clinical outcome of newly diagnosed crohn’s disease

7/21/2019 Clinical Outcome of Newly Diagnosed Crohns Disease

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Clinical outcome of newly diagnosed Crohns disease:

a comparative, retrospective study before and after infliximab

availabilityE. D O M EN EC H * , * * , Y . Z A B A N A * , * * , E . G A R C I A - P L AN EL L A , * * , A . L OP EZ S A N R O M AN , P . N O S , * * ,

D . G I N A R D , J . G O R D I L L O , F . M A R T IN EZ - S I L VA , B . B EL T R AN ,* * , M . M A NO S A * ,* * , E . C A B R E* , **

& M . A . G A S S U L L * , **

*Hospital Universitari Germans Trias i

Pujol, Badalona, Catalonia, Spain;

Hospital de la Santa Creu i Sant Pau,

Barcelona, Spain; Hospital Ramon y

Cajal, Madrid, Spain; Hospital

Universitario La Fe, Valencia, Spain;

Hospital Son Dureta, Ciutat de

Palma, Mallorca, Spain; **Centro de

Investigacion Biomedica en Red de

Enfermedades Hepaticas y Digestivas

(CIBERehd), Spain

Correspondence to:

Dr E. Domenech, IBD Unit,

Gastroenterology Department,

Hospital Universitari Germans Trias i

Pujol, 5 planta edifici general,

Carretera del Canyet, sn, 08916

Badalona, Catalonia, Spain.

E-mail:[email protected]

Publication data

Submitted 21 August 2009

First decision 14 September 2009

Resubmitted 7 October 2009

Accepted 9 October 2009

Epub Accepted Article 13 October

2009

SUMMARY

Background

Infliximab (IFX) could change the course of Crohns disease (CD) by

reducing steroid use, surgery or prompting earlier introduction of

immunomodulators (IMM).

Aim

To evaluate the impact of IFX availability on the course of early CD.

Methods

Two cohorts of newly diagnosed CD patients were identified: The first

cohort included patients diagnosed from January 1994 to December

1997 and the second from January 2000 to December 2003. All patients

were diagnosed, treated and followed up in the same centre until

December 1999 (first cohort) or December 2005 (second cohort). Devel-

opment of disease-related complications, steroid, IMM or IFX require-ments and intestinal resections during follow-up were registered.

Results

A total of 328 patients were included (146 first cohort, 182 second

cohort). A similar proportion of patients in both cohorts received ste-

roids, but steroid exposure resulted significantly more intense in the

first cohort (P = 0.001). In the second cohort, 14% of patients received

IFX. Thiopurines were used more (P= 0.001) and earlier (P = 0.012) in

the second cohort. No differences in surgical requirements or the devel-

opment of disease-related complications were found.

Conclusions

Following a step-up therapeutic algorithm, IFX availability did not

reduce surgical requirements or the development of disease-related

complications.

Aliment Pharmacol Ther31 , 233239

Alimentary Pharmacology& Therapeutics

2010 Blackwell Publishing Ltd 233

doi:10.1111/j.1365-2036.2009.04170.x


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INTRODUCTION

Crohns disease (CD) is a chronic relapsing and remit-

ting inflammatory condition of the intestine. Although

most patients present with uncomplicated disease at

the time of diagnosis, a great proportion of them will

either present chronic inflammatory activity despiteconventional therapy or develop penetrating complica-

