cognitive behavioural and personalised exercise interventions for fatigue in inflammatory rheumatic diseases (LIFT), 2022, Bachmair et al

[Sly Saint]

Merged thread

full title
Remotely delivered cognitive behavioural and personalised exercise interventions for fatigue severity and impact in inflammatory rheumatic diseases (LIFT): a multicentre, randomised, controlled, open-label, parallel-group trial

Summary
Background
Chronic fatigue is a poorly managed problem in people with inflammatory rheumatic diseases. Cognitive behavioural approaches (CBA) and personalised exercise programmes (PEP) can be effective, but they are not often implemented because their effectivenesses across the different inflammatory rheumatic diseases are unknown and regular face-to-face sessions are often undesirable, especially during a pandemic. We hypothesised that remotely delivered CBA and PEP would effectively alleviate fatigue severity and life impact across inflammatory rheumatic diseases.
Methods
LIFT is a multicentre, randomised, controlled, open-label, parallel-group trial to assess usual care alongside telephone-delivered CBA or PEP against usual care alone in UK hospitals. Patients with any stable inflammatory rheumatic disease were eligible if they reported clinically significant, persistent fatigue. Treatment allocation was assigned by a web-based randomisation system. CBA and PEP sessions were delivered over 6 months by trained health professionals in rheumatology. Coprimary outcomes were fatigue severity (Chalder Fatigue Scale) and impact (Fatigue Severity Scale) at 56 weeks. The primary analysis was by full analysis set. This study was registered at ClinicalTrials.gov (NCT03248518).
Findings
From Sept 4, 2017, to Sept 30, 2019, we randomly assigned and treated 367 participants to PEP (n=124; one participant withdrew after being randomly assinged), CBA (n=121), or usual care alone (n=122), of whom 274 (75%) were women and 92 (25%) were men with an overall mean age of 57·5 (SD 12·7) years. Analyses for Chalder Fatigue Scale included 101 participants in the PEP group, 107 in the CBA group, and 107 in the usual care group and for Fatigue Severity Scale included 101 in PEP, 106 in CBA, and 107 in usual care groups. PEP and CBA significantly improved fatigue severity (Chalder Fatigue Scale; PEP: adjusted mean difference −3·03 [97·5% CI −5·05 to −1·02], p=0·0007; CBA: −2·36 [–4·28 to −0·44], p=0·0058) and fatigue impact (Fatigue Severity Scale; PEP: −0·64 [–0·95 to −0·33], p<0·0001; CBA: −0·58 [–0·87 to −0·28], p<0·0001); compared with usual care alone at 56 weeks. No trial-related serious adverse events were reported.
Interpretation
Telephone-delivered CBA and PEP produced and maintained statistically and clinically significant reductions in the severity and impact of fatigue in a variety of inflammatory rheumatic diseases. These interventions should be considered as a key component of inflammatory rheumatic disease management in routine clinical practice.
Funding
Versus Arthritis

https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(22)00156-4/fulltext

 

[Sly Saint]

the 'new' 'acceptable' name for GET?, PEP (personalised exercise programmes) one to watch for.

 

[Andy]

From the paper, my bolding

"Procedures
All participants were aware that the trial interventions were designed specifically to reduce fatigue. As a minimum, all participants received usual care in the form of a Versus Arthritis (formerly Arthritis Research UK) education booklet for fatigue. This booklet addresses the principal domains of fatigue, which can be amenable to self-management and represents usual care in almost all rheumatology services in the UK.

The CBA and PEP active treatments were therapist based, with accompanying manuals. They were adapted, with patient involvement, from previous fatigue-specific cognitive behavioural and exercise interventions
12, 13 to ensure that they were suitable for remote delivery via telephone, and were applicable to the broad spectrum of inflammatory rheumatic diseases. A detailed description of each intervention is available in the appendix (pp 3–8). Briefly, CBA was a psychological intervention that targeted unhelpful beliefs and behaviours and aimed to replace them with more adaptive ones. PEP was an exercise programme that was individually tailored and combined with a graded exposure behavioural therapy that was aimed to normalise misperceptions of effort and enhance exercise tolerance."

