NICE guideline on ME/CFS: robust advice based on a thorough review of the evidence, 2024, Barry et al.

SNT Gatchaman

SNT Gatchaman

Senior Member (Voting Rights)
Staff member
NICE guideline on ME/CFS: robust advice based on a thorough review of the evidence
Peter Walter Barry; Kate Kelley; Toni Tan; Ilora Finlay

In 2021, the National Institute for Health and Care Excellence produced an evidence-based guideline on the diagnosis and management of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a disabling long-term condition of unknown cause. The guideline provides clear support for people living with ME/CFS, their families and carers, and for clinicians.

A recent opinion piece published in the journal suggested that there were anomalies in the processing and interpretation of the evidence when developing the guideline and proposed eight areas where these anomalies were thought to have occurred. We outline how these opinions are based on a misreading or misunderstanding of the guideline process or the guideline, which provides a balanced and reasoned approach to the diagnosis and management of this challenging condition.

Link | PDF (Journal of Neurology, Neurosurgery & Psychiatry)

https://web.archive.org/web/2024052...np/early/2024/02/28/jnnp-2023-332731.full.pdf
 
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Defining ME/CFS

It is instead a diagnosis based on the exclusion of other disorders, and the recognition of a cluster of characteristic symptoms, many of which are individually also seen in other conditions.
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The guideline committee examined the criteria currently in use to assess which might be most appropriate for suspecting and establishing a diagnosis of ME/CFS. [...] All criteria were found to have serious or very serious limitations.
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While the Institute of Medicine (IoM) criteria are potentially more encompassing than the International Consensus Criteria, reducing the probability of missing a diagnosis, the IoM criteria are narrower than others such as the Fukuda criteria, reducing the risk of overdiagnosis. The decision of the committee to use a slightly modified version of the IoM criteria derived from assessment of the quality, benefits and harms, and usability of the criteria. It does not represent a new set of diagnostic criteria.
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NICE evaluated scientific evidence for ME/ CFS as it is currently defined, based on the IoM criteria. This is the definition that the US Center for Disease Control uses when providing information to healthcare providers. Other reviews on ME/CFS, such as the recent one by IQWiG in Germany, have used a similar approach.
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The committee’s criteria for diagnosing ME/ CFS are more restrictive than in the previous NICE guideline, since patients are required to have all the following: debilitating fatigue, PEM, unrefreshing sleep and cognitive difficulties.
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The fact that these individual symptoms are not specific to ME/CFS does not invalidate their mandatory inclusion in the diagnostic criteria. Fever, for example, is a mandatory feature in the American Heart Association diagnostic criteria for Kawasaki disease, but those criteria are not invalidated just because fever also occurs in tonsillitis.
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PEM is a required component of the Revised Canadian Consensus Criteria, the International Consensus Criteria and the IoM diagnostic criteria. Wider definitions, such as the Oxford criteria or the London criteria, both used in the PACE trial, do not mandate the inclusion of PEM and therefore risk including people with fatigue from other causes. In one study of over 6000 participants, 85% of those identified by the Oxford criteria as having CFS were healthy subjects with mild fatigue who had been inappropriately labelled.
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The committee agreed that papers that had used diagnostic criteria that did not include PEM would be downgraded due to ‘indirectness’ in the GRADE assessment. This does not mean that papers were ignored or excluded, but that the uncertainty as to whether some trials accurately represent the population with ME/CFS was taken into account when assessing the evidence.
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Endpoints to assess efficacy

This process defines what outcomes and endpoints will be used when determining clinical and cost effectiveness. These are defined before evidence is examined. Any inference that the committee looked at the evidence review and picked the outcomes which best matched their pre-conceptions is simply incorrect.
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In this guideline, the longest follow-up time point for which data were available from each study was extracted. The committee considered long-term data of treatments for ME/ CFS to be more reflective of real-world efficacy, and so more helpful for decision-making and implementation in clinical practice. ME/CFS is, after all, a long-term condition.
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In 2019, stakeholder feedback regarding the NICE guideline on depression expressed concern that NICE had not considered long-term outcomes. They requested that ‘NICE should conduct a proper analysis of 1 and 2-year follow-up data where available and prioritise treatment recommendations made on the basis of this data’ and subsequently stated that ‘long-term follow-up, where available, must be included and prioritised’. This is precisely what NICE has done in the ME/CFS guideline.
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The guideline committee found that the early differences between interventions and controls reported in some studies were not maintained over time. There are several possible explanations for this. Initial improvements might be due to response bias or a placebo effect, or due to participants receiving alternative treatments after the initial trial interventions. However, in two major trials, exploratory analysis suggested that additional treatment received after randomisation did not explain the lack of long-term benefit from the intervention.
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Data on treatment harm

