Monitoring the activity of Crohn's disease

Authors

  • L. Biancone,

    1. Cattedra di Gastroenterologia, Dipartimento di Medicina Interna, Università degli Studi di Roma ‘Tor Vergata’, Roma, Italy; Centro di Eccellenza per lo Studio del Rischio Genomico in Patologie Complesse Multifattoriali, Università degli Studi di Roma ‘Tor Vergata’, Roma, Italy; * Fondazione Promoter, Roma, Italy
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  • F. De Nigris,

    1. Cattedra di Gastroenterologia, Dipartimento di Medicina Interna, Università degli Studi di Roma ‘Tor Vergata’, Roma, Italy; Centro di Eccellenza per lo Studio del Rischio Genomico in Patologie Complesse Multifattoriali, Università degli Studi di Roma ‘Tor Vergata’, Roma, Italy; * Fondazione Promoter, Roma, Italy
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  • G. Del Vecchio Blanco,

    1. Cattedra di Gastroenterologia, Dipartimento di Medicina Interna, Università degli Studi di Roma ‘Tor Vergata’, Roma, Italy; Centro di Eccellenza per lo Studio del Rischio Genomico in Patologie Complesse Multifattoriali, Università degli Studi di Roma ‘Tor Vergata’, Roma, Italy; * Fondazione Promoter, Roma, Italy
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  • I. Monteleone,

    1. Cattedra di Gastroenterologia, Dipartimento di Medicina Interna, Università degli Studi di Roma ‘Tor Vergata’, Roma, Italy; Centro di Eccellenza per lo Studio del Rischio Genomico in Patologie Complesse Multifattoriali, Università degli Studi di Roma ‘Tor Vergata’, Roma, Italy; * Fondazione Promoter, Roma, Italy
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  • P. Vavassori,

    1. Cattedra di Gastroenterologia, Dipartimento di Medicina Interna, Università degli Studi di Roma ‘Tor Vergata’, Roma, Italy; Centro di Eccellenza per lo Studio del Rischio Genomico in Patologie Complesse Multifattoriali, Università degli Studi di Roma ‘Tor Vergata’, Roma, Italy; * Fondazione Promoter, Roma, Italy
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  • A. Geremia,

    1. Cattedra di Gastroenterologia, Dipartimento di Medicina Interna, Università degli Studi di Roma ‘Tor Vergata’, Roma, Italy; Centro di Eccellenza per lo Studio del Rischio Genomico in Patologie Complesse Multifattoriali, Università degli Studi di Roma ‘Tor Vergata’, Roma, Italy; * Fondazione Promoter, Roma, Italy
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  • F. Pallone*

    1. Cattedra di Gastroenterologia, Dipartimento di Medicina Interna, Università degli Studi di Roma ‘Tor Vergata’, Roma, Italy; Centro di Eccellenza per lo Studio del Rischio Genomico in Patologie Complesse Multifattoriali, Università degli Studi di Roma ‘Tor Vergata’, Roma, Italy; * Fondazione Promoter, Roma, Italy
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Dr F. Pallone, Dipartimento di Medicina Interna, Università degli Studi di Roma ‘Tor Vergata’, Via Montpellier 1, 00133 Roma, Italy.
E-mail: pallone@med.uniroma2.it

Summary

Crohn's disease is characterized by a chronic inflammation of the intestine of unknown aetiology. One of the main problems when treating patients with Crohn's disease, is the identification of patients undergoing early clinical relapse, for timely treatment and the possible prevention of complications. No sub-clinical markers are currently available that predict relapse during remission. Several parameters have been proposed for this purpose. Although none have proven useful, growing evidence suggests a possible benefit in the clinical management of Crohn's disease. Among these, we may identify: clinical behaviour, the characteristics of the host, clinical activity, markers of intestinal inflammation and markers of immune activation. In particular, the possible relationship between cytokine pattern and the clinical behaviour of Crohn's disease has been addressed. Overall, these observations suggest that mucosal immune activation is a feature of Crohn's disease, and may persist in the form of activated immunocompetent cells during remission. On the basis of this evidence, studies are currently investigating whether the down-regulation of immune activation markers is associated with clinical remission in Crohn's disease. It has been shown that higher mucosal levels of TNF-α and an increased state of activation of lamina propria mononuclear cells in patients with inactive Crohn's disease, are significantly associated with an earlier clinical relapse of the disease. These observations suggest that a persistent local immune activation during remission may represent a marker of early clinical relapse of Crohn's disease.

Introduction

Crohn's disease is a chronic inflammatory condition of the intestine of unknown aetiology. No curative treatment is currently available for it. The disease follows a chronic relapsing course, with marked individual differences in terms of the type and severity of intestinal symptoms, extraintestinal manifestations and responsiveness to medical treatment. The heterogeneity of Crohn's disease is related to variations in the site, extent and type of the intestinal lesions. Several variables affect its clinical course and approach to management,1, 2 and the standard criteria of assessment approach to management for most of them still are not available. Critical issues include the definition of disease activity and of the clinical behaviour of Crohn's disease (Figure 1). An additional issue is the identification of patients in early clinical relapse, to allow timely treatment and a possible prevention of complications. No sub-clinical markers are currently available that predict the likelihood of relapse during remission.

