Re: The long wait for a breakthrough in chronic fatigue syndrome
Dear Editors
As a patient I read Lloyd and van der Meer’s article [1] with some interest; given the title I was hoping that it would put recent research into context and provide hope, hints and encouragement for future research directions. However they did not mention some of the recent interesting results that have caught patients' imagination such as Nakatomi et als [2] PET study indicating mircoglia activation; or Hornig and Lipkin’s recent publications on cytokines [3]. They did not even mention Fluge and Mella’s older Rituximab study [4] that has given much hope to patients suggesting a subset involves autoimmunity (leading to a current multi-site trial). Given their push for exercise based therapies it is surprising they do not cite research studying the biological effects of exercise such as that by Light et al [5] which could help in understanding of the dynamics of a complex disease. It is clear that these studies need replication to see which clues stand up to scrutiny and over which subgroups but without discussion visible to the wider medical community and funding this will not happen and patients like me will be consigned to years more suffering.
Lloyd and van der Meer talk of the PACE trial [6] testing CBT and GET; they clearly realise that the quoted recovery figures are misleading. I believe that when talking of PACE we should all be calling for the freeing of the results data from the confines of a database held under guard at QMUL. This should include pushing for the publication of the measures defined in the protocol [7] – some 5 years after the completion of the trial we should see their non-publication as unacceptable. Their lack of publication also makes the results the authors choose to publish uninterpretable.
The methodological elephant on the therapists couch needs to be addressed when suggesting theories as to why GET gave the modest quoted results from PACE. That is PACE was an unblinded trial where therapies addressed how patients perceived their symptoms yet primary outcomes were subjective patient judgements on their symptoms. Perhaps the surprise with PACE was their results were not better given therapies involved telling patients to ignore symptoms and they will get better and measurement looked at the change in how patients view their illness and disabilities.
A truly independent and transparent look at the data (including checking correlations in changes of fitness and walking measures and the subjective outcomes) may help illuminate the elephant but even then the enormity of the methodological issues should dominate any discussion. Unfortunately those who conducted the PACE trial see criticism and requests for clarity in their results as harassment [8] rather than an essential part of scientific endeavour driving us nearer to the truth.
I am also concerned by their statement that there is no evidence of harm from GET. There are plenty of patient surveys reporting relapses after GET including when carried out at specialist centres. Given [5] this is not surprising. Sampling techniques for such patient surveys are not sufficient to give good quantitative rates but reported deterioration rates of (33.1% much worse [9]; 34% worse including 31% at specialist centres [10]) this seems like pretty compelling evidence for a counter example to their statement of safety.
ME/CFS is certainly a baffling disease that would seem to stretch our understanding of how human biological systems work. But this is also what should make it a fascinating research topic. There are potential clues but they need replicating and treating with caution. As patients many of us have suffered and been exiled form normal life for many years. We need to see the medical research community doing good quality research into ME/CFS so that we have hope of eventual treatments or cures. Please give us that hope.
[1] Lloyd, A.R. and van der Meer, J.W.M., (2015) The long wait for a breakthrough in chronic fatigue syndrome, BMJ 2015;350:h2087
[2] Yasuhito Nakatomi, Kei Mizuno, Akira Ishii, Yasuhiro Wada, Masaaki Tanaka, Shusaku Tazawa, Kayo Onoe, Sanae Fukuda, Joji Kawabe, Kazuhiro Takahashi, Yosky Kataoka, Susumu Shiomi, Kouzi Yamaguti, Masaaki Inaba, Hirohiko Kuratsune, Yasuyoshi Watanabe, “Neuroinflammation in patients with chronic fatigue syndrome/myalgic encephalomyelitis: a 11C-(R)-PK11195 positron emission tomography study”, The Journal of Nuclear Medicine, vol.55, No.6, 2014, DOI: 10.2967/jnumed.113.131045
[3] Hornig, M, Montoya, J.G., Kilmas, N.G., Levine, S. Felsenstein, D., Bateman, L., Peterson, D.L., Gottschalk, C.G., Schultz, A.F., Che, X., Eddy, M.L., Komaroff, A.L., and Lipkin, W.I. (2015), Distinct plasma immune signatures in ME/CFS are present early in the course of illness. Science Advances Vol 1(1).
