Stimulated by Khadour et al 2025.[1,2]
This image feature previously on the blog – EA for guinea pig OAK.
EA – electroacupuncture
JIA – juvenile idiopathic arthritis
IF – impact factor
ELISA – enzyme-linked immunosorbent assay
Caspase-1 – cystine aspartic protease 1 (a pro-inflammatory protease linked to pyroptosis, which is a pro-inflammatory form of apoptosis)
GSDMD – gasdermin D
NRLP3 – NOD-, LRR-, pyrin domain-containing protein 3 (an inflammasome)
IL – interleukin
LC3 – light chain 3β (a protein involved in autophagy)
Beclin 1 – part of a class III phosphatidylinositol 3 kinase (an initiator of autophagy)
CIA – collagen induced arthritis
SD – Sprague-Dawley (a strain of rats bred for laboratory use)
AAV – adeno-associated virus– key to acronyms
This is a set of two linked papers in the journal Clinical Rheumatology (IF 2.9) – a clinical trial of EA in JIA (in Syria) and an experimental study on an equivalent rodent model (in China).
The authors are the same on both papers and it looks as though the first author studied for a time in Wuhan, China, at the institution of the last author, although is now listed as being in Homs, Syria.
The first paper is a 2-arm clinical trial of EA versus a superficial penetrating sham in children (n=106) with JIA. Children aged 8 to 16 (mean 12 years) were treated with EA or sham for 30 minutes per session for 28 sessions over 8 weeks. That was 5 sessions a week for the first 2 weeks and 3 sessions a week for the remaining 6 weeks.
The points used were Xiyan (the eyes of the knee), extra points at the highest point of each malleolus (medial and lateral), LI11 to LI4, and SI3. The EA device used was the KWD-8081, which has 6 outputs and currently costs less than £60 on AliExpress. I was handed down one of these devices by Adrian White some 30 years ago. It seemed to work perfectly well, although in those days EA was only applied to the least sensitive patients.
We are told that 0.30x50mm needles were used and they were inserted 30 to 70mm. You can insert a 50mm needle 70mm if you compress the soft tissue layer by 20mm and insert the needle to the hilt, but you cannot do that at any of the points above.
It is conceivable that the Xiyan points can be needled deeply, although this is not recommended, as I frequently mention here. The points on the malleoli will only go in less than 10mm of course.
The frequency used was not stated, but a continuous wave was used and there was reference to visible twitching, so from that I assume it was a low frequency. We are told that the intensity was set at 0.1 to 1.0mA, but the device they used does not control or display current. Manual stimulation of needles was performed every 10 minutes, which seems unnecessary, and a bit fiddly since they were connected to EA leads.
The sham was described as being 2cm lateral to the real points and the needles inserted 5 to 10mm and not stimulated. EA leads were attached, but no stimulus was applied. Slightly shorter 0.30x40mm needles were used, but it is hard to interpret what 2cm lateral would mean for some of the points, such as the extra points at the tips of the malleoli.
The patients were evaluated by a paediatric rheumatologist at baseline, 4 weeks, 8 weeks, 3 months and 6 months. The evaluation included blood tests. The latter used ELISA tests for a variety of pyroptosis-related proteins (Caspase-1, GSDMD, NRLP3), pro-inflammatory cytokines (IL-1β, IL-18), and markers for autophagy (LC3, Beclin 1).
No primary outcome is indicated, and the study is referred to as a pilot study. There is no discussion of statistical corrections (of the p value) for multiple tests, of which there are many.
There were significant differences between groups from 4 weeks in a variety of outcomes and from 8 weeks in all the blood parameters. Considering the nature of the penetrating sham, I was surprised to see absolutely no effect on pain in this group, indeed the mean values increased rather than decreased. An absence of any placebo effect, even after 28 sessions, and adequate blinding of patients seems rather unusual.
The second paper is an experimental study on a rodent model. CIA was induced in the usual way, by injecting type 2 collagen (bovine source) in Complete Freund’s adjuvant (oily antigenic mixture) into the tails of SD rats. A second immunisation was performed after 2 weeks at different sites. The difference in this experiment was that 2 weeks prior to initiation of CIA, the rats in 2 of the 6 groups were injected into ‘the joint’ (presumably the one used in histological and other outcomes) with an AAV encoding for the inflammasome NRLP3 (see a previous blog discussing inflammasomes for the first time).
EA was applied to the points around the knee and ankle, as used in the clinical trial on JIA. EA was applied for 20 minutes, 5 days a week for 5 weeks using the same apparatus mentioned above and probably similar parameters. There is no mention of a sham EA procedure or equivalent restraint. The severity of arthritis was evaluated in a blind manor by 2 rheumatologists, but there is no mention of any of the other outcomes being performed blind.
EA reduced the severity of arthritis and related outcomes.
Injection of the AAV prior to induction of CIA caused a worsening of the model and EA reduced this to some degree as well. EA seemed to modulate parameters associated with autophagy and the authors concluded that it decreased expression of NRLP3, although I cannot find any direct measurements of this inflammasome. It doesn’t help that the figure legends are all next to the wrong figures in this paper.
Overall, it is a nice story. I want to believe it, but the results just might be a little bit too good…
References
1 Khadour FA, Khadour YA, Xu T. Electroacupuncture for juvenile idiopathic arthritis: clinical efficacy and its role in modulating pyroptosis and autophagy pathways. Clin Rheumatol. Published Online First: 28 February 2025. doi: 10.1007/s10067-025-07346-7
2 Khadour FA, Khadour YA, Xu T. Electroacupuncture delays the progression of juvenile collagen-induced arthritis via regulation NLRP3/ NF-κB signaling pathway -mediated pyroptosis and its influence on autophagy. Clin Rheumatol. Published Online First: 11 March 2025. doi: 10.1007/s10067-025-07354-7
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