tions, intestinal stenosis or perianal disease within the

first five to 10 years after CD diagnosis,13 leading to

the deterioration of the patients quality of life. Efforts

have been made to identify early those patients who

will have a more aggressive course of the disease. In

this sense, Beaugerie and colleagues evaluated the

development of what they arbitrarily called disabling

disease in a retrospective series of more than one

thousand CD patients, and found an estimated preva-

lence of 5992% within the first 5 years from diagno-

sis. In this study, the initial need for systemic steroids

and the presence of perianal disease at CD onset or

disease diagnosis under the age of 40 years were inde-

pendent predictive factors of disabling disease.3

Thiopurines have proven to be effective in reducing

steroid exposure, maintaining disease in remission and

inducing mucosal healing.4, 5 Under this perspective, it

was thought that they might also change the natural

course of CD; in a classical retrospective study, Cosnes

et al. showed that the increasing use of thiopurines in

the last decades was not associated with a diminished

rate of intestinal resection.6

To prevent or delay theoccurrence of disease complications, a trend towards

an earlier andor more intensive therapeutic approach

has emerged in the last years. Markowitz et al. demon-

strated in a RCT with new onset paediatric CD patients

that early introduction of mercaptopurine significantly

reduced steroid requirements and increased the likeli-

hood to remain in clinical remission as compared to

placebo.7 More recently, DHaens et al. showed that in

adults with early CD, a more intensive therapeutic

regimen using an induction regimen with infliximab

(IFX) followed by maintenance therapy with thiopu-

rines achieved disease control significantly earlier and

led to mucosal healing in a greater proportion of

patients as compared with conventional therapy.8

The aim of the present study was to assess if the

availability of IFX for the treatment of CD has had

any impact on the CD outcome within the first years

from diagnosis. In the 1990s, the use of immunomod-

ulators (IMM) for CD management was widely estab-

lished in our centres and open-label IFX use for

induction and maintenance of disease remission was

approved in Europe in 2000. This was the reason why

we chose to compare two historical periods to eluci-

date, in a clinical practice setting, whether the avail-

ability of IFX for the treatment of CD has had any

impact on CD outcome within the first years fromdiagnosis. For this, we evaluated the clinical outcome

and therapeutic requirements within the first 25 years

of disease in two hospital-based inception cohorts of

CD patients, basically differing by the availability of

IFX treatment.

PATIENTS AND METHODS

Two cohorts of CD patients were identified: the IMM

cohort included patients diagnosed with CD between

January 1994 and December 1997 and the IFX cohort

included patients diagnosed between January 2000

and December 2003. All patients were identified from

the IBD databases of five referral Spanish centres. The

study was approved by the Institutional Review Board

of the steering centre (Hospital Universitari Germans

Trias i Pujol, Badalona). Diagnosis of CD was based on

the classic Lennard-Jones criteria.9 Patients were diag-

nosed, treated and followed up in a single centre until

death or the end of follow-up that was decided to be

December 1999 (first cohort) and December 2005 (sec-

ond cohort). Patients lost to follow-up for any cause

(except death) for more than 6 months within thestudy period, were excluded. As one of the main

objectives of the study was to assess the development

of disease complications within the first years from CD

diagnosis, those patients in whom an intestinal resec-

tion was performed within the first 3 months were

excluded. Demographic and epidemiological baseline

characteristics, as well as the initial Montreal classifi-

cation (that includes location and behaviour of the

disease, and the presence of perianal involvement)10

were recorded. To evaluate disease outcomes, the use

and timing of introduction of systemic steroids, IMM

or IFX, together with surgery requirements during

follow-up were carefully addressed. In addition, any

change in the initial Montreal classification (develop-

ment of intestinal stenosis, intra-abdominal abscess or

fistulae, perianal disease, changes in disease location)

was also assessed and recorded. In summary, we

evaluated retrospectively the clinical outcome and

therapeutic requirements within the first 25 years of

234 E . D O M EN E C H et al.


2010 Blackwell Publishing Ltd


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disease in two hospital-based inception cohorts of CD

patients, basically differing by the availability of IFX

treatment.

Statistical analysis

Data are expressed as mean standard deviation or

frequencies. Baseline characteristics between both

cohorts were compared with chi-square analysis for

qualitative variables and Student t-test for quantitative

variables. Risk factors for IMM introduction and intes-

tinal resection were univariately analysed by the log-

rank test. Multivariate analysis of those variables

reaching statistical significance was then performed

with a Cox regression. Cumulative probabilities of

IMM introduction, IFX introduction and intestinal

resection for the whole series as well as for each study

cohort were calculated by the KaplanMeier method.

All statistical analyses were performed using SPSS 12.0package for Windows (SPSS Inc., Chicago, IL, USA).

RESULTS

A total of 328 CD patients were included, 146 of them

in the first cohort and 182 in the second cohort.