Figure 1.

Schematic representation of parameters used define clinical behaviour in Crohn's disease.

Several clinical, haematochemical and immunological parameters have been proposed for the assessment of Crohn's disease patients. Although none of them have proven clinically useful, growing evidence suggests that they may have relevance in the clinical management of Crohn's disease (Figure 2).

Figure 2.

Indicators of clinical behaviour in Crohn's disease.

Clinical behaviour

Characteristics of the intestinal lesions, including the site, type and extent, have been subgrouped into inflammatory, stricturing and fistulizing patterns.3 Disease duration, clinical course, the presence of complications, drug responsiveness and previous surgery also affect the patient outcome. The fibrostenotic subtype is characterized by a greater requirement for surgery due to subobstructive/obstructive symptoms, but it may respond to bowel rest and to corticosteroid treatment.4–6 The fistulizing disease has a high incidence of complications, including abdominal abscesses requiring surgical treatment. It also follows a more aggressive course, but may respond to antibiotic treatment and immunomodulatory drugs. Early post-operative recurrence is frequently observed in these patients.7, 8 The inflammatory subtype, showing neither stenosis nor fistulae, is usually characterized by responsiveness to corticosteroids, but related to disease extent. It has a tendency to recur with early clinical relapses related to incomplete clinical remission.3–8

Host characteristics

Age at diagnosis, risk factors (including appendectomy, familial history of inflammatory bowel disease, smoking),9–11 compliance and lifestyle significantly influence the clinical course of the disease. An early onset of Crohn's disease or a familial history of inflammatory bowel disease may be associated with a more aggressive course of the disease, with extensive intestinal lesions including the upper gastrointestinal tract and the small bowel, and with responsiveness to corticosteroids and immunomodulatory drugs.9, 12, 13

Clinical activity

A standardized and quantitative evaluation of clinical ‘activity’ is needed. A number of symptom scores have been put forward using different parameters and are based on different principles. These scores or indexes have addressed the problem of quantifying clinical judgement, but have left unsolved the issue of a specific and sensitive measure of the activity of ongoing intestinal inflammation.14 A score defining eight Crohn's disease subgroups has been developed, including symptom score, non-specific markers of inflammation and markers of intestinal inflammation (Table 1).14

Table 1.  Subgrouping of patients with Crohn's disease according to symptoms score, non-specific markers of inflammation and indicators of intestinal inflammation
ScoreSymptomsInflammatory parametersIntestinal lesionsTherapeutic decision
  1. MT = Maintenance treatment; AT = Active treatment; ST = Symp- tomatic treatment.

Group 1ST
Group 2+MT
Group 3+ST
Group 4++AT
Group 5+ST
Group 6++ST
Group 7++AT
Group 8+++AT

Among the various proposed scores (Bristol Simple Index, van Hees, etc.), the Crohn's disease Activity Index (CDAI) represents the most widely used and accepted for assessing the clinical activity of the disease.15 The CDAI includes clinical parameters (number of liquid stools, abdominal pain, well being, abdominal mass, extraintestinal manifestations, body weight) and haematocrit values. A CDAI value > 200 defines active Crohn's disease, while a values < 150 indicate that the patients are in clinical remission. Several studies have reported that an incomplete remission, defined by a CDAI score of between 150 and 200, is associated with earlier clinical relapse.15

Markers of intestinal inflammation

No haematochemical parameters have been shown to significantly predict the clinical course of Crohn's disease.16 However, data suggest that a higher erythrocytesedimentation rate (ESR) during remission is associated with an earlier relapse of the disease, and a more active course.16 As with other parameters, however, this refers to a trend and does not imply that the finding of a higher ESR in an individual patient with inactive Crohn's disease will predict clinical relapse.

As with the ESR values, a positive test for C Reactive Protein (CRP) during clinical remission has been reported to be associated to an earlier clinical relapse.17 However, this finding does not imply that this parameter will predict Crohn's disease relapse in all patients. Other haematological parameters which have been assessed, including white blood cells, haemoglobin, orosomucoids and serum iron, are not useful in predicting the clinical course of Crohn's disease. Recent evidence suggests that a higher intestinal permeability, as assessed by several techniques, may be capable of identifying a sub-group of patients with inactive Crohn's disease at high risk of early relapse. In particular, a greater excretion of faecal calprotectin has recently been reported in clinically inactive Crohn's disease patients with a likelihood of early relapse.18 This parameter has therefore been proposed as a marker of early clinical relapse in Crohn's disease patients in clinical remission.

