Monitoring

National Clinical Guideline Centre (UK)

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National Clinical Guideline Centre (UK). Crohn's Disease: Management in Adults, Children and Young People. London: Royal College of Physicians (UK); 2012 Oct 10. (NICE Clinical Guidelines, No. 152.)

Update information: NICE's original guidance on Crohn's disease: management in adults, children and young people was published in October 2012; it was partially updated in May 2016 when a new recommendation on inducing remission was added. It has now undergone a further partial update published in May 2019. The full, current recommendations can be found on the NICE website. This document preserves evidence reviews and committee discussions for areas of the guideline that have not been updated in 2019. Black shading indicates text from 2012 replaced by the 2019 update in the pdf.

This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

Crohn's Disease: Management in Adults, Children and Young People.

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10Monitoring

10.1. Monitoring for osteopenia and assessment of fracture risk

10.1.1. Clinical introduction

Osteopenia is the precursor to osteoporosis and the attendant risks associated with that condition. Its frequency has been reported as between 3% and 77%. However, in a population-based study from Limburg in the Netherlands male patients and those less than 18 years at diagnosis were more at risk of low bone mass at the lumbar spine. The prevalence of osteoporosis in postmenopausal women with Crohn's disease was 29% compared with 3% in premenopausal patients (odds ratio: 12).²⁴⁴ In another study, bone mineral density was negatively correlated with lifetime glucocorticosteroid exposure, but not with previous bowel resection or current disease activity and fracture rate was not correlated with the bone mineral density or lifetime glucocorticosteroid dose.²⁶⁸ In children, low bone mineral density has been associated with hypoalbuminemia, exposure to nasogastric tube feeds, total parenteral nutrition, mercaptopurine, and glucocorticosteroid treatment.²⁴⁸

The lack of clear causality between osteopenia and fracture in patients with Crohn's disease encouraged the GDG to focus on issues which were of practical concern to patients and impacted on daily life. Fractures are the clearest example of this. They do not need to be obviously symptomatic at the time of their occurrence. For example recurrent silent vertebral fractures can lead to long-term disability. However, in order to ensure early and effective treatment any predisposition to osteoporosis needs to be identified early and so the GDG elected to pose the question:

“In adults and children diagnosed with Crohn's disease, what is the clinical and cost effectiveness of DEXA compared with no monitoring for changes in bone mineral density on patient outcomes (fracture rate)?”

However, during the development of this guideline, the NICE clinical guideline on ‘Osteoporosis: assessing the risk of fragility fracture’ ¹⁹⁰ in adults was developed. It identifies people at high risk of fragility fracture, and includes most people with Crohn's disease on the basis of glucocorticosteroid exposure, low body mass index (BMI), or both. This work supersedes the question originally posed by the GDG for people over 18 years. Readers are advised to refer to the NICE clinical guideline on osteoporosis. The GDG was nevertheless aware of the lack of guidance for children and young adults with Crohn's disease. They were interested to review any data that might indicate that children and young adults with Crohn's disease should be monitored in the same way as adults, as per the Osteoporosis Guideline. They therefore asked permission to change the question from the one originally posed.

10.1.2. Clinical question

In children and young people with Crohn's disease what is the risk of fracture?

10.1.3. Clinical evidence

This guidance cross refers to the NICE clinical guideline on ‘Osteoporosis: assessing the risk of fragility fracture’ (June 2012)¹⁹⁰. However, the NICE guidance excludes young people under the age of 18. Therefore, a systematic review was undertaken to evaluate the literature on risk of fracture in children with Crohn's disease. One recent case-control study ¹⁴⁷ was identified which assessed this outcome in a paediatric population.

$Table 85. Evidence profile: fracture risk in children with Crohn's disease.$

Table 85

Evidence profile: fracture risk in children with Crohn's disease.

10.1.3.1. Evidence statement - clinical

In one large paediatric case control study (n = 2734)¹⁴⁷ there was no significant difference in any fracture occurring in cases, versus controls (OR 0.8 [ 0.6 to 1.1]).[VERY LOW QUALITY].

10.1.4. Economic evidence

No published data were found and original modelling was not undertaken for this question.

