), and steroid-free remission (B) between early
immunomodulator therapy and conventional therapy groups.

immunomodulators or biologics is thought to prevent immunomodulators might have much more benefit in
progressive destruction of joints [12]. achieving clinical remission than the conventional strat-
There are few studies on the efficacy of early immuno- egy. Moreover, the steroid-free remission rate was also
modulator therapy in patients with CD, and they report significantly higher in the early immunomodulator
many differences in clinical outcomes. These studies have group. The maintenance of steroid-free remission is a
shown that early administration of immunomodulators in major issue and one of the major treatment goals in
patients with CD resulted in superior clinical outcomes these patients.
when compared to conventional therapy, with a compar- It is important to consider how long specific treatments
able safety profile [13]. On the contrary, in other studies, maintain clinical remission when evaluating the effective-
early immunomodulator therapy had no significant impact ness of a treatment. In a recent study, administration of
on CD course [2,14,15]. immunomodulative agents within 6 months in CD patients
D'Haens G et al. found that early immunomodulator was no more effective than conventional management in
and biologic therapy was more effective than conven- increasing the duration of clinical remission [14]. Similarly,
tional management for induction of remission [5]. Like- in our study, there was no difference in the disease relapse
wise, we showed that early immunomodulator therapy rate between the two groups. There are some possible ex-
demonstrated a higher rate of remission than conven- planations for the above results. Most importantly, many of
tional therapy, suggesting that early intervention with the patients might have been included in the early therapy

A B C
Cumulative relapse-free survival rate (%)

Cumulative surgery-free survival rate (%)

100 100 100

Cumulative hospitalization-free

80 80 80
survival rate (%)

60 60 60

40 40 40

20 P=0.827 20 P=0.228 20 P=0.326

Early immunomodulator therapy Early immunomodulator therapy Early immunomodulator therapy
0 Conventional therapy 0 Conventional therapy 0 Conventional therapy

