On 2017 May 03, Lily Chu commented:

I have written a comment which was published on the Annals of Internal Medicine online comments section linked to this article, which can be accessed here:

http://annals.org/aim/article/2607809/cytokine-inhibition-patients-chronic-fatigue-syndrome-randomized-trial

I asked whether the authors had considered subgrouping subjects by infectious/ inflammatory symptoms and comparing their responses to treatment and mention two trials using another cytokine inhibitor (of TNF-alpha), etanercept, in the treatment of ME/CFS. Materials related to those trials can be accessed here:

1. Vallings R. A report from the 5th International AACFS Conference. Availablet at: http://phoenixrising.me/conferences-2/a-report-from-the-fifth-international-aacfs-conference-by-dr-rosamund-vallings.
2. Fluge, O. Tumor necrosis factor-alpha inhibition in chronic fatigue syndrome. Available at: https://clinicaltrials.gov/ct2/show/NCT01730495.

On 2017 Mar 11, Andrew Kewley commented:

I thank the authors for conducting this study and note that such studies are of value even if the outcome is a null result.

While I agree with the overall conclusion that subcutaneous anakinra is ineffective, I carefully note that the published manuscript contains an error.

In the abstract of the article, it states: "At 4 weeks, 8% (2 of 25) of anakinra recipients and 20% (5 of 25) of placebo recipients reached a fatigue level within the range reported by healthy persons."

The closest reference in the body of the manuscript is the following: "In the anakinra group, 2 patients (8%) were no longer severely fatigued after the intervention period (reflected by a CIS-fatigue score <35 [47]), compared with 5 patients (20%) in the placebo group difference, -12.0 percentage points [CI, -31.8 to 7.8 percentage points]; P = 0.22)."

Where the reference [47] was: 47. Wiborg JF, van Bussel J, van Dijk A, Bleijenberg G, Knoop H. Randomised controlled trial of cognitive behaviour therapy delivered in groups of patients with chronic fatigue syndrome. Psychother Psychosom. 2015;84:368-76. [PMID: 26402868] doi:10.1159 /000438867

However the claims made in the abstract refer to healthy ranges, but this is not the same as "severe fatigue" as operationalised by a CIS-fatigue score of less than or equal to 35.

The healthy ranges are instead provided by another study which has also been cited: 41. Vercoulen JH, Alberst M, Bleijenberg G. The Checklist Individual Strength (CIS). Gedragstherapie. 1999;32:131-6.

That study found in a group of 53 healthy controls (mean age of 37.1, SD 11.5) had a mean CIS-fatigue score of 17.3 (SD 10.1). This would provide a cut-off for the "healthy range" of ~27. The manuscript of the present RCT does not provide the results of how many patients met this cut-off score.

Also of note, in a study co-authored by one of the authors of the present study utilised a threshold for a "Level of fatigue comparable to healthy people" as less than or equal to 27.

See: Knoop H, Bleijenberg G, Gielissen MFM, van der Meer JWM, White PD: Is a full recovery possible after cognitive behavioural therapy for chronic fatigue syndrome? Psychother Psychosom 2007; 76: 171–176.

Therefore the claim made in the abstract of patients reaching "a fatigue level within the range reported by healthy persons" is not based on evidence provided in the manuscript, or is simply incorrect. I ask the authors to provide the results of how many patients in both groups met the criteria of having a CIS-fatigue score of less than 27.

On 2017 Mar 11, Andrew Kewley commented:

I thank the authors for conducting this study and note that such studies are of value even if the outcome is a null result.

While I agree with the overall conclusion that subcutaneous anakinra is ineffective, I carefully note that the published manuscript contains an error.

In the abstract of the article, it states: "At 4 weeks, 8% (2 of 25) of anakinra recipients and 20% (5 of 25) of placebo recipients reached a fatigue level within the range reported by healthy persons."

The closest reference in the body of the manuscript is the following: "In the anakinra group, 2 patients (8%) were no longer severely fatigued after the intervention period (reflected by a CIS-fatigue score <35 [47]), compared with 5 patients (20%) in the placebo group difference, -12.0 percentage points [CI, -31.8 to 7.8 percentage points]; P = 0.22)."

Where the reference [47] was: 47. Wiborg JF, van Bussel J, van Dijk A, Bleijenberg G, Knoop H. Randomised controlled trial of cognitive behaviour therapy delivered in groups of patients with chronic fatigue syndrome. Psychother Psychosom. 2015;84:368-76. [PMID: 26402868] doi:10.1159 /000438867

However the claims made in the abstract refer to healthy ranges, but this is not the same as "severe fatigue" as operationalised by a CIS-fatigue score of less than or equal to 35.

The healthy ranges are instead provided by another study which has also been cited: 41. Vercoulen JH, Alberst M, Bleijenberg G. The Checklist Individual Strength (CIS). Gedragstherapie. 1999;32:131-6.

That study found in a group of 53 healthy controls (mean age of 37.1, SD 11.5) had a mean CIS-fatigue score of 17.3 (SD 10.1). This would provide a cut-off for the "healthy range" of ~27. The manuscript of the present RCT does not provide the results of how many patients met this cut-off score.

Also of note, in a study co-authored by one of the authors of the present study utilised a threshold for a "Level of fatigue comparable to healthy people" as less than or equal to 27.

See: Knoop H, Bleijenberg G, Gielissen MFM, van der Meer JWM, White PD: Is a full recovery possible after cognitive behavioural therapy for chronic fatigue syndrome? Psychother Psychosom 2007; 76: 171–176.

Therefore the claim made in the abstract of patients reaching "a fatigue level within the range reported by healthy persons" is not based on evidence provided in the manuscript, or is simply incorrect. I ask the authors to provide the results of how many patients in both groups met the criteria of having a CIS-fatigue score of less than 27.

On 2017 May 03, Lily Chu commented:

I have written a comment which was published on the Annals of Internal Medicine online comments section linked to this article, which can be accessed here:

http://annals.org/aim/article/2607809/cytokine-inhibition-patients-chronic-fatigue-syndrome-randomized-trial

I asked whether the authors had considered subgrouping subjects by infectious/ inflammatory symptoms and comparing their responses to treatment and mention two trials using another cytokine inhibitor (of TNF-alpha), etanercept, in the treatment of ME/CFS. Materials related to those trials can be accessed here:

1. Vallings R. A report from the 5th International AACFS Conference. Availablet at: http://phoenixrising.me/conferences-2/a-report-from-the-fifth-international-aacfs-conference-by-dr-rosamund-vallings.
2. Fluge, O. Tumor necrosis factor-alpha inhibition in chronic fatigue syndrome. Available at: https://clinicaltrials.gov/ct2/show/NCT01730495.