Inspired by Bao et al 2022.[1]
CD – Crohn’s Disease
key to acronyms
MA – manual acupuncture
CDAI – Crohn’s Disease Activity Index
EA – electroacupuncture
CDEIS – Crohn’s Disease Endoscopic Index of Severity
HS – Histopathological Score
Th1 – pro-inflammatory T helper cells leading to an increased cell-mediated response
Th17 – pro-inflammatory T helper cells producing IL-17
ITT – intention to treat (an analysis that includes everyone randomised)
PP – per protocol (including only those who followed the protocol)
INF – interferon
IL – interleukin
TNF – tumour necrosis factor
This paper was published online on the 11th February 2022, and popped up on PubMed searches about 2 weeks later. It is published in eClinical Medicine, which is a relatively new open access publication and one of the Lancet journals.
I had a look because there are not many trials of acupuncture in Crohn’s disease (CD), and I remember when the first was published,[2] and later meeting the first author at a conference in Berlin. I subsequently suggested she write a chapter on gastrointestinal conditions in the second edition of Medical Acupuncture – A Western Scientific Approach.[3]
Those days were prior to us recognising the potential value of EA in engaging a systemic anti-inflammatory effect via vagal reflexes, so I was quite surprised that Stefanie had demonstrated some effects in her trial.
The current paper comes from Shanghai, and the first author figures in almost all of the papers published on the subject in recent years. The first of his papers was published 10 years after Stefanie’s in 2014 and it appeared in the World Journal of Gastroenterology.[4] It was remarkably similar in design and indeed is also very similar to the current one. All three were sham controlled trials using MA and moxibustion versus a minimal sham. The trial from 2004 and 2014 used superficial off-point sham controls, but the current one used a non-penetrating sham with flat tipped needles (not the expensive ones that disappear into the handles). Another important difference is that the length of follow-up increased from 12 weeks to 24 weeks and finally to a whopping 48 weeks.
Primary outcomes were all based on the CDAI score, although rather than using the absolute change in score, as was done in the first 2 trials in 2004 and 2014, the current trial used the proportion of patients with clinical remission, which was defined as a reduction of CDAI to below 150 and a change from baseline of at least 70.
All three studies used points on the legs and abdomen, and a combination of MA and moxibustion to different points, but the 2004 study, based in Germany, also used points on the back. The German study applied 10 sessions in 4 weeks, but the studies from Shanghai (2014 and 2022) both applied 36 sessions in 12 weeks.
It is interesting to note that the Shanghai research group performed 3 other studies on CD between these two sham-controlled trials. The first studied improvements in tight junction protein expression in CD patients treated with acupuncture and moxibustion and compared this with those on mesalazine.[5] The group then went to look into the brains of CD patients treated with either EA or moxibustion.[6,7] They found that both EA and moxibustion improved CD but that different areas of the brain were involved. This research did not seem to influence their subsequent second sham-controlled trial, since the treatment was pretty much the same and involved a combination of MA and moxibustion.
The sham-controlled studies were of similar sizes with 51 (2004), 92 (2014) and 66 (2022) randomised to real treatment or sham. What is exceptional about the most recent study is the length of follow-up and the fact that all patients had ileocolonoscopy and biopsy before treatment and at week 48. The latter allowed further outcomes to evaluated – CDEIS and HS respectively. In addition to these outcomes the gut microbiome was analysed to observe changes and compared with analysis of 30 healthy control subjects. Faecal calprotectin was measured, which rises when neutrophils migrate into the intestinal mucosa, thus indicating inflammation. Serum inflammatory markers were also measured assessing both intestinal barrier function as well as Th1 and Th17 activity.
Patients with mild to moderate CD were included if they had evidence of active inflammation, for example having a CDAI of 150 or more and less than 450, and who were unresponsive to, or intolerant of, drug treatment.
clinical remission rate of over 60% in the acupuncture group
The results were impressive, with a clinical remission rate of over 60% in the acupuncture group and just over 20% in the sham group at 12 weeks. There was little difference between the ITT and PP analyses since only 1 person dropped out of the treatment group and 2 from the sham group – an attrition rate of less than 5%. The results for the acupuncture group improved to just under 80% at 24 weeks, were maintained to 36 weeks and then improved again to almost 85% at 48 weeks. The sham group improved quite a bit from 12 to 24 weeks, reaching nearly 50% remission, but then declined to under 40% at 48 weeks.
Most of the myriad of secondary outcomes favoured acupuncture and I was interested to see that all the serum inflammatory markers (IFN-γ, IL-17A, IL-23, TNF-α, IL-1β) returned to normal values in the acupuncture subgroup tested (n=15). This was not the case for the sham subgroup (n=15). Intestinal barrier function also improved in the acupuncture subgroup (n=15), but this did not quite reach the level of the healthy controls tested (n=30).
I am still unfamiliar with the analytical methods of the intestinal microbiome and the figures used to demonstrate these. One of the latter is called a cladogram and it is wonderfully colourful and interesting, but also rather too esoteric for me. I will just have to trust the authors, who tell us in their paper that 5 genera of microbes were significantly lacking in the patient groups compared with healthy controls:
- Faecalibacterium
- Lachnospira
- Coprocococcus
- Roseburia
- Oscillospira
Of these, the Faecalibacterium and the Lachnospira improved significantly more in the acupuncture group than the sham group, and at the species level the big winners in the acupuncture group were:
- Faecalibacterium prausnitzii
- Roseburia faecis
The first of these makes up more than 5% of the gut microbiome ferments dietary fibre, has anti-inflammatory properties, and can improve gut barrier function. The species is named after the German physician, bacteriologist and hygienist Otto Carl Willy Prausnitz (1876–1963).
References
1 Bao C, Wu L, Wang D, et al. Acupuncture improves the symptoms, intestinal microbiota, and inflammation of patients with mild to moderate Crohn’s disease: A randomized controlled trial. EClinicalMedicine 2022;45:101300. doi:10.1016/j.eclinm.2022.101300
2 Joos S, Brinkhaus B, Maluche C, et al. Acupuncture and moxibustion in the treatment of active Crohn’s disease: a randomized controlled study. Digestion 2004;69:131–9. doi:10.1159/000078151
3 Joos S. Acupuncture for gastrointestinal conditions. In: Medical Acupuncture – A Western Scientific Approach. London: : Elsevier 2016. 368–75.
4 Bao C-H, Zhao J-M, Liu H-R, et al. Randomized controlled trial: moxibustion and acupuncture for the treatment of Crohn’s disease. World J Gastroenterol 2014;20:11000–11. doi:10.3748/wjg.v20.i31.11000
5 Shang H-X, Wang A-Q, Bao C-H, et al. Moxibustion combined with acupuncture increases tight junction protein expression in Crohn’s disease patients. World J Gastroenterol 2015;21:4986–96. doi:10.3748/wjg.v21.i16.4986
6 Bao C, Liu P, Liu H, et al. Different brain responses to electro-acupuncture and moxibustion treatment in patients with Crohn’s disease. Sci Rep 2016;6:36636. doi:10.1038/srep36636
7 Bao C, Wang D, Liu P, et al. Effect of Electro-Acupuncture and Moxibustion on Brain Connectivity in Patients with Crohn’s Disease: A Resting-State fMRI Study. Front Hum Neurosci 2017;11:559. doi:10.3389/fnhum.2017.00559
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