| Relative value of different outcomes | Signs and symptoms The GDG recognised a lack of evidence for the signs and symptoms of coeliac disease (CD), and in particular the most commonly recognised presenting signs and symptoms such as gastrointestinal dysfunction, weight loss, and abdominal pain. The group discussed this and agreed that, because CD is such a well-established disorder in terms of recognition of the common features, there is no impetus to conduct research into this area, and therefore no evidence to support established clinical knowledge. The GDG further recognised that differentiating between symptoms in terms of those that should prompt clinicians to offer serological testing, and those where clinicians should consider serological testing, is further made difficult by the lack of supportive evidence to differentiate between these two classes of recommendations. Coexisting conditions and active case-finding The GDG raised the importance of increasing recognition of CD, which is widely underdiagnosed in the UK. Outlining which particular coexisting conditions have an increased risk of CD is of utmost importance in order to increase awareness for, and testing for, CD in these populations. This can be difficult due to an overlap or masking of CD-like symptoms with symptoms of coexisting conditions. The group noted that they would expect a gain in health-related quality of life after a diagnosis of CD was made in those with coexisting conditions; however no evidence was found for this outcome. Long-term complications The GDG felt that raising awareness of CD to increase diagnosis was of particular importance in order to minimise the likelihood of the development of serious long-term complications. |
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| Trade-off between benefits and harms | Signs and symptoms of CD The GDG was clear about the importance of serological testing for CD in any person where a clinical suspicion has arisen. The group cited the estimate that 4 out of 5 people with CD are currently undiagnosed, and that it is of utmost importance to improve diagnoses of these individuals by increasing both clinical and community awareness of CD and the associated signs and symptoms. The GDG agreed that there were certain signs and symptoms and coexisting conditions that are sufficiently associated with CD that people with them should be offered serological testing, and developed recommendations to reflect this. The GDG further discussed the non-specific nature of many of the signs and symptoms and consequently added ‘unexplained’ and ‘chronic’ to the description of some signs and symptoms to ensure that people who may have CD are identified. Neurological symptoms were discussed in detail, as the group recognised that the literature to support suspicion of CD in this population was scarce. However, it was noted that a considerable number of individuals were detected by neurologists on the basis of recommendations in the previous guideline, which changed their practice substantially and subsequently led to a greater awareness of CD in patients with neurological symptoms. For this reason the GDG was convinced that serological testing should be considered in populations with neurological symptoms, especially ataxia or peripheral neuropathy, which have been reported in numerous case reports. The GDG agreed a list of further signs, symptoms and coexisting conditions for which they wanted to raise awareness of the link with coeliac disease. Therefore recommendations were developed that identified where offering serological testing for CD should be considered. The GDG also recognised that prolonged fatigue was a very common presenting feature of a myriad of disorders, both physical and psychiatric. However, members of the group cited research by Hin et al. (1999) which suggests that up to 3% of those who present with unexplained prolonged fatigue were positive for CD antibodies. The group also cited their vast clinical anecdotal experience in which many people who had previously thought of themselves as asymptomatic retrospectively recognised that they had been very tired for up to a decade before diagnosis was made. The importance of addressing the cause of prolonged fatigue was also raised as of high importance in paediatric patients, in whom fatigue is highly uncommon. Active case-finding The GDG emphasised that anyone who has symptoms suggestive of CD should be offered serological testing regardless of any coexisting conditions or characteristics. Therefore, the population of interest for the assessment of case-finding strategies should comprise people who are not currently experiencing such symptoms to a degree that leads them to seek advice from healthcare professionals. Following the conventions of the Oslo consensus statement on definitions for coeliac disease and related terms (Ludvigsson et al., 2012), the GDG preferred to refer to this group of people as experiencing ‘subclinical’ CD. This term is preferable to ‘asymptomatic’ disease, as it is clear that many people with undiagnosed CD have a history of symptoms that are retrospectively considered significant once a diagnosis has been established; moreover, it is common for people to report an improvement in such symptoms when they start a gluten-free diet (GFD). Therefore, people with subclinical CD should not be considered truly asymptomatic; instead, they are defined as people who experience ‘disease that is below the threshold of clinical detection without signs or symptoms sufficient to trigger CD testing in routine practice’ (Ludvigsson et al., 2012). First-degree relatives Current practice is to offer serological testing to first-degree relatives. The assumption that people do or do not have CD at the time of testing is incorrect. People may undergo