Baseline characteristics were similar in both cohorts,

although patients in the first cohort were significantly

younger at diagnosis (Table 1). None of the Montreals

classification parameters differed at the time of CD

diagnosis between both cohorts. A majority of patients

were diagnosed between 17 and 40 years of age, most

of them had ileal disease (either alone or together with

colonic involvement) and 78% had an initial inflam-

matory behaviour of disease. Perianal disease was

present at onset in 12% of patients. Interestingly,

almost half of the patients were current smokers at

diagnosis.

Follow-up features of patients in both cohorts are

summarized in Table 2. No death was recorded during

the study period, after a mean follow-up of

45 months. At least one-third of patients continued

smoking during follow-up with a significant greater

proportion of current smokers in the first cohort.

Smoking was not associated with a worse outcome as

judged by the development of stenosing or penetrating

complications, perianal disease, need for steroids,

IMM, or intestinal resections.

Twenty-three percent of patients modified their

initial Montreal classification after a mean of 40

16 months from disease diagnosis, mainly because of

the change in the behavioural pattern of CD (15%) or

the development of perianal disease (8%). No differ-ences between the two cohorts were found either in

the proportion of patients developing stenosing or

intra-abdominal penetrating disease complications or

in the time for their occurrence (Table 2). The develop-

ment of de novo perianal disease was similar in both

cohorts, but this occurred earlier in the first cohort

than in the second cohort (P= 0.007).

Seventy percent of patients required at least one

course of steroids during the follow-up. Although the

proportion of patients requiring a course of steroids was

not different between the two cohorts, the total time on

steroids during follow-up was significantly longer in the

first cohort (P= 0.001). Thiopurines were introduced in

43% of patients during follow-up. Main indications for

Table 1. Demographic and clinical characteristics of patients at diagnosis

All patients

(n = 328)

Cohort 19941997

(n = 146)

Cohort 20002003

(n = 182) P

Age (years) 30 12 28 10 32 13 0.005

Gender (MF) 5446 6040 5050 N.S.

Active smokers 48 50 46 N.S.Age at diagnosis (A1A2A3) 87616 78112 97120 N.S.

CD location (L1L2L3+L4) 4524313 3923372 5024262 N.S.

CD behaviour (B1B2B3) 78148 75169 80128 N.S.

Perianal disease 12 14 11 N.S.

Extraintestinal manifestations 12 14 12 N.S.

Expressed in mean s.d. or frequencies.

Age, location, and behaviour according to the Montreal classification of Crohns disease.10

C R O H N S D I S E A S E O U T C O M E B E F O R E A N D A F T E R I N F L I X I M A B 235




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IMM introduction were steroid-dependence (67%), peri-

anal disease (20%), and prevention of post-operative

recurrence (15%). According to clinical outcomes, indi-

cations were similar in both cohorts, except for steroid-

dependence that accounted for a greater proportion of

IMM-treated patients of the first cohort (76% vs. 62%).

The cumulative probability of IMM introduction in the

whole series was 19%, 33% and 41% after 1, 2 and

3 years from diagnosis respectively. Of interest, IMM

were started significantly earlier (P = 0.003) and in a

higher proportion of patients (P= 0.049) in the second

cohort, leading to a cumulative probability of IMM

introduction in the first and the second cohorts of 11%

and 26% at 1 year, 22% and 40% at 2 years and 34%

and 48% at 3 years respectively (P= 0.0089) (Figure 1).

The multivariate analysis (Cox model) showed that a

change in the initial Montreal classification (P= 0.001),

male gender (P= 0.01) and belonging to the first cohort(P= 0.002) were the only independent predictors of

IMM introduction.

Infliximab was introduced in 14% of patients of the

second cohort and only in 1% in the first cohort, as

expected. All patients treated with IFX also received

thiopurines: 12 for at least 6 months, nine for less

than 6 months and six started thiopurines conco-

mitantly to IFX. When those patients in whom IFX

was introduced were excluded, no differences between

the two cohorts were found in the timing for IMM

introduction.

Table 2. Clinical features during follow-up

All patients

(n = 328)

Cohort 19941997

(n = 146)

Cohort 20002003

(n = 182)

P

Follow-up (months) 45 13 44 13 47 13 0.03

Active smokers (yesnounknown) 293635 363133 234037 0.008

Change in Montreal classification 23 23 23 N.S.Time to change Montreal classification

(months)

40 16 39 15 41 16 N.S.