Spoiler: And guess what reference 12 is...

• White PD
• Goldsmith KA
• Johnson AL
• et al.

Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial.

So full on PACE 2.0.

Alison Wearden is one of the named authors. And tucked away in the appendix PDF file is the fact that Peter White (Queen Mary University of London, UK) is listed as a study group member.

 

[Mij]

Here's one, REST (Restricted Exercise Safety Therapy). Most likely a better outcome.

 

[Sean]

unhelpful beliefs and behaviours... ...misperceptions of effort...

None of which have ever been demonstrated to exist in patients, let alone to be the problem. They are simply asserted to be true.

This is the real psychopathology.

 

[rvallee]

At this point, it becomes legitimate to consider this level of obsession as a cognitive deficit. It's not normal to be so obsessed with something so mediocre.

These interventions should be considered as a key component of inflammatory rheumatic disease management in routine clinical practice.

But the publishing industry and academia are to blame for this. That such blatant speculation, out of fuzzy maths that can literally show anything with the right bias, can lead to such a strong assertion is not something you see when things have been failing for a bit. It's what you see when they have been failing for so long that everyone may as well have given up doing their job and it wouldn't even make any difference. This is phoning in phoning it in.

And of all the things, it's a minor squabble, but none of those programs are ever personalized, no more than a horoscope or 12 flavors of ice cream. It's outrageous that some small details like this are so routine that no one notices them anymore. They're as personalized as a car with a different paint color is from one another of the same make and model. Ridiculous.

But the Orwellian play on words here, explicitly using the poor evidence base for CBT and GET, citing it, and actually involving Peter White it seems, but renaming them both so that most people won't make the connection. This is truly the stuff of tobacco companies renaming themselves. It shows they understand the issues, but aren't bothered by it, in fact exploit the same dishonest methods with explicit intent.

If the future of medicine is to be the best liars around, the whole system needs reform. All of it, none of this is normal, it doesn't even exist in any other profession.

 

[rvallee]

Since we're on the topic of renaming things, I would offer: Customized Rehabilitation Activation Protocol.

 

[cassava7]

Merged thread

A cursory look at this study.

Participants

The participants had the following conditions and were all stable (low inflammation markers):

Of those treated, 202 (55%) were diagnosed with rheumatoid arthritis, 78 (21%) with connective tissue disease, 72 (20%) with axial spondyloarthritis, 14 (4%) with other inflammatory rheumatic diseases, and 1 requested their data to be withdrawn.

The inclusion criterion regarding fatigue was that it had to be persistent (>3 months) and clinically significant, defined as “≥6 on numerical rating 0–10 scale measuring average level of fatigue during the past 7 day”.

Interventions

The active interventions (personalised exercise a.k.a. PEP and CBT) were delivered by therapists over the phone, with at most 7 one-to-one sessions of up to 45 mins per participant, over 14 weeks. The number of sessions received by each participant was decided individually between them and their therapist, but a booster session was added at 22 weeks for all participants. PEP participants received a median of 5 sessions (IQR 1-8) and CBT participants a median of 8 sessions (IQR 2-8).

Both interventions were based on the usual exertion fear-avoidance model of the PACE trial, which is directly cited (ref. 12, as @Andy pointed out):

Briefly, CBA was a psychological intervention that targeted unhelpful beliefs and behaviours and aimed to replace them with more adaptive ones. PEP was an exercise programme that was individually tailored and combined with a graded exposure behavioural therapy that was aimed to normalise misperceptions of effort and enhance exercise tolerance.

The usual care consisted of “a Versus Arthritis education booklet for fatigue” (no therapist involved), which seems to be this one from a quick Google search. It essentially explains adaptative pacing as in the PACE trial, i.e. trying to gradually increase exercise while recommending “the four P’s”: problem solving, planning, prioritising and pacing.