seroconversion, which is problematic as a clinician may tell someone that they are not CD positive, but that person may develop CD at a later time. Ruling HLA DQ2/DQ8 out is important, as a clinician can then definitively conclude that if someone suspected of CD does not have HLA DQ2/DQ8, then they will never develop CD. While this could be very useful, it is pragmatically very difficult as a GP cannot request HLA DQ2/DQ8 testing as this needs to be requested by a specialist. Thus, patients would have to be referred to a specialist to request this test, which becomes expensive and time consuming, and therefore, in the opinion of the GDG, impractical. Type 1 diabetes The GDG raised the important notion that it is not sufficient to just test adults who present with gastrointestinal (GI) symptoms, as suggested in the current diabetes guideline. When people present at a diabetic clinic they are commonly only asked about diabetic features i.e. sugar, eyes, feet, etc., and GI symptoms are not discussed as part of a patient’s diabetic review so go unnoticed and therefore untested. It is estimated that 15–20% of people have GI symptoms, but people don’t realise that these may be relevant to their diabetes and so do not raise it with their diabetes consultant. The group felt strongly that it was very important to have a low threshold for testing people with diabetes to optimise dietary management of their diabetes and their potential CD-related symptoms. The GDG discussed current recommendations within the diabetes guideline relating to testing for CD when a low BMI is noted. The group discussed that weight loss and low BMI are a feature of CD and noted that, although weight loss can be a symptom of CD, the traditional view of a person with CD being underweight is no longer true and that people with diabetes may present underweight, at a normal weight or overweight. It is therefore important that low BMI should not be highlighted as the only circumstance in which suspicion of CD should be raised in someone with diabetes. The GDG also discussed testing for CD at the time of diagnosis of diabetes, and noted that this could be problematic in some circumstances. The group recognised that it may be too emotionally or cognitively difficult for the patient to take on the importance of each of their separate diagnoses. For these reasons, the GDG considered that it would be reasonable for a short delay (unlikely to be more than 6 months) between diagnosis of type 1 diabetes and testing for CD. The group chose not to complicate its recommendations with explicit discussion of this issue, as it believed that most clinicians would use their discretion in providing tests and information in an appropriate timeframe, and it did not want to detract from the importance of providing the test for everyone who has received a diagnosis of type 1 diabetes. Long-term complications The GDG felt that the available evidence highlighted the very serious nature of the potential long-term complications of undiagnosed CD. Osteoporosis was felt to be the most common potential long-term complication and the GDG felt that the evidence adequately reflected clinical experience. The GDG noted that, although there is an increased risk of malignancy with undiagnosed CD, the overall risk of developing specific cancers is low. The evidence for infertility was somewhat inconsistent. However, due to the serious emotional impact infertility has on a couple trying to conceive, the group still felt that it was important to raise awareness that CD could be contributing to this, and that clinicians should consider serological testing if other causes of infertility have been ruled out. Overall, the group felt strongly that serological testing is inexpensive and non-invasive, and that, if potentially very serious long-term complications could be avoided by having a diagnosis of CD made, the benefit of doing so far outweighs the potential detriment in having to follow a GFD. This trade-off was explored explicitly in original health economic modelling (see below). |
| Economic considerations | Active case-finding The original health economic analysis for this question was based on a modified version of the model developed to compare various serological testing strategies. Therefore, many of the considerations discussed in that question apply here (see 5.2.6). It was a potential weakness of the analysis that no evidence was found to estimate the diagnostic accuracy of different testing strategies in the populations of interest. Therefore, it was assumed that the sensitivity and specificity of the tests did not differ between populations, and data from the review of diagnostic accuracy in people presenting with symptoms suggestive of CD were used (see 5.1.3 and 5.2.3). In the original health economic model, the benefits of identifying people with subclinical CD are captured in 2 ways. Firstly, the quality of life of the proportion of people who follow advice to adopt a GFD will improve. Secondly, those people are subject to reduced incidence of long-term complications of CD, some of which have an impact on life expectancy. The GDG understood that, in all the populations simulated in the model, a reduction in long-term complications (with attendant improvement in life expectancy) was not, on its own, sufficient to counterbalance the costs and harms of testing (including serological assays and endoscopic biopsy in people who test positive). In contrast, the day-to-day quality of life benefit associated with a true-positive diagnosis only had to be small to make case-finding good value for money. The quality of life evidence used in the model’s base case was drawn from an Argentinian study in which quality of life was measured (using the SF-36) at the point of diagnosis and following 3 months’ treatment