[4] Fluge Ø, Bruland O, Risa K, Storstein A, Kristoffersen EK, Sapkota D, et al. (2011) Benefit from B-Lymphocyte Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and Placebo-Controlled Study. PLoS ONE 6(10): e26358. doi:10.1371/journal.pone.0026358
[5] Light AR, White AT, Hughen RW, Light KC. Moderate exercise increases expression for sensory, adrenergic and immune genes in chronic fatigue syndrome patients, but not in normal subjects. The journal of pain : official journal of the American Pain Society. 2009;10(10):1099-1112. doi:10.1016/j.jpain.2009.06.003
[6] White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL, Bavinton J, Angus BJ, Murphy G, Murphy M, O'Dowd H, Wilks D, McCrone P, Chalder T, Sharpe M; PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011 Mar 5;377(9768):823-36. doi: 10.1016/S0140-6736(11)60096-2. Epub 2011 Feb 18.
[7] White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R; PACE trial group. (2007) Protocol for the PACE trial: a randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BMC Neurol. 2007 Mar 8;7:6.
[8] Matthees, A (2015) In response to ICO decision notice FS-50558352: 'Timing of changes to PACE Trial recovery criteria' https://b1ad200d-a-62cb3a1a-s-sites.googlegroups.com/site/pacefoir/FOIR2...
[9] ME Society, (2010) 2010 Patient Survey Results http://www.meassociation.org.uk/wp-content/uploads/2010/09/2010-survey-r...
[10] Action For ME, (2008) ME 2008: What Progress, http://www.actionforme.org.uk/Resources/Action%20for%20ME/Documents/get-...
Rapid Response:
Re: The long wait for a breakthrough in chronic fatigue syndrome
Dear Editors
As a patient I read Lloyd and van der Meer’s article [1] with some interest; given the title I was hoping that it would put recent research into context and provide hope, hints and encouragement for future research directions. However they did not mention some of the recent interesting results that have caught patients' imagination such as Nakatomi et als [2] PET study indicating mircoglia activation; or Hornig and Lipkin’s recent publications on cytokines [3]. They did not even mention Fluge and Mella’s older Rituximab study [4] that has given much hope to patients suggesting a subset involves autoimmunity (leading to a current multi-site trial). Given their push for exercise based therapies it is surprising they do not cite research studying the biological effects of exercise such as that by Light et al [5] which could help in understanding of the dynamics of a complex disease. It is clear that these studies need replication to see which clues stand up to scrutiny and over which subgroups but without discussion visible to the wider medical community and funding this will not happen and patients like me will be consigned to years more suffering.
Lloyd and van der Meer talk of the PACE trial [6] testing CBT and GET; they clearly realise that the quoted recovery figures are misleading. I believe that when talking of PACE we should all be calling for the freeing of the results data from the confines of a database held under guard at QMUL. This should include pushing for the publication of the measures defined in the protocol [7] – some 5 years after the completion of the trial we should see their non-publication as unacceptable. Their lack of publication also makes the results the authors choose to publish uninterpretable.
The methodological elephant on the therapists couch needs to be addressed when suggesting theories as to why GET gave the modest quoted results from PACE. That is PACE was an unblinded trial where therapies addressed how patients perceived their symptoms yet primary outcomes were subjective patient judgements on their symptoms. Perhaps the surprise with PACE was their results were not better given therapies involved telling patients to ignore symptoms and they will get better and measurement looked at the change in how patients view their illness and disabilities.
A truly independent and transparent look at the data (including checking correlations in changes of fitness and walking measures and the subjective outcomes) may help illuminate the elephant but even then the enormity of the methodological issues should dominate any discussion. Unfortunately those who conducted the PACE trial see criticism and requests for clarity in their results as harassment [8] rather than an essential part of scientific endeavour driving us nearer to the truth.