Change in CD location 5 4 5 N.S.

Change in CD behaviour 15 14 16 N.S.

New onset of perianal disease 8 10 8 N.S.

Time to new perianal disease (months) 37 20 34 19 40 20 0.007

Extraintestinal manifestations 11 11 11 N.S.

New steroid course 70 74 68 N.S.

Time on steroids (months) 8 10 11 12 7 8 0.001

AZA introduction 43 37 48 0.049

Time to AZA introduction (months) 17 14 21 15 14 13 0.003

IFX introduction 8 1 14


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One quarter of patients required intestinal resectionduring follow-up. Indication for surgery was intestinal

stenosis in 57%, intra-abdominal penetrating compli-

cations in 41% and refractory luminal disease in 2%.

The cumulative probability of intestinal resection was

11%, 15% and 21% at 1, 2 and 3 years after diagnosis

respectively. According to the data related to the

changes in Montreal classification, no differences

between the two cohorts were found regarding the

timing, indication and the proportion of patients

requiring intestinal resection (Table 3, Figure 2). The

multivariate analysis demonstrated that only an

aggressive disease behaviour pattern (fistulizing or ste-

nosing) either at CD diagnosis (P < 0.0001) or during

follow-up (P< 0.0001) was an independent predictor

of resectional surgery.

DISCUSSION

Several studies have shown that CD management by

means of a conventional therapeutic algorithm (intro-

ducing IMM only in case of chronically active or

refractory disease) is associated with a high risk of

early development of disease-related complications.1, 2

Most of these studies were performed before biological

agents became available in clinical practice. Recently,

the concept that a more intensive treatment strategy

could change the natural history of the disease has

emerged. This intensive treatment strategy, although

yet to be clearly defined, implies the use of powerful

drugs (i.e. IMM or biologicals) from the time of disease

diagnosis. Early introduction of azathioprine after

inducing clinical remission with prednisone7

or IFX8

has been shown to reduce the likelihood of clinical

relapse and steroid requirements and also to increase

the rate of mid-term mucosal healing. However, there

are many drawbacks in this intensive therapeutic

approach: first, the follow-up periods of these RCTs

were not long enough to assess if these strategies also

reduce the development of stenosing and penetrating

complications or even surgery requirements. Second,

Table 3. Requirements and

characteristics of resectional

surgeries during follow-up

All patients

(n = 328)

Cohort 19941997

(n = 146)

Cohort 20002003

(n = 182) P

Intestinal resection 24 29 21 N.S.

Time to first resection

(months)

22 15 24 16 19 14 N.S.

Resection for intestinal

stenosis

14 16 13 N.S.

Time to resection for

stenosis (months)

22 16 22 16 22 16 N.S.

Resection for penetrating

complications

10 12 9 N.S.

Time to resection for

penetrating complications

(months)

20 14 24 15 16 10 N.S.

Expressed in mean s.d. or frequencies.

1.0

0.8

0.6

0.4

0.2

0.0

0 20 40 60 80

Time (months)

Second cohort

P= 0.0089

First cohort

Figure 2. Cumulative probability of intestinal resection

during follow-up.





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data comparing early introduction of IMM orand

early use of biologicals as maintenance treatments are

still lacking. Finally, early introduction of these drugs

would result in the overtreatment of 3050% of

patients who will not develop a disabling disease

within the first 5 years from diagnosis, putting them

at risk for drug-related adverse effects. Our study

aimed to assess if the availability of IFX changed the

initial course of CD in patients managed in a conven-

tional manner. The obtained results suggest that

although the availability of IFX prompted an earlier

and wider use of IMM, it did not lead to an improve-

ment in CD natural history as measured by the devel-

opment of disease-related complications. Nevertheless,

we also found that IFX availability was associated

with a significant reduction in steroid exposure. There

are several explanations for these findings. First,

patients in the first cohort could have a more aggres-

sive course of the disease as long as they were youn-ger at disease diagnosis and had a greater proportion