10.1.5. Linking evidence to recommendations

Table 86Linking evidence to recommendations – monitoring for osteopenia in children and young people

Clinical question	In children and young adults diagnosed with Crohn's disease, what is the risk of fracture?
Recommendations	Refer to ‘Osteoporosis: assessing the risk of fragility fracture’ (NICE clinical guideline 146) for recommendations on assessing the risk of fragility fracture in adults. Crohn's disease is a cause of secondary osteoporosis. 37. Do not routinely monitor for changes in bone mineral density in children and young people. 38. Consider monitoring for changes in bone mineral density in children and young people with risk factors, such as low body mass index (BMI), low trauma fracture or continued or repeated glucocorticosteroid use.
Relative values of different outcomes	The GDG was aware that the Osteoporosis Guideline Update for adults would supersede any work done during development of this guideline. To support any recommendation for monitoring children with Crohn's disease for changes in bone mineral density, the GDG was keen to review the most stringent outcome measure - fracture risk.

Trade off between benefits and harms	Because no data were found indicating a best practice method for monitoring for bone density changes in children, the GDG felt that it could not specify a monitoring method. Hence an assessment of the balance of benefit and harm was not possible.

Economic considerations	To assess the cost-effectiveness of monitoring of bone mineral density would require the specification of a treatment protocol and estimates of effectiveness of treatment for specific population identified to be at risk, in addition to estimates of diagnostic accuracy. These are difficult to estimate for Crohn's disease.

Quality of the evidence	Only one case control study with 733 children matched to three controls, was identified, and critically appraised (Kappelman, 2008).¹⁴⁶ Participants were identified using US administrative database. Glucocorticosteroid exposure was measured using national drug codes and a sensitivity analysis conducted to determine the effect of glucocorticosteroid treatment on fracture risk in children. Children with Crohn's disease and ulcerative colitis were analysed separately. Limitations to Kappelman data were noted: Fragility fracture and high impact fracture were not analysed separately (considering that well children participate in high impact sports and children who are unwell tend to be less exposed to trauma) Data relating to fractures in people on glucocorticosteroid treatment were not subdivided into Crohn's disease and ulcerative colitis (total IBD population) Children and young people were defined in the study as those less than 20 (Mean age in the study was 15) – not exactly in line with formal definition of less than 18 years, but the GDG did not consider this to be important. Although the point estimate of the odds ratio (0.8) suggests that Crohn's disease appears to be protective against fracture, when confidence intervals are taken into account there is no statistically significant difference between children with Crohn's disease and n = 3287 controls i.e. children with Crohn's disease were not at greater risk of fracture.

Other considerations	In the absence of evidence the GDG were unable to make any paediatric recommendations specifically pertaining to the use of fracture risk assessment tools, monitoring or service provision implications. Again in the absence of evidence the GDG agreed making a ‘consider’ recommendation for children based upon extrapolation from the adult Osteoporosis guideline indicating what factors might put children with Crohn's disease at high risk for fracture (for example low body mass index or repeated glucocorticosteroid use). The GDG agreed that decisions should be considered based on the clinical picture, but did not wish to specify either the method of monitoring or who would be best placed to manage the child should treatment be required.

10.2. Recommendations

Refer to ‘Osteoporosis: assessing the risk of fragility fracture’ (NICE clinical guideline 146) for recommendations on assessing the risk of fragility fracture in adults. Crohn's disease is a cause of secondary osteoporosis.

37.: Do not routinely monitor for changes in bone mineral density in children and young people.
38.: Consider monitoring for changes in bone mineral density in children and young people with risk factors, such as low body mass index (BMI), low trauma fracture or continued or repeated glucocorticosteroid use.

10.3. Research recommendation

The GDG did not prioritise any future research in this area.

10.4. Early relapse

10.4.1. Clinical introduction

The concept that early detection of a relapse in Crohn's disease would lead to earlier treatment and therefore less severe and destructive disease is the basis for much of the long-term management of this condition. It appeals to both patient and clinician. It introduces the hope that effective treatment could alter the natural course of Crohn's disease. With this in mind there has been an ongoing search for indicators of an impending relapse. These have varied from a patient's own assessment of how they feel through to sophisticated monitoring of a range of inflammatory markers.