Outcomes

The primary outcome was the Chalder fatigue scale (0-33 rating) and, because there was an improvement, the FSS was also included. They were both evaluated at 10, 28 and 56 weeks. The following mean changes at 6 months post-treatment (56 weeks) are reported:

- PEP compared to usual care:

CFS: -3.03, 97.5% CI [-5.05, -1.02] (p = 0.0007)

FSS: -0.64 [-0.95, -0.33] (p = 0.0058)

- CBT compared to usual care:

CFS: -2.36 [-4.28, -0.44] (p < 0.0001)

FSS: -0.58 [-0.87, -0.28] (p < 0.0001)

The authors chose half a standard deviation as the minimally important difference (MID, i.e. the minimal change that can be considered clinically significant) on the Chalder fatigue scale:

The clinically minimally important effect was 0.5 [22], equating to 2 points in the Chalder Fatigue Scale (assuming [a standard deviation] of 4 points), based on the trials that evaluated similar non-pharmaceutical interventions. [Note: no citation of such interventions is provided here]

However, this seems inappropriate. First, their choice of half a SD is based on a small review of 32 studies that reported quality-of-life outcomes; this rule of thumb has been contested. [1] Second, they chose a smaller MID than those reported previously for lupus & rheumatoid arthritis on the CFS and the FSS, which respectively ranged from 2.3 to 3.3 and 0.5 to 1.2. [2] Third, the interventions are directly based on the PACE trial, as was the GETSET trial; in contrast, a MID of 3 points for the CFS was chosen in the latter. Importantly, all reported confidence intervals for the CFS and the FSS include values under their respective MIDs.

It is unfortunate that the authors reported a “clinically significant” change of “medium size” despite their results 1) showing uncertainty that they even reached MIDs, 2) likely owing to response bias on the questionnaires rather than a true effect from the intervention, considering the small differences compared to usual care.

In particular, for participants who received 3 or more sessions of PEP, either exercise was indeed slightly more effective than usual care and CBT or response bias might have been particularly pronounced, as there was a greater improvement on the CFS and the confidence interval did not include the MID:

The adjustment for participants receiving at least three sessions of active treatment enhanced the effect size of PEP on fatigue severity (Chalder Fatigue Scale mean difference −4·44 [97·5% CI −5·66 to −3·21], p<0·0001), but had no impact on the treatment effect of PEP on fatigue impact or CBA effect size on either primary outcome (appendix p 16).

In any case, this is a disappointing result: if the reported improvement owed to the treatment itself as opposed to bias, it is likely that a dose-dependent relationship would have emerged. This is not the case.

Further, while there was a reported improvement with PEP on the Work Productivity and Activity Impairment questionnaire (which concerns the prior 7 days) on “overall work impairment” (p = 0.010), none was observed on the “valued life activities” subscale of this questionnaire. Generally, despite “statistically significant” changes being reported on some secondary outcomes, they were not corrected for multiple comparisons, and other important secondary outcomes were null:

In particular, the effect [of PEP] on overall work impairment (Work Productivity and Activity Impairment −15·58 [95% CI −27·41 to −3·74], p=0·010) at 56 weeks was large. By contrast, neither treatment significantly improved pain, anxiety, or physical health-related quality of life (table 2).

Conclusion

Overall, it seems fairly clear from the results that the interventions were not effective. I do not understand why the Lancet’s peer reviewers did not point this out and agreed to publish the article as such, that is, with the claims of improvement that it makes.

While the authors mention that they will report on cost-effectiveness in a later article, I cannot see how they can make the case that their interventions are cost-effective (3+ months of treatment for barely reaching MIDs).

Perhaps the most unfortunate part of this trial is that it was funded by the charity Versus Arthritis. Prof Gary MacFarlane, one of the co-authors, is VA’s vice-director; surely this must have helped securing funding.

[1] Norman, G. R., Sloan, J. A., & Wyrwich, K. W. (2003). Interpretation of changes in health-related quality of life: the remarkable universality of half a standard deviation. Medical care, 41(5), 582–592. https://doi.org/10.1097/01.MLR.0000062554.74615.4C

[2] Nordin, Å., Taft, C., Lundgren-Nilsson, Å., & Dencker, A. (2016). Minimal important differences for fatigue patient reported outcome measures-a systematic review. BMC medical research methodology, 16, 62. https://doi.org/10.1186/s12874-016-0167-6

 

[Peter T]

Cognitive behavioural approaches (CBA) and personalised exercise programmes (PEP) can be effective, but they are not often implemented because their effectivenesses across the different inflammatory rheumatic diseases are unknown

Doesn’t this imply they had already prejudged the issue? Unblinded with subjective outcomes, is this another ocean liner launched towards a predetermined destination.