Treatment harm and side effects are routinely considered in evaluations of interventions, and qualitative evidence, appropriately analysed, is important for assessing patient impact in NICE guidelines.
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In studies relating to GET or other exercise interventions, participants reported that following the exercise programme was ‘hard work’ and in some, this led to worsening of symptoms after each session. For others, trying to persist with the exercise programme led to a worsening of their symptoms in the longer term. Debilitating exacerbation of symptoms was a reason for discontinuation. In one study, up to 74% of patients have reported experiencing harms after GET.
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A recent meta-analysis found that harms of graded exercise versus inactive controls were not well reported in clinical trials.
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Previous reports have also expressed concern that the reporting of adverse events in psychological treatments is weak and the criteria used may not be appropriate.
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In conclusion, the committee was presented with contested evidence of only limited and short-term benefits of GET (compared with ‘SMC’), benefits that were found to be even less outside of the setting of a clinical trial. This was contrasted against considerable, but methodologically low-quality evidence of patient harm, which by some accounts was quite devastating. After reviewing all this evidence, the committee agreed that GET should not be offered to patients.
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Fatigue as an outcome

A lack of blinding in clinical trials can introduce performance and detection bias due to the participants’ and assessors’ knowledge of the intervention. This bias is likely to be exacerbated if the outcomes of interest are measured subjectively rather than objectively. For unblinded trials, all subjective outcomes, including fatigue measured subjectively, were downgraded consistently for this risk of bias in the GRADE analysis. This is standard practice. Blinded trials that used fatigue as an outcome were not downgraded for this risk of bias. ‘Downgrading’ in critical appraisal indicates the quality of the evidence, it does not mean exclusion of the evidence. Fatigue was one of ‘the outcomes that matter most’ in the evidence review.
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Many of the intervention studies for ME/CFS rely on unblinded subjective outcomes. Where reported, objective outcomes data such as activity levels, employment levels, disability payments or fitness data showed no or minimal improvement in these trials.
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Evidence synthesis methodologies

GRADE methodology is not used to exclude or reject evidence, but to assess the quality and certainty of the evidence. All studies that met the inclusion criteria in the protocols were included in the evidence reviews, and these were synthesised and presented to the committee for discussion. The evidence review was quality assured externally, and the rating of the evidence as ‘low to very low quality’ is consistent with other reviews, including the Cochrane review on exercise therapy for ME/CFS.
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Graded exercise therapy

Aside from the different definitions of the term ‘graded exercise therapy’, the content and application of such programmes also differ. GET was defined in the guideline as consisting of establishing a baseline of achievable exercise or physical activity and then making fixed incremental increases in the time spent being physically active, based on the deconditioning and exercise avoidance theories of ME/CFS.
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This definition reflects the descriptions of GET included in the evidence reviewed. For instance, the GET Therapists manual from the PACE Trial instructs practitioners to ‘negotiate meaningful goals’ and then, as its next step, to increase the duration of exercise by a fixed increment, such as ‘add 20% duration, up to 30 min’. If people have exacerbation of their symptoms, they are encouraged to maintain the same exercise level that led to their deterioration and told that ‘hurt does not equal harm’.
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Some stakeholders stated that GET, as defined in the guideline, is not what is delivered in practice. Others report that GET, as defined in the guideline, is still used and that has caused significant harm.
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Cross-referencing NICE guidance

Pain is commonly experienced in many conditions, including in people with ME/CFS who comprise less than 1% of the total population with chronic pain. Some describe neuropathic-type pain, some have headache or other pain symptoms and may benefit from support from specialist pain services, as is recommended in the ME/CFS guideline.
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People with ME/CFS differ from people with chronic primary pain who are the main focus of the Chronic Pain Guideline, making other guidance more appropriate for these individuals. Although exercise has been shown to improve chronic pain, exercise in individuals with ME/CFS can exacerbate both fatigue-related and pain-related PEM. Management strategies differ depending on the underlying condition.
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Evidence about energy management

There is a lack of evidence supporting energy management in people with ME/CFS, and no evidence that it is a ‘cure’. But there is also no signal of harm or deterioration with energy management programmes, unlike with GET.
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One principle of energy management is an attempt to avoid PEM, and so there is no drive to increase activity by setting graded goals and no suggestion that worsening symptoms are a natural response to increased activity, as there is in GET.
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Conclusions

The new guideline on ME/CFS was produced by an independent committee of clinicians who look after people with the condition, and people with lived experience of ME/CFS. Development followed a transparent process that conformed to recognised standards for guideline development, including extensive consultation with stakeholders prior to publication.
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All evidence needs interpretation: evidence alone cannot determine the content of a recommendation. Criticisms of the guideline discussed in this paper are misplaced. The guideline has been welcomed and widely accepted by patient groups and clinicians leading services for people with ME/CFS in the UK.
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