0 10 20 30 40 0 10 20 30 40 0 10 20 30 40
Time to relapse Time to hospitalization Time to surgery
Figure 2 The cumulative probabilities avoiding disease relapse (A), hospitalization (B), and surgery (C) between early immunomodulator
therapy and conventional therapy groups.
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Table 2 Univariate logistic regression analysis of baseline between the two groups (Log Rank test P =0.326). There
factors related to relapse are some possible reasons for the differences in surgical
Valuables OR (95% CI) P-value resection rates between these studies. First, the diverse
Age 0.999 (0.967-1.032) 0.940 genetic predisposition of the subjects may be one of the
Gender Male major factors causing these differences [18]. Second, in
the study by Lakatos et al., patients who had used bio-
Female 0.769 (0.337-1.754) 0.533
logical agents were included in the early treatment group,
BMI 0.980 (0.866-1.109) 0.748
which may also play a role. In Korea, biologics were
CDAI severity Mild launched into market very late, and patients are allowed
Moderate 1.957 (0.186-20.614) 0.576 to use biologics only after the failure of immunomodula-
Severe 2.203 (0.222-21.849) 0.500 tors and corticosteroids.
ESR* > 15 mm/hr 0.745 (0.321-1.727) 0.492 The disease-related hospitalization rates observed in our
study showed no difference between the two groups. Simi-
CRP† > 8.0 mg/L 3.000 (1.504-5.983) 0.002
larly, the AZTEC study investigated by Sans M et al. dem-
Hct‡ > 40.4% 1.203 (0.622-2.329) 0.583
onstrated that early use of immunomodulators did not
CDAI, Crohn’s disease activity index; BMI, body mass index; ESR, erythrocyte
sedimentation rate; CRP, C-reactive protein; Hct, hematocrit; *cut-off value, 15;
reduce the disease-related hospitalization rate [19].
†cut-off value, 8.0; ‡cut-off value, 40.4. Several biomarkers have been evaluated as indicators
of disease activity and predictors of the risk of relapse in
group receive earlier immunomodulator therapy because patients with CD who are in remission [20]. CRP has
of their poor clinical features at the start of treatment. Fur- been reported to be useful in predicting short-term
thermore, a considerable number of patients with conven- prognosis and relapse [21-23]. In previous reports, a
tional therapy initiated treatment with immunomodulators high baseline CRP was an independent predictor of
as time passed in our study, which was also seen by relapse [23,24]. According to our results, patients with a
D'Haens G et al. [5]. baseline elevated CRP levels showed a higher relapse
In choosing a treatment, we also should consider the rate. Thus, this could play a role in predicting relapse at
adverse events and side effects. Early immunomodulator the start of treatment in newly diagnosed CD patients.
therapy showed a higher frequency of adverse events in this So far, nearly all studies on the efficacy of early im-
study. Because of these problems, it is important to identify munomodulator therapy have focused on Caucasians.
the prognostic factors at the time of diagnosis, and earlier ad- However, the clinical features of CD in Asian popula-
ministration of immunomodulators should be recommended tions might be different from that in Caucasians [25].
in selected CD patients with poor prognostic factors. Some studies investigating Asian populations suggest
Surgical resection rates vary widely over time among that the prognosis might be better in Asians compared
published studies, ranging from 25 to 61% at 5 years in a to Western patients [26]. In this respect, this is the first
recent review [16]. There are a few studies showing that study from an Asian population, which is one of the
early use of immunomodulators reduces surgical rates. strengths of our study. Another strength of this study is
For example, Lakatos et al. found that early immunomod- that we demonstrate the efficacy and safety of early im-
ulator use was associated with a significantly decreased munomodulator therapy in CD patients from a clinical
time to first surgery in patients with CD [17]. However, practice setting. Patients encountered in real clinical
we observed no significant difference in surgery rates practice often differ from those included in registra-
tional trials. The former have a more heterogeneous
Table 3 Adverse events
mix of patients with co-morbidities and often have
poorer treatment adherence than the latter. Thus, it is
Early immuno- Conventional P-value
suppressive therapy therapy necessary to analyze the data from real clinical practice
Abdominal 1 – to confirm treatment efficacy.
pain The major limitation of our study is that it was a
Bone marrow 4 – retrospective, observational study, which had the poten-
failure tial for selection bias and confounding factors. Another
Diarrhea – 1 limitation comes from the small size of the studied
Nausea and 4 – population, which necessitates further prospective stud-
vomiting ies with a large number of patients.
Edema 1 –
Dermatitis 1 –
Conclusion
In conclusion, our study found that early immunomodula-
Total 11 (10.8) 1 (1.5) 0.029
tor therapy was more efficient than conventional therapy
Kwak et al. BMC Gastroenterology 2014, 14:85 Page 6 of 6
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in terms of achieving clinical remission. However, early Travis S, Stange E, European Crohn's and Colitis Organisation (ECCO): The
immunomodulator therapy failed to maintain clinical second European evidence-based Consensus on the diagnosis and
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Competing interests 14(7):949–954.
No potential conflict of interest relevant to this article was reported. 14. Cosnes J, Bourrier A, Laharie D, Nahon S, Bouhnik Y, Carbonnel F, Allez M,
Dupas J-L, Reimund J-M, Savoye G, Jouet P, Moreau J, Mary JY, Colombel JF,
Authors’ contributions Groupe d'Etude Thérapeutique des Affections Inflammatoires du Tube
MSK and JHC contributed to the conception and design of the study. DHK, Digestif (GETAID): Early administration of azathioprine vs conventional
SJP, TIK, SPH, and WHK were responsible for acquisition, analysis and management of Crohn's disease: a randomized controlled trial.
interpretation of data. MSK and JHC drafted the manuscript. All authors read Gastroenterology 2013, 145(4):758–765.
and approved the final manuscript. 15. Panés J, López-SanRomán A, Bermejo F, García-Sánchez V, Esteve M, Torres
Y, Domènech E, Piqueras M, Gomez-García M, Gutiérrez A, Taxonera C, Sans
Acknowledgements M, AZTEC Study Group: Early azathioprine therapy is no more effective
This study was supported by a grant (2013-E63004-00) from the Research of than placebo for newly diagnosed Crohn’s disease. Gastroenterology 2013,
Korea Centers for Disease Control and Prevention and a grant of the Korean 145(4):766–774.
Health Technology R&D Project, Ministry of Health & Welfare, Republic of 16. Wolters FL, Russel MG, Stockbrügger RW: Systematic review: has disease
Korea (grant number A120176). outcome in Crohn's disease changed during the last four decades?
Aliment Pharmacol Ther 2004, 20(5):483–496.
Author details 17. Lakatos PL, Czegledi Z, Szamosi T, Banai J, David G, Zsigmond F, Pandur T,
1
Department of Internal Medicine, Graduate School, Yonsei University Erdelyi Z, Gemela O, Papp J, Lakatos L: Perianal disease, small bowel
College of Medicine, Seoul, Korea. 2Department of Internal Medicine and disease, smoking, prior steroid or early azathioprine/biological therapy
Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, are predictors of disease behavior change in patients with Crohn's
Korea. 3Department of Internal Medicine, Yonsei University College of disease. World J Gastroenterol 2009, 15(28):3504–3510.
Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea. 18. Kim ES, Kim WH: Inflammatory bowel disease in Korea: epidemiological,
genomic, clinical, and therapeutic characteristics. Gut Liver 2010, 4(1):1–14.
Received: 6 February 2014 Accepted: 28 April 2014 19. Sans M, López-San Román A, Esteve M, Bermejo F, García-Sánchez V, Torres Y,
Published: 3 May 2014 Domenech E, Piqueras M, Aceituno M, Gomez-Garcia M, Taxonera C, Gisbert JP:
Early use of azathioprine Has a steroid sparing effect on recently diagnosed
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