I have no idea about the relevance of these interventions in this situation, but sad that this is research that will not advance our knowledge.

 

[cassava7]

Another newspaper article on this study (paywalled).

https://www.thetimes.co.uk/article/talking-therapy-and-exercise-relieve-arthritis-sufferers-fatigue-6szxvk6s5

 

[Hutan]

That's a great analysis @cassava7. Have you looked to see if you can submit a comment to the journal? Do you plan to send it to the charity that funded the study?


I haven't read the study, but this bit wasn't quite clear to me:

In particular, for participants who received 3 or more sessions of PEP, either exercise was indeed slightly more effective than usual care and CBT or response bias might have been particularly pronounced, as there was a greater improvement on the CFS and the confidence interval did not include the MID:

The adjustment for participants receiving at least three sessions of active treatment enhanced the effect size of PEP on fatigue severity (Chalder Fatigue Scale mean difference −4·44 [97·5% CI −5·66 to −3·21], p<0·0001), but had no impact on the treatment effect of PEP on fatigue impact or CBA effect size on either primary outcome (appendix p 16).

In any case, this is a disappointing result: if the reported improvement owed to the treatment itself as opposed to bias, it is likely that a dose-dependent relationship would have emerged. This is not the case.

I think it's arguable that there was a dose-dependent relationship:
It sounded as though there was a sort of a dose dependent relationship (2 or less PEP sessions versus 3 or more sessions), even if it's just a single step increase at that threshold?

I'm also not sure that a dose-dependent relationship is proof of lack of bias in an open-label subjective outcome trial. Your earlier comment that "a response bias might have been particularly pronounced" in those who completed 3 or more sessions also seems to cast doubt on that idea. Those who have made a lot of effort to be compliant with the treatment, who have invested more in teh treatment being helpful, might be more inclined to evaluate the outcome more positively. They also had more contact with the therapists and so were more likely to have been swayed by suggestions that the treatment is effective.

 

[dave30th]

Alison has been staring at the beautiful tree for five hours.

Is this Alison Wearden???

 

[cassava7]

That's a great analysis @cassava7. Have you looked to see if you can submit a comment to the journal? Do you plan to send it to the charity that funded the study?

Thank you for your feedback. I have done neither of these things as I do not have the energy to formalize this cursory analysis, even though I would like to send a short letter to the editor.

In my opinion, it would not be of much use to contact Versus Arthritis directly as they are very much in favour of BPS interventions for chronic pain and fatigue. One of the two laypersons who sat on the NICE committee for the chronic primary pain guideline, which ended up recommending CBT and exercise, is a member of VA.

I haven't read the study, but this bit wasn't quite clear to me:

I think it's arguable that there was a dose-dependent relationship:
It sounded as though there was a sort of a dose dependent relationship (2 or less PEP sessions versus 3 or more sessions), even if it's just a single step increase at that threshold?

I'm also not sure that a dose-dependent relationship is proof of lack of bias in an open-label subjective outcome trial. Your earlier comment that "a response bias might have been particularly pronounced" in those who completed 3 or more sessions also seems to cast doubt on that idea. Those who have made a lot of effort to be compliant with the treatment, who have invested more in teh treatment being helpful, might be more inclined to evaluate the outcome more positively. They also had more contact with the therapists and so were more likely to have been swayed by suggestions that the treatment is effective.

Indeed. It seems like for PEP, the number of sessions received maximized response bias on the CFS, which may be more prone to it than the FSS given its mental health-oriented questions. So there seems to be a dose-dependent relationship in response bias, but not in the actual effect of the treatment, as evidenced by the fact that those who followed 3 or more sessions did not fare better on the FSS.