In order for such an approach to be effective it is essential that the marker changes significantly ahead of clinical deterioration. In other words changes in such markers need to be predictors of a clinical relapse rather than the consequence of it. For routine monitoring to be worthwhile these changes need to precede clinical deterioration by months rather than weeks. In addition there needs to be a clear level at which an abnormality is an effective predictor of disease relapse and there should not be significant overlap with levels that can be recorded during remission. Finally if such predictors of relapse can be identified they need to be of clinical value -they need to lead to interventions which can be shown objectively through randomised controlled trials to prevent or shorten disease relapse and to be reflected in a better quality of life for patients.

10.4.2. Clinical questions

Does predicting early relapse through monitoring

Unintended weight loss
CRP
ESR
MRI
Calprotectin
Colonoscopy/capsule endoscopy or
Growth in children

compared with standard care, improve patient outcomes (quality of life, future surgery, hospitalization)?

10.4.3. Clinical evidence

There were no Cochrane reviews or RCTs identified for this prognostic review. A systematic review of the literature identified 11 cohort studies which met the inclusion criteria for this review. There were no studies which addressed the use of unintended weight loss, MRI, colonoscopy, endoscopy or growth in children for prediction of early relapse. Studies utilising faecal calprotectin (FC), CRP and ESR in adults²⁷^,³²^,⁴⁴^,⁵⁹^,⁹⁷^,¹⁰³^,¹⁴²^,¹⁴⁹^,²⁸¹^,³⁰⁶ and children²⁹⁷ for prediction of early relapse were reviewed. These studies were prognositic in design and assessed asymptomatic patients who were then followed to relapse.

Table 87

Faecal calprotectin, CRP and ESR as predictors of early relapse – evidence profile.

The normal ranges for faecal calprotectin, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are presented below. Measurement methods for faecal calprotectin in the included studies varied and all values are subject to laboratory specific variations.

Faecal calprotectin μg/g
Ages 2-9 years	< 166
Ages 10-59 years	< 51
Ages ≥ 60	< 112

Faecal calprotectin mg/kg
Upper limit of normal	< 50

Faecal calprotectin mg/L
Upper limit of normal	< 10

CRP mg/L
Low risk IBD relapse (Normal)	< 10
Average risk IBD relapse	10 to 30
High risk IBD relapse	> 30

ESR mm/hour (upper limit of normal)
Ages	20	55	90 years
Men	12	14	19
Women	18	21	23
Neonatal to puberty	3 to 13

For this prognostic review, time to event data, with multivariate analysis was extracted if possible. Cut-off values determined by ROC curves constructed to predict risk in individual studies are presented.

In this review the prognostic factor is a dichotomous variable and the outcome is time-to-event/dichotomous. The results (OR/RR/HR) describe the effect on the outcome of the presence compared with the absence of the prognostic factor. Presence versus absence means above versus below the threshold. The forest plots presented in Appendix G: show that when the odds ratio, relative risk or hazard ratio is greater than 1, values above the threshold predict relapse, and when below 1, values above the threshold predict protection against relapse.

10.4.3.1. Evidence statements - clinical

In a summary of five studies (n = 327)⁹⁷^,¹⁰³^,¹⁴²^,²⁸¹^,²⁹⁷ faecal calprotectin appears to be effective for assessing risk of relapse in Crohn's disease. One study (n = 65)⁵⁹ showed no effect. Each study used different thresholds for prediction of relapse.[LOW QUALITY]
In one study (n = 65)⁵⁹ CRP appears to be effective for assessing risk of relapse in Crohn's disease. A summary of three studies (n = 225)²⁷^,⁴⁴^,¹⁴² showed no effect. Each study used different thresholds for prediction of relapse.[LOW QUALITY]
In one study (n = 71)⁴⁴ ESR appears to be effective for assessing risk of relapse in Crohn's disease. One study (n = 65)⁵⁹ showed no effect. Each study used different thresholds for prediction of relapse.[LOW QUALITY]

10.4.4. Economic evidence

No published data were found and original modelling was not undertaken for this question.