I am also concerned by their statement that there is no evidence of harm from GET. There are plenty of patient surveys reporting relapses after GET including when carried out at specialist centres. Given [5] this is not surprising. Sampling techniques for such patient surveys are not sufficient to give good quantitative rates but reported deterioration rates of (33.1% much worse [9]; 34% worse including 31% at specialist centres [10]) this seems like pretty compelling evidence for a counter example to their statement of safety.
ME/CFS is certainly a baffling disease that would seem to stretch our understanding of how human biological systems work. But this is also what should make it a fascinating research topic. There are potential clues but they need replicating and treating with caution. As patients many of us have suffered and been exiled form normal life for many years. We need to see the medical research community doing good quality research into ME/CFS so that we have hope of eventual treatments or cures. Please give us that hope.
[1] Lloyd, A.R. and van der Meer, J.W.M., (2015) The long wait for a breakthrough in chronic fatigue syndrome, BMJ 2015;350:h2087
[2] Yasuhito Nakatomi, Kei Mizuno, Akira Ishii, Yasuhiro Wada, Masaaki Tanaka, Shusaku Tazawa, Kayo Onoe, Sanae Fukuda, Joji Kawabe, Kazuhiro Takahashi, Yosky Kataoka, Susumu Shiomi, Kouzi Yamaguti, Masaaki Inaba, Hirohiko Kuratsune, Yasuyoshi Watanabe, “Neuroinflammation in patients with chronic fatigue syndrome/myalgic encephalomyelitis: a 11C-(R)-PK11195 positron emission tomography study”, The Journal of Nuclear Medicine, vol.55, No.6, 2014, DOI: 10.2967/jnumed.113.131045
[3] Hornig, M, Montoya, J.G., Kilmas, N.G., Levine, S. Felsenstein, D., Bateman, L., Peterson, D.L., Gottschalk, C.G., Schultz, A.F., Che, X., Eddy, M.L., Komaroff, A.L., and Lipkin, W.I. (2015), Distinct plasma immune signatures in ME/CFS are present early in the course of illness. Science Advances Vol 1(1).
[4] Fluge Ø, Bruland O, Risa K, Storstein A, Kristoffersen EK, Sapkota D, et al. (2011) Benefit from B-Lymphocyte Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and Placebo-Controlled Study. PLoS ONE 6(10): e26358. doi:10.1371/journal.pone.0026358
[5] Light AR, White AT, Hughen RW, Light KC. Moderate exercise increases expression for sensory, adrenergic and immune genes in chronic fatigue syndrome patients, but not in normal subjects. The journal of pain : official journal of the American Pain Society. 2009;10(10):1099-1112. doi:10.1016/j.jpain.2009.06.003
[6] White PD, Goldsmith KA, Johnson AL, Potts L, Walwyn R, DeCesare JC, Baber HL, Burgess M, Clark LV, Cox DL, Bavinton J, Angus BJ, Murphy G, Murphy M, O'Dowd H, Wilks D, McCrone P, Chalder T, Sharpe M; PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet. 2011 Mar 5;377(9768):823-36. doi: 10.1016/S0140-6736(11)60096-2. Epub 2011 Feb 18.
[7] White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R; PACE trial group. (2007) Protocol for the PACE trial: a randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BMC Neurol. 2007 Mar 8;7:6.
[8] Matthees, A (2015) In response to ICO decision notice FS-50558352: 'Timing of changes to PACE Trial recovery criteria' https://b1ad200d-a-62cb3a1a-s-sites.googlegroups.com/site/pacefoir/FOIR2...
[9] ME Society, (2010) 2010 Patient Survey Results http://www.meassociation.org.uk/wp-content/uploads/2010/09/2010-survey-r...
[10] Action For ME, (2008) ME 2008: What Progress, http://www.actionforme.org.uk/Resources/Action%20for%20ME/Documents/get-...
Competing interests: No competing interests