That said, and importantly, the authors did not report in the appendix whether comparisons between {the PEP or CBA “complier” groups (3+ sessions) vs usual care} vs {the PEP or CBA “non-complier” groups vs usual care} were statistically significant. Given the small mean difference between these two comparisons for PEP on the CFS (-4.44 vs -3.03, i.e. under the author-specified MID of 2 points) and the overlapping 97.5% confidence intervals ([-5.66, -3.21] vs [-5.05, -1.02]), I am not sure that this comparison is statistically significant, let alone clinically significant, and instead appears to be a bit of cherry-picking.

Still, assuming that the result is significant, the hypothesis that the number of sessions maximizes response bias does not hold when comparing both intervention groups. Participants in the PEP arm were less in contact with therapists than those in the CBA arm, as they received a median of 5 vs 8 sessions respectively. Also, according to the appendix, PEP telephone sessions (30 mins, 1h for the first one) were shorter than CBA ones (30-45 mins, 1h for the first two). Yet those who received 3 CBA sessions or more did not achieve a larger decrease on the CFS, which is what one would have expected.

While the analysis reports that PEP was slightly more effective than CBA on secondary outcomes, I believe few of these results, if any, would have survived correction for multiple comparisons.

In the end, I am not sure what to make of this finding. It does not seem significant. I would appreciate some feedback on my reasoning.

 

[petrichor]

I agree with the analysis from @cassava7, which is very good, and also @Hutan's comments. It's indisputible that these are small effect sizes, especially for the CBT. A 2-3 point reduction on a 33 point scale isn't much, and their choice of Minimal Important Difference is pretty arbitrary

 

[cassava7]

Thanks to @Lucibee for highlighting another significant problem with the CFS: the fact that it is uninterpretable as an outcome measure because it is not an absolute scale.

To summarize briefly: the CFS asks the patient to rate changes in fatigue intensity over time, rather than fatigue intensity itself at a given time.

While the main timepoint for comparison in the questionnaire is “as usual”, the short description at the beginning confusingly mentions two other timepoints: “in the last month” and “if you have been tired for a long while, then compare yourself to how you felt when you last felt well”. A participant might select (or be made to select) different timepoints every time they fill the questionnaire, even though the same timepoint (that chosen at baseline) should be used for all comparisons.

For example, the participant could understand “as usual” as “a month ago” the first time, but as “compared to the beginning of the trial” subsequently (instead of using once again “one month before the beginning of the trial”). This is problematic because if their fatigue does not change throughout the trial, they might rate it as “worse than usual” at baseline but “no more than usual” at outcome. This will result in an artificial improvement on the CFS at outcome, only because the comparison timepoints have changed. Similarly, any reported improvement in fatigue (“less than usual” at outcome) will be artificially boosted.

Importantly, this also introduces variability between each participant on their choices of comparison timepoints. In practice, unless all participants are asked to refer to the same specific timepoint every time they fill the questionnaire (e.g. a month prior to the beginning of the trial or when they last felt well), it is impossible to know which one(s) they will choose.

Even if participants were to use the same timepoint for all comparisons, recall bias would arise. At baseline, they may be able to remember how fatigued they felt during the preceding month, but at outcome (e.g. 1 year later) they would not be able to recall it accurately. Further, if “they have felt tired for a long while”, they would likely not be able to recall how they felt “when they were last well” with much accuracy, especially the longer that they have been ill.

All in all, within- and between-patient variability in comparison timepoints and recall bias prevent from using the CFS as an outcome measure. By contrast, an absolute scale measures fatigue intensity itself at a given time (e.g. rating fatigue in the past 7 days from 0 to 10), which allows for comparisons between arbitrary timepoints.

As a result, the small improvement in CFS between baseline and at 6 months post-treatment (which is not replicated on the FSS if a more suitable MID than that picked by the authors is used) could simply be a consequence of this issue and/or response bias due to the lack of blinding.

 

[rvallee]

In any case, this is a disappointing result: if the reported improvement owed to the treatment itself as opposed to bias, it is likely that a dose-dependent relationship would have emerged. This is not the case.

This is where the whole paradigm just falls flat into comparing apples and colors, one more reason why evidence-based medicine needs to stop.

It's discussed a lot, but it makes no sense to speak of "dose" in this context. 10 seances of CBT do not amount to 10x as much CBT as just one. Not in the sense of what dose means in science, where 100mg of something really is 10x 10mg. CBT is a qualitative thing, it can't be added or multiplied, is not quantifiable.