of active smokers during follow-up; however, this was

not reflected in a higher prevalence of disease compli-

cations such as intestinal stenosis or intra-abdominal

abscesses. Second, a change in general treatment strat-

egies of CD among the treating physicians could occur

in the last decade. Finally, this reduction in steroid use

might be related to the use of IFX given that the ear-

lier and wider use of IMM was clearly because of the

availability of the former. Although the incidence of

infectious complications was not addressed in this

study, the reduction in steroid exposure might be rele-

vant as it has been recently shown that steroid use is

one of the major risk factors to develop severe infec-

tions among patients with inflammatory bowel dis-

ease.11, 12 Some clinical observations suggest that the

earlier inflammatory activity is controlled, the higher

is the likelihood to remain in clinical remission7, 13 or

to achieve mucosal healing.8 In addition, the effective-

ness of a given drug may depend on how early it is

introduced. For instance, an induction scheme with 3

infusions of IFX appears to be more effective for

inducing remission in new onset CD8

than in lateCD.14 Opposite to the results obtained by Cosnes

et al.,6 it has been recently shown that thiopurines are

able to reduce the risk of intestinal resection when

introduced early in the course of the disease.15 This

improved efficacy and better outcomes of a given drug

in early CD as compared to late CD seems to be related

to different cytokine profiles and immune responses at

different time settings of the disease.16

In the present study, only 14% of patients in the

second cohort were treated with IFX and when used,

IFX was not introduced early after diagnosis in most

cases. Our aim was to assess the impact of the avail-

ability (not the use) of IFX on the natural course of

CD. Consequently, as it occurred with IMM,6 we can

only conclude that IFX do not alter CD natural history

when used in the setting of a step-up therapeutic algo-

rithm. Although those patients who underwent an ini-

tial intestinal resection were excluded from the study,

we still found a high incidence of disease-related com-

plications early in the course of the disease. About

one-fourth of patients underwent an intestinal resec-

tion (most of them because of stenosis or intra-abdom-

inal penetrating complications) after a mean time of

2 years from diagnosis, and almost 10% of patients

developed perianal disease within the first 3 years. It

could be argued that IMM were indicated in only 43%

of patients, a figure that is clearly lower than thatreported in the step-uptop-down study where almost

70% of patients in the step-up arm required IMM

within the first year.8 However, when evaluating the

second cohort alone, IMM were introduced in almost

50% of patients after a mean of 14 months from diag-

nosis (closer to the figures reported by DHaens), but

with a similar incidence of disease-related complica-

tions as in the first cohort. It could also be argued that

the proportion of patients who used IFX in the second

cohort was unusually low (14%) and that this pre-

cludes a proper comparison between the two study

cohorts. However, this percentage of patients treated

with IFX is far from unusual: an identical proportion

of patients needing IFX were reported after 2 years

among patients in the step-up group in the DHaens

study, showing that our data reflect a conventional

therapeutic algorithm.8 From this point of view, it is

uncertain if a cohort with patients whose diagnosis

was made within 20032005 would have resulted in

an earlier andor more widespread prescription of IFX.

These data reinforce the idea that IMM andor IFX

should be introduced at the time of CD diagnosis if a

change in natural history of CD is warranted.In conclusion, our results seem to indicate that the

availability of IFX has little impact in the initial

course of new onset CD if a conventional step-up ther-

apeutic algorithm is used. The development of stenos-

ing and penetrating complications, perianal disease

and the need for intestinal resections remain

unchanged. However, the opportunity to use biologi-

cals seems to accelerate the introduction of IMM and

238 E . D O M EN E C H et al.




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to spare steroid exposure. A change in the natural his-

tory of CD is not likely to occur with the currently

available drugs when used in the setting of a conven-

tional step-up algorithm.

ACKNOWLEDGEMENTS

Declaration of personal interests: Eugeni Domenech has

served as a speaker and/or consultant for Schering-

Plough, Abott Immunology, Falk Pharma and Ferring

Pharmaceuticals. Antonio Lopez San Roman and Miquel

Angel Gassull have served as speakers and/or consul-

tants for Schering-Plough, Falk Pharma and Ferring

Pharmaceuticals. Eduard Cabre has served as a speaker

for Schering-Plough. Yamile Zabana, Mriam Manosa

and Francisca Martenez-Silva received an educational

grant from Schering-Plough. Declaration of funding

interests: This study was partly supported by CIBERehd

of Fondo de Investigacion Sanitaria of the Instituto de

Salud Carlos III from the Spanish Ministry of Health.

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