Pasted below is an excerpt of a letter published by M Sharpe, T Chalder and J Stone published in the leading scientific journal, Nature, this month (Feb 2018). The authors position themselves as crusaders stating that CFS patients “often feel ignored or dismissed by the medical profession”. In response to a Nature article published in Jan 2018 (and highlighted widely on the internet), they argue that its “regrettable” that some have rejected behavioural treatments for CFS as ineffective. In the letter the authors make the claim that “these therapies can be beneficial.” Both Sharpe and Chalder were authors of original clinical trial papers (the PACE trials) claiming that cognitive behavioural therapy (CBT) and graded exercise therapy (GET) could provide significant improvements for those suffering CFS (Lancet 2011; 377: 823–36; Lancet Psychiatry 2015; 2: 1067–74). The findings of the PACE trial led to wide adoption of CBT and GET therapies in the treatment of CFS. However, it wasn’t long before patients, clinicians and researchers began to criticise the use of CBT/GET and question the validity of the research data. Since their publication, the PACE trials have been one of the most widely criticized clinicial trials. Its worth pointing out that research critiques published in scientific journals are usually tempered by unimpassioned language that is highly reserved. Science after-all is about the evidence. However, the criticism of the PACE trials have been scathing. Experts in CFS, trial design and chronic diseases have itemized serious flaws and inadequacies in the PACE trial and published withering criticisms in numerous peer-reviewed scientific journals. I think its worthwhile quoting just a few in order to highlight some of the deficiencies identified by others in the PACE trial. For example, in a series of articles examining the PACE trial, Steven Lubert wrote, “In defense of the PACE trial, Petrie and Weinman employ a series of misleading or fallacious argumentation techniques, including circularity, blaming the victim, bait and switch, non-sequitur, setting up a straw person, guilt by association, red herring, and the parade of horribles.(Journal of Health Psychology 2017, Vol. 22(9) 1201–1205). In the same series of articles, Susanna Agardy said that there was little evidence that CBT and GET significantly improved CFS symptoms due to the “failure of PACE to achieve evidence of recovery through cognitive behaviour therapy and graded exercise therapy in either selfreports or the objective measure of the 6-minute walking test.” (Journal of Health Psychology 2017, Vol. 22(9) 1206–1208). @Jonathon Edwards (who made many many incredibly valuable contributions to PR but sadly no longer posts here) said that PACE “fails to address the key design flaw, of an unblinded study with subjective outcome measures, apparently demonstrating a lack of understanding of basic trial design requirements.( Journal of Health Psychology 2017, Vol. 22(9) 1155–1158) Other criticisms published in the Lancet are also critical of the subjective methodology issue mentioned by @jonathon Edwards (above) indicating that “activity levels before and after therapy were similar, despite improvements being reported on fatigue and other subjective measures.”(Lancet, May 28, 2011) The above is only a small fraction of the published criticisms of the PACE trials. But in addition to the scientific criticisms, several authors of the PACE trial have been criticised for conflicts of interest because they held “double role as advisers to the UK Government Department of Work and Pensions (DWP), a sponsor of PACE, while at the same time working as advisers to large insurance companies who have gone on record about the potential financial losses from ME/CFS being deemed a long-term physical illness.” ( Journal of Health Psychology 2017, Vol. 22(9) 1103–1105). Of course, once CFS patients begun to undergo CBT/GET as the treatments were rolled out, they quickly understood that CBT/GET didnt work. A core symptom of CFS is decreased functionality and increased symptoms after exercise (ie PEM). CFS patients understand the dire consequences that even even moderate amounts of exercise can have on their heath. In the face of the many wide-ranging and serious criticisms published in scientific journals, it has been noted that “there was a consistent pattern of resistance to the debate” by the authors of the PACE trial and their supporters. ( Journal of Health Psychology 2017, Vol. 22(9) 1103–1105). With the publication of their letter (pasted below), it appears M Sharpe, T Chalder and J Stone continue their unwavering support of PACE despite the widespread criticism. But, surely they recognize the futility? In many countries, recommendations for CBT and GET in the treatment of CFS have already been removed from public health recommendations and treatment protocols. At what point do the authors of the PACE trial (and their supporters) acknowledge that the serious deficiencies of their studies make it impossible to claim that CBT/GET is a validated treatment for CFS? How long will PACE be doggedly defended despite its serious deficiencies? Well, the answer to those questions comes in the letter below. PACE supporters have published yet another defence of CBT/GET in the Nature journal. No doubt, such a letter will be a bitter disappointment for those patients who have suffered (some continuing to suffer) the consequences of PACE. Not only can such trials cause needless suffering in patients, they can put scientific research back decades.The first PACE results were published in 2011 and it is only very recently that PACE treatment protocols have begun to be withdrawn. Unfortunately however, CBT and GET continues to be embraced by at least some physicians and it may take years to reverse the consequences of PACE. But at least CFS patients can take solace in knowing that PACE is no longer the standard of care in the treatment of CFS in many countries and that the numbers of those who vociferously defend it are dwindling. Rodger //////////////////////////////////// Don’t reject evidence from CFS therapy We welcome your article on research into chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis or systemic exertion intolerance disease (see Nature 553, 14–17;2018). In our view, however, you underestimate the benefits of current treatments: namely, graded exercise and cognitive behaviour therapy (CBT). As you point out, people with the disease often feel ignored or dismissed by the medical profession — a situation that, as clinicians, we deplore. It is regrettable that some patients and others link behavioural treatments with dismissal of a person’s condition, when in fact these therapies can be beneficial. Aside from the results of the PACE trial you mention (co-authored by two of us, T.C. and M.S., among others), further scientific evidence supports the effectiveness of interventions such as exercise and CBT (see, for example, L. Larun et al. Cochrane Database Syst. Rev. http://doi.org/ cjp6; 2017 and J. R. Price et al. Cochrane Database Syst. Rev. http://doi.org/dcs37d; 2008). We think that patients deserve the best research and treatments. In our view, there is no place for stigmatizing any avenue of research or therapy that might help us to improve the lives of people with this long-term debilitating illness. Michael Sharpe University of Oxford, UK. Trudie Chalder Guy’s, King’s and St Thomas’s School of Medicine, London, UK. Jon Stone University of Edinburgh, UK.