with a GFD. This suggested that people with subclinical CD who adopt a GFD experience quality of life that is, on average, approximately 1.5% better than those who continue to ingest gluten (Nachman et al. 2009). Although the study appears to have been well conducted, the sample of patients of interest to this model is very small; as a result, the estimate of effect is very uncertain. However, this uncertainty is appropriately propagated through the model, which presents a probabilistic synthesis of all parameters. The GDG expressed a clear view that it was appropriate to make a base-case assumption that adopting a GFD improves quality of life in people who were not complaining of symptoms at the time of diagnosis. Members of the group advised that, in their experience, many people who are diagnosed with subclinical CD report a history of symptoms that, while troublesome, had not led them to seek medical advice. Furthermore, the GDG reported that such people commonly report an improvement in such symptoms when starting a GFD. Finally, the fact that most people who have been diagnosed with subclinical disease elect to continue with a GFD is an indication that they are conscious of a perceptible improvement in quality of life. The GDG understood that a difference in quality of life of the magnitude used in the model’s base case to estimate the benefit of a GFD for people with subclinical CD is very small (1.5%). For comparison, the smallest effect that is detectable by the EQ-5D instrument and UK tariff (that is, the smallest change in quality of life that would result from an improvement in a single domain score) is equivalent to more than a 4% improvement in quality of life. Therefore, it was reasonable to assume that, if the quality of life of an average person with subclinical CD who adopts a GFD is improves by a degree that is perceptible to that person, a gain of at least 1.5% – and probably greater – on a quantitative measure could be expected. In this context, the base-case value should be seen as conservative. In all 4 populations simulated, the original health economic model suggested that case-finding in adults is likely to represent reasonable value for money. Base-case ICERs ranged between £14,000 per QALY gained (first-degree relatives) and £26,000 per QALY gained (autoimmune thyroid disease) for the best serological strategy compared with no testing. Case-finding was slightly more expensive in children than in adults, largely due to the increased costs associated with endoscopic biopsy in children (which usually requires anaesthesia). Nevertheless, case-finding resulted in improved quality of life, with ICERs ranging between £18,800 per QALY gained (first-degree relatives) and £28,300 per QALY gained (autoimmune thyroid disease). Although base-case ICERs exceeded £20,000 in type 1 diabetes (children only) and autoimmune thyroid disease (children and adults), the GDG felt these were likely to be somewhat underestimated, as the model only captured health gains that are associated with the diagnosis and management of CD. However, the group believed that, in both these conditions, correct identification of CD would also lead to superior management of the underlying condition, with associated improvement in quality of life. In the case of type 1 diabetes, the glycaemic control of people with subclinical CD is known to be improved by adopting a GFD. Additionally, dietary management is complex in people with both conditions, as each imposes its own requirements; in this context, the GDG believed it is critical for children to have access to appropriate dietetic support, so diagnosis of subclinical CD is very important. In the case of autoimmune thyroid disease, untreated coeliac enteropathy interferes with the absorption of oral medications that are critical to managing the condition. Correct identification of CD, therefore, should be associated with more stable and effective medication requirements, improving the person’s quality of life. In both these instances, the GDG felt that, although the additional benefits would be very hard to quantify without a complicated model of 2 concurrent disease processes, they were examples of ‘change in the quality of life [that] is inadequately captured’ in the analysis and, therefore, good reasons to recommend case-finding in populations that had base-case ICERs in the range £20–30,000. In all cases, results were very sensitive to the degree to which a GFD was assumed to improve the health-related quality of life of people with subclinical CD. However, the GDG felt confident that such benefits are observed in practice, so the group was happy to recommend case-finding, on the expectation that the true-positive identification of people with subclinical CD would lead to this kind of health gain. Although it is theoretically possible that different serological strategies might be optimal in different populations (according to expected prevalence of CD and other population-specific characteristics), little evidence was found to suggest that anything other than the strategies recommended in section 5.2 should be preferred. Therefore, it was not necessary to make separate recommendations about the tests that should be used in a case-finding context; it was sufficient to recommend that serological testing should be offered, and recommendations elsewhere in the guideline would be followed. One potential exception to this rule was that, in sensitivity analysis for child first-degree relatives of people with coeliac disease, some results suggested that it could theoretically be worth adding routine genotyping (HLA DQ2/DQ8 testing) to the diagnostic strategy. However, the GDG pointed out that, in practice, this would be of very limited value: if one family member is HLA DQ2/DQ8 positive (as the index