10.4.6. Linking evidence to recommendations

Table 88Linking evidence to recommendations – monitoring for early relapse

Clinical question	Does predicting early relapse through monitoring Unintended weight loss CRP ESR MRI Calprotectin Colonoscopy or capsule endoscopy Growth in children compared with standard care, improve patient outcomes (quality of life, future surgery, hospitalization)?
Recommendation	None made.
Relative values of different outcomes	The GDG wished to gather any evidence that might support the use of any of a list of alternative monitoring methods. The GDG felt that in order to be able to recommend monitoring for relapse, any test would need to demonstrate the ability to predict a relapse at a time period sufficiently early enough for action to be taken to avoid symptomatic relapse. Review of the literature revealed no studies pertaining to unintended weight loss, MRI, colonoscopy/capsule endoscopy or growth in children as predictors of relapse in Crohn's disease. In addition, thresholds associated with high relapse risk for any of the tests listed above, were not universally defined in the literature. There was wide variation in threshold levels and the outcomes reported thereby making it very difficult for the GDG to compare data. The GDG made the following points: The timing of faecal calprotectin assay is important in interpreting the results. If faecal calprotectin was assessed immediately after an exacerbation, it would have different implications to if it was assessed at random time-points, for example at routine follow-ups. All patients in the studies reviewed were initially assessed in an asymptomatic state, after they had been in remission for at least one month. It is important to highlight that this question considers the potential of a test to predict relapse before people become symptomatic, rather than looking at the tests to assess their value in confirming a relapse, which is symptomatic. Even if there is a test that can predict relapse before symptoms occur, that the best course of action based upon this information is as yet undemonstrated i.e. to treat or not treat, and if so, with what?

Trade off between benefits and harms	The GDG did not consider the process of having a blood test to cause substantial harm. The GDG did consider whether a false positive test predictive of relapse might expose people to unnecessary harm should they be unnecessarily treated. As neither “accepted management” for this situation yet been agreed, nor was this the question posed, the GDG could not make an informed assessment of this issue.

Economic considerations	To assess the cost-effectiveness of monitoring of early relapse would require the specification of a treatment protocol and estimates of effectiveness of treatment for specific population identified to be at risk, in addition to estimates of diagnostic accuracy. The GDG was not aware of any trials that have evaluated the effects of early treatment. If monitoring for early relapse is found to be effective then it is possible that monitoring could be a more cost-effective strategy than maintenance therapy.

Quality of the evidence	A prognostic approach using cohort studies was undertaken. Cox regression analysis is considered the best way to analyse prognostic data, but this was not always available in the studies identified. Studies reviewed used ROC intersection of optimal specificity and sensitivity curves to determine the threshold of a given test to potentially indicate a high relapse risk. Studies were found reporting these thresholds for faecal calprotectin, ESR and CRP. In order to compare the value of each heterogeneous test in predicting relapse, the standard error for each study was calculated. Each of these common measures of each statistic was put into a non-pooled forest plot. Results: Faecal calprotectin appeared to predict potential relapse, but the data did not indicate when or how often the test should be done. The GDG felt this to significantly limit the value of this monitoring approach and acknowledged that future research in this area would be useful. They did not however prioritise it for a research recommendation. The GDG considered the CRP data to be less convincing, with two results crossing the line of no effect. The GDG considered CRP possibly to be helpful but on the basis of the above results and without more robust data it was difficult to draw a firm conclusion. Two studies looking at ESR had directly conflicting results. Therefore the GDG did not consider ESR to be helpful in predicting relapse. The GDG looked for data which might provide evidence for the intervals at which patients should be assessed in order to predict relaps, prior to symptomatic presentation. This information could not be extracted from the available data. Given the paucity and low quality of the evidence, the GDG were unable to make a recommendation. Whilst the GDG acknowledged there was limited evidence currently available, the GDG did not give high priority to a future research recommendation in this area.

Other considerations	The GDG sought the views of the patient members of the GDG and noted the comment “If you can predict you are heading towards a flare-up, and something can be done to minimise or avert it, that would be a huge benefit” and, however, that “Colonoscopy is as bad as the disease”. They noted that patients may not accept frequent ongoing monitoring of this relatively invasive nature (as opposed to follow-up endoscopy/colonoscopy after surgery or biological treatments which are “once-off” investigations checking for endoscopic recurrence or mucosal healing respectively). In any event, the literature was searched, and no evidence found for the capsule endoscopy/colonoscopic monitoring element of the question. The GDG felt it important to stress that even if a test could predict relapse before symptoms occur, best practice in responding to this information is as yet undetermined i.e. treat/do not treat, and if so, with what? Changes in outcomes have not yet been proven.

10.5. Recommendation and research recommendation

Whilst the GDG did not feel there was enough evidence to make a recommendation they also did not designate high priority to future research in this area because they believed there to be ongoing commercial interests in the assessment of a range of biomarkers in this field.

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