Faecal α1-antitripsin clearance (AAT clearance) is a test which reflects protein loss through the bowel wall. Previous studies have shown that a high faecal AAT clearance 6 months after intestinal resection for Crohn's disease may represent a noninvasive parameter capable of detecting endoscopic recurrence.19 On the basis of this observation, a prospective longitudinal study tested whether this parameter predicted clinical relapse.20 Preliminary findings confirmed that higher levels of faecal AAT clearance during the inactive phase of Crohn's disease are found in the sub-group of patients with early (< 6 months) clinical relapse of the disease.20

Markers of immune activation as a guide for assessing disease activity

The possible relationship between the cytokine pattern of Crohn's disease and its clinical behaviour has been assessed. mRNA expression for IL-1 receptor antagonist (IL1-RA) and IL-1β is significantly lower in intestinal lesions from patients with perforating Crohn's disease when compared to patients with the non-perforating pattern.21 It has also recently been shown that LPMC from established inflammatory type lesions have an up-regulated IL-12 receptor β2 subunit when compared to patients with ulcerative colitis.22 Studies in the peripheral blood have shown that serum levels of IL-6 are significantly greater in patients with the inflammatory pattern of the disease when compared to stricturing Crohn's disease.23 Taken together, however, current observations do not provide clear evidence that the cytokine profile will predict the clinical behaviour of Crohn's disease. In particular, there is no evidence that any clinical sub-group is related to a specific cytokine secretion pattern.

In the Crohn's disease gut mucosa there is an increased state of activation of LPMC, as reflected by a higher percentage of cells expressing activation markers such as the Interleukin-2 receptor (IL-2R). It has also been shown by scintigraphy that 123I-labelled IL-2 selectively binds in vivo to IL-2 receptor expressing cells in Crohn's disease. By using this scintigraphic technique, it appears that IL-2 intestinal uptake is significantly higher in Crohn's disease than in controls.24 A prospective longitudinal study also demonstrated that the percentage of IL-2R positive LPMC, as reflected by IL-2 intestinal uptake, falls during steroid-induced remission, although it remains higher than in controls,24(Figure 3). More recently, intestinal levels of TNF-α and NFκB p65 have been investigated for assessing the clinical response in patients treated with anti-TNF-α monoclonal antibody.25 These ex-vivo observations indicate that both TNF-α and NFκB p65 mucosal levels fall significantly in patients in clinical remission induced by anti-TNFα monoclonal antibody.25 Taken together, these in vivo, ex-vivo and in vitro observations support the concept that immunological parameters reflect the clinical response to immunomodulatory drugs and the clinical activity of Crohn's disease. However, none of them have demonstrated clinical effectiveness in predicting the course of Crohn's disease.

Figure 3.

Scintigraphy using 123I-labelled Interleukin-2 for assessing the degree of intestinal infiltration by activated IL-2 receptor positive cells. The degree of infiltration significantly lowers during clinical remission, although persisting higher than in normal subjects.

Studies are currently investigating whether the down-regulation of immune activation markers is associated with clinical remission in Crohn's disease. Among the different cytokines under study, serum levels of IL-6, a pleiotropic mediator related to the hepatic release of inflammatory parameters as CRP, has been reported as a good predictor of clinical relapse in patients with steroid-induced remission. In particular, a 17-fold increase in the likelihood of relapse was found in patients with serum levels of IL-6 greater than 20 pg/mL.23Ex-vivo studies have also investigated the possible utilization of levels of IL-1β and TNF-α released by LPMC from patients with inactive Crohn's disease in predicting the clinical relapse of the disease.26 Mucosal levels of TNF-α greater than 70 pg/mL were associated with a clinical relapse of Crohn's disease within the following year. This finding confirms the persistence of a mucosal immune activation in Crohn's disease patients, even during remission and the possible usefullness of this parameter in predicting the clinical relapse of the disease. A recent prospective longitudinal study in patients with inactive ileal Crohn's disease using 123I-IL2 scintigraphy showed that a higher percentage of activated LPMC expressing IL-2R (as reflected by the degree of IL-2 intestinal uptake), is associated with earlier clinical relapse.24 Similarly, it has been shown that TNF-α and NFκB p65 levels in patients in remission (induced by anti-TNF-α monoclonal antibody treatment) are higher in the sub-group who relapse following treatment. Taken together, these observations support the concept that persistent local immune activation, as detected by various immunological parameters, is associated with early clinical relapse.

Overall, the above studies indicate that no evidence as yet suggests that any clinical sub-group is associated with a definite cytokine secretion pattern. However, there is convincing evidence that a persistent local immune activation is associated with clinical relapse. This provides a future line of research that may identify a sub-group of patients at risk of early relapse and suitable for timely treatment. Whether this sub-group of patients with inactive Crohn's disease showing persistent increased mucosal immune activation should be considered for treatment as active patients to prevent relapse requires further investigation.

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