Same thing with measure. Dose has a meaning, it implies a measure. Nothing is measured here. Those words are simply used as incorrectly as would using the colloquial meaning of theory, the whole concept is invalid and is nothing but cheap manipulation of the exact same kind that was commonplace before science became a serious thing. This is straight up from the time when evidence was rhetoric and peer review was an adoring crowd.

 

[cassava7]

@rvallee I am not sure that I agree with your view. Indeed, referring to a “dose” of a non-pharmacological intervention as opposed to a medication may be somewhat of a stretch or a shortcut, but the number of sessions is quantifiable and still counts.

Indeed, what the patient and the therapist agree on doing in the first CBT or PEP session(s) needs to be implemented and adjusted over the next sessions, not only because of the graded approach to increasing activity but also because of setbacks and other difficulties that the patient may encounter. One would reasonably expect that more sessions lead to better and sustained implementation of physical activity, and perhaps to reduced fatigue. Conversely, it is also reasonable to expect that there is a cap on the number of sessions above which more of them does not improve outcomes further. In effect, this is a dose-dependent relationship as for a drug.

(Interestingly, it can be argued that unlike most drugs, a lower number of sessions or “dosage” could lead to more adverse effects because the patient is not informed enough on how to implement the therapist’s guidance properly — if the intervention is truly safe in the first place.)

Something is in fact being measured: bias(es), as artifacts of the combination of flawed outcome measures used in this trial and its design. What is being measured may not be relevant to the question the trial is attempting to address (i.e. are GET and CBT effective in inflammatory rheumatic diseases?), but it is precisely because we have to assess whether the trial succeeds in addressing this question that it is important to clarify what it is being measured.

 

[rvallee]

@rvallee I am not sure that I agree with your view. Indeed, referring to a “dose” of a non-pharmacological intervention as opposed to a medication may be somewhat of a stretch or a shortcut, but the number of sessions is quantifiable and still counts.

It's a massive stretch. Qualitative things don't become quantified just because there's an independent number somewhere. This means as much as talking about 10 mindfulnesses. Nothing is being measured here, they are rated, scored. Ratings and scores can be meaningful but they are different from quantitative measures that have a graded scale, one where 2x as many of something has a literal quantified meaning. Here every séance is explicitly different, they are not equal, in fact nothing is equal here.

It's just borrowing language from medicine and chemistry to make this sound more credible than it is. Given everything I've seen from this field, this is obviously the explicit intent. This is what pseudoscience is made of: take BS, make it sound scientific with language and framing borrowed from science.

 

[MSEsperanza]

Not able to post properly probably for a while so just leave that RAFT here (think hasn't been posted on the forum yet) ...

Reducing Arthritis Fatigue - clinical Teams using cognitive behavioural approaches (RAFT)

https://www.isrctn.com/ISRCTN52709998

 

[rvallee]

Not able to post properly probably for a while so just leave that RAFT here (think hasn't been posted on the forum yet) ...

Reducing Arthritis Fatigue - clinical Teams using cognitive behavioural approaches (RAFT)

https://www.isrctn.com/ISRCTN52709998

Uh. Weird. Essentially the same as the CBT arm of PACE. But they assume it works and jumped straight to cost-effectiveness:

We recently developed and studied a psychologist-led CBT approach course to help people manage RA fatigue. The intervention proved to be effective in improving fatigue impact, severity and coping, mood, sleep and disability. We understand that few rheumatology teams have psychologists and have now designed a more practical method suitable for delivery by rheumatology health professionals who are not CBT therapists, using a detailed manual. This study aims to find out how well this method works and the cost/savings to the NHS in comparison to usual fatigue management.

Overall trial end date: 2018. No citation provided for how the intervention "proved" to be effective. Registered as a controlled trial. Not properly controlled, aka not controlled.

This entire paradigm is useless, worse than useless even, it's counterproductive. It works on timescales of years simply to answer bad questions and can't even do that, everything is interpreted and biased. There's a strong case to make that overall, this is the most incompetent thing in all the professions. Literally all of them. And by a wide margin.