Markers of Intestinal Inflammation as Predictors of Clinical Relapse in Patients With Quiescent IBD

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Markers of Intestinal Inflammation as Predictors of Clinical Relapse in

Patients With Quiescent IBD

J.A. Tibble, MRCP, MD, MSc, I. Bjarnason, DSc, MD, Department of Medicine,

Guy's, Kings, and St. ' School of Medicine and Dentistry, London,

England

[Medscape Gastroenterology, 3(2) 2001. © 2001 Medscape, Inc.]

Introduction

Crohn's disease and ulcerative colitis are related conditions characterized

by periods of remission marked by episodes of clinical relapse. The landmark

of a clinical relapse, namely an increase in symptoms, is usually due to

acute intestinal inflammation. Treatment is primarily aimed at reducing

inflammation during relapse and secondarily at prolonging the time spent in

remission. Conventionally, both of these aims are governed by consideration

of clinical symptoms rather than objective evidence of inflammatory

activity. Symptoms of inflammatory bowel disease (IBD) often appear to be

the direct consequence of the inflammatory process itself, and frequently

vary, depending on the location of the inflammation. Most patients with

quiescent IBD have low-grade inflammation and it is possible that

symptomatic relapse occurs only when the inflammatory process reaches a

critical intensity. Furthermore, because inflammation is a continuous

process, direct assessment of the level of inflammatory activity may provide

a quantitative presymptomatic measure of impending disease relapse. The

clinical implications of this knowledge, if substantiated, are considerable.

It may allow targeted treatment at an earlier stage (with fewer side

effects) to avoid the relapse, as well as assessment of new therapeutic

strategies for maintenance of symptomatic remission. This article reviews

the utility of different parameters in predicting relapse of IBD.

Clinical Disease Activity Indices

The natural course of inflammatory bowel disease (IBD) is that of a chronic

inflammatory process characterized by periods of clinical quiescence that

are interrupted by flare-ups or relapses. However an important question

should be asked: How is disease relapse defined? The most direct answer is

that it may be defined as a worsening of disease activity -- that is, an

increase in a patient's symptoms. This type of definition is based on the

use of clinical disease activity indices, such as the Crohn's Disease

Activity Index (CDAI) and the Harvey Bradshaw Index (HBI). Changes that

occur in such indices over time have been suggested as predictors of relapse

in patients with IBD. For example, a gradual increase in the indices within

the normal range may predict clinical relapse.[1,2] However a particular

problem with these indices is that they heavily weigh subjective criteria

symptoms and, therefore, are a measure of severity of illness rather than of

mucosal inflammatory activity. In addition, included in indices such as the

CDAI are extraintestinal manifestations of disease (ie, arthralgia, iritis,

among others) that may have little if any relation to the intestinal

inflammatory activity.

Another pitfall of using clinical features (pain, diarrhea, fever, malaise)

to predict disease relapse is that these parameters are essentially the same

as the end point we are trying to predict. And, as pointed out by Sachar,[3]

we have not gained much new knowledge or practical advantage if we have to

observe a patient's clinical signs and symptoms worsening before we can

" predict " that he or she is about to " relapse. "

Few clinicians use these indices on a day-to-day basis with the goal of

altering management. However, if we are to identify other parameters that

may truly allow us to predict which patients in remission may relapse, then

such strict definitions are required. Most studies have therefore defined a

relapse using these indices, thereby allowing comparison of different

predictors of relapse.

Laboratory Predictors of Relapse

A reliable, predictive laboratory test would be more appealing in this

setting, because it has greater potential for being objective, reproducible,

and sensitive. A number of laboratory parameters of disease activity --

erythrocyte sedimentation rate, C-reactive protein levels, platelet and

white blood cell counts, and concentrations of interleukin (IL)-6, tumor

necrosis factor-alpha, and IL-1 beta[4-8] -- that reflect the systemic

consequences of inflammation have been proposed as predictors of clinical

relapse of IBD, but with varying degrees of success.

In a study by Louis and colleagues,[5] serum IL-2 receptor (sIL-2R) levels,

a measure of mucosal immune activation, were shown to correlate with both

the CDAI and other plasma markers of inflammation. This finding, however,

has not been universally confirmed.[9] Additionally, high levels of sIL-2R

measured when patients were in clinical remission gave a relative risk of

relapse of 9.9, suggesting that persisting immune activation -- in

particular of mucosal T-lymphocytes in CD -- may lead (after a variable

period of time) to clinical relapse.