case almost certainly would be), the chances of the rest of that family being HLA DQ2/DQ8 positive is very high. Therefore, the utility of doing that test in further family members is negligible. This shows that there are some areas in which population-specific diagnostic accuracy data might improve the accuracy of results. The original health economic model did not cover children with Down’s syndrome, as this population was not among the GDG’s top priorities for modelling. However, the GDG was presented with details of a published cost–utility analysis (Swigonski et al., 2006), which found that screening was not cost effective in this population. This analysis was confined to a single outcome of preventing lymphoma and the original health economic analysis conducted in other populations had shown that relatively little of the benefit of true-positive identification of CD could be ascribed to this outcome. Therefore, it was unsurprising that Swigonski et al. found insufficient benefit to justify the costs of case-finding. The GDG inferred that a fuller analysis, accounting for a wider range of benefits, would be likely to reach a different conclusion. However, the group did not feel that it had enough evidence to support an ‘offer’ recommendation, so concluded that case-finding should be considered in this population. |
| Quality of evidence | The group recognised that overall the quality of evidence available to answer this question was of a low quality. This was recognised to be a product of the lack of evidence available, the retrospective nature of the majority of studies, and the bias inherent in the way study participants were selected, how prevalence estimates were generated, the lack of precision in the presented estimates, and the lack of endoscopic intestinal biopsy to prove CD diagnosis in a great number of the studies available. |
| Other considerations | Irritable Bowel Syndrome (IBS) The GDG felt that it was important that those with a diagnosis of IBS should be tested for coeliac disease, as the two conditions have very similar phenotypic manifestations, notably in terms of gastrointestinal symptoms and abdominal pain. The group discussed that children are not routinely diagnosed with IBS, and are more likely to be labelled with ‘recurrent abdominal pain’ or ‘abdominal migraine’. IBS diagnosis is only typically given to adults with the same symptoms. Children may also have a diagnosis of inflammatory bowel disease. A child could hypothetically present to a number of clinicians and be given a number of different diagnoses for same symptoms because of this lack of consistency in characterising ‘IBS-like’ symptoms in the paediatric population. It was also raised as common for children to be diagnosed with IBS-like symptoms rather than a diagnosis of IBS. The group further raised the notion that, technically, children should be covered by recommendations on children or adults with recurrent GI symptoms, so whether this is labelled as IBS or not in children it is essentially irrelevant to their being investigated for CD. Repeat serological testing The group thought it highly important that both patients and healthcare professionals should be aware that people with risk factors for CD who test negative initially may remain at increased risk of developing CD in the future. The GDG was aware that some researchers have recommended routine periodic testing of people whose initial serological results are negative, especially those with type 1 diabetes. The original health economic model suggested that testing people with type 1 diabetes for CD at diagnosis could probably be considered to provide reasonable value for money (see above); however, the group was aware that this conclusion was relatively finely balanced, and small adjustments to the parameters of the model would produce different results. In particular, if prevalence of CD was any lower than estimated in the model’s base case, it would not be cost effective to offer case finding. The model was not designed to examine the cost effectiveness of periodic repeat testing. However, it could be inferred that the prevalence of CD among people who initially tested negative would be lower than in the incident type 1 diabetes cohort. Therefore, it is extremely unlikely that repeat testing would achieve health gains at a cost that would be considered an effective use of NHS resources. This result would arise partially because of the costs of repeat serology itself, but more particularly because of the costs incurred and quality of life forgone by performing endoscopic biopsies in people with positive serology in a context where those people were more likely to have false-positive findings owing to lower prevalence of CD (that is, the positive predictive value of all serological tests would be lower in a retesting setting). Nevertheless, the GDG were keen to emphasise that, if people with risk factors for CD who have previously been found to be serologically negative develop CD-like symptoms over time, there should be a low threshold for retesting for CD. The group were mindful of the evidence and experience (noted above) that people with subclinical CD frequently experience mild symptoms that do not lead them to seek medical advice. Therefore, the group recommended that people who initially test negative are advised to treat any future CD-like symptoms seriously, and not to hesitate to seek advice from their healthcare providers. For treating clinicians, it was emphasised that, if a person has risk factors for CD and even mild symptoms that are suggestive of CD, a historical negative serological test should not be used as a reason not to offer repeat serological testing. |
From: 4, Evidence for the recognition of coeliac disease
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