Other Factors

Other investigators have identified different patient characteristics

(disease topography, young age at time of initial diagnosis, length of

interval since previous relapse, previous surgery for CD), which may be used

to predict risk of relapse,[10-12] but these factors may lack biological

justification. The overall predictive values of these different parameters

in identifying patients at risk of relapse have been disappointing. This

finding may be attributed to the fact that these measures are nonspecific,

are affected by a variety of nonintestinal diseases, and most important, do

not measure the degree of intestinal inflammation directly. This concept was

highlighted in a study by Cellier and coworkers,[2] in which the

relationships between 11 discrete laboratory parameters, CDAI, and the

Crohn's Disease Endoscopic Index of Severity (CDEIS) were assessed. The

study authors showed by stepwise linear regression that the laboratory

measures were poorly predictive of the CDEIS, and moreover, that clinical,

endoscopic, and biologic findings were poorly correlated in CD. Thus, it was

concluded that CD clinical activity was virtually independent of the

severity of macroscopic mucosal lesions.

It may be that clinical severity depends more on acute inflammation in

patients with CD, and that this is independent of the macroscopic

appearances. Indeed, in CD, there is a striking discordance between

inflammatory activity as assessed by 111indium white-cell scanning, and

endoscopic appearances following treatment of patients with active disease

who completed a 4-week course of therapy with an elemental diet.[13] If the

former is true, a direct measure of mucosal inflammatory activity may be

more useful in assessing disease severity and risk of relapse.

An increase in intestinal permeability -- which may be a surrogate marker of

inflammation[14] -- has been suggested as a predictor of clinical relapse in

patients with CD.[15,16] With a sensitivity of 81% and a specificity of 73%,

this parameter represents a substantial improvement over the nonspecific

markers. The permeability ratio differs from other indices in that it is not

based on concentrations of plasma proteins, but rather represents functional

changes in the intestinal mucosa (which are a direct consequence of

intestinal inflammation).

Fecal Calprotectin and Prediction of IBD Relapse

Until recently, the utility of measuring intestinal inflammation directly as

a means of predicting relapse has not been assessed. Indium leukocyte

scanning and quantitative fecal 111indium-labeled leukocyte excretion have

been used for localization of disease and assessment of disease severity,

respectively, in patients with IBD.[17,18] However, the exposure to

radiation and the 4-day collection of stools make it an unsuitable method

for outpatient monitoring of mucosal inflammatory activity.

A recent study has demonstrated the usefulness of fecal calprotectin in

predicting relapse of IBD.[19] Calprotectin, first isolated from

granulocytes by Fagerhol and colleagues,[20] was initially termed " L1

protein, " but subsequent to the identification of its calcium binding and

antimicrobial properties, was renamed " calprotectin. " [21] Within the

neutrophil, calprotectin is found in the extra lysosomal cytosol, and

constitutes up to 60% of the cytosolic protein fraction of these cells.[22]

Calprotectin resists metabolic degradation by intestinal bacteria and is

stable in stool for up to 1 week at room temperature.[23] Fecal calprotectin

levels correlate significantly with histologic and endoscopic assessment of

disease activity in ulcerative colitis (UC),[24] as well as with fecal

alpha-1-antitrypsin levels and fecal excretion of 111indium-labeled white

blood cells in patients with CD.[23, 25-27]

In patients with clinically quiescent IBD (UC and CD), it was shown that

fecal calprotectin levels greater than 50 mg/L could be used to predict the

likelihood of clinical relapse of disease within a few months, with over 80%

sensitivity.[19] Most patients with quiescent IBD have low-grade

inflammation,[28] and it is suggested that symptomatic relapse occurs only

when the inflammatory process reaches a critical intensity. Furthermore, if

inflammation is a continuous process, it may be that direct assessment of

the level of inflammatory activity can provide a quantitative presymptomatic

measure of imminent clinical disease relapse.

Clinical Implications of Predicting Relapse

The clinical implications of predicting which patients with IBD are likely

to relapse are considerable. Such knowledge may allow targeted treatment at

an earlier stage (with fewer side effects) to avert the relapse, as well as

assessment of new therapeutic strategies for maintaining symptomatic

remission.[29]

Presently, early therapy to avert relapse is implemented with some degree of

success via the rather indiscriminate use of sulfasalazine, 5-aminosalicylic

acid, and azathioprine -- all of which are associated with side effects.

However, the calprotectin methodology can offer guidance regarding whom to

treat at this early stage and with what degree of intensity. Theoretically,

such treatment should lead to a dramatic reduction in the frequency and

severity of clinical relapses, with an associated improvement in the

patient's quality of life.

In addition, the identification of patients at high risk of relapse will

help improve the design of clinical trials intended to assess the efficacy

of therapeutic regimens for maintaining remission. In most such trials, the

population of patients studied is generally heterogeneous, including both

those at high and low risk of relapse. This factor introduces a potential

bias when assessing response to a particular therapy because of the

imbalance of high-risk patients in each treatment arm. Stratification of

cohorts by risk, using fecal calprotectin, would minimize the possibility of

such a bias.

It is also a possibility that the lack of power in detecting a response to

treatment may be due to the study of a large number of patients at

low/intermediate risk of relapse, in whom all treatments may show the same

efficacy. Therefore, clinical trials studying a homogeneous, high-risk group

may be more powerful in detecting a difference in treatment efficacy.