Stimulated by Xu et al 2026.[1]
IF – impact factor
RCT – randomised controlled trial
CEA – clinician’s erythema assessment
AA – auricular acupressure
IGA – investigator global assessment
CGRP – calcitonin gene-related peptide
IL-6 – interleukin 6
LL-37 – cathelicidin antimicrobial peptide
TNFα – tumour necrosis factor α
hCAP18 – human cathelicidin antimicrobial protein 18– key to acronyms
This is a paper just out in JAMA Dermatology (IF 10.9). It is a moderately large RCT (n=204) of what is referred to as ‘device-free auricular acupressure’ for rosacea.
The authors opening statement suggests that transcutaneous auricular vagus nerve stimulation (taVNS) is effective for rosacea. That was news to me, so I checked the single reference they quoted,[2] which was published in the same journal last year (I guess it did not come up on my searches). It was a small trial (n=72) of taVNS vs sham. It looks as though it was a well conducted and reported trial, and it was positive for the primary outcome (CEA score) after 3 weeks treatment, and the effects were maintained up to the 27-week follow-up.
The current trial is considerably larger (n=102 per group) and compared AA with 2 Vaccaria segetalis seeds either placed in the concha of the ear (symba concha and cavum concha) or 2 seeds placed at the root of the superior antihelix crus. So, these were 2 active AA groups that only differed by virtue of the different innervation of these parts of the ear. Interestingly, there was no reference to auricular acupuncture points. The seeds were replaced every 3 days by the same nurse, and presumably she could not be blind to group allocation. There is also no mention of whether the groups were seen on different days, and there was no mention of any evaluation of blinding. There certainly seems some potential for differences in patient expectation, but the primary outcome was semi-objective and blind (see below).
Patients were instructed to press on the seeds 3 times a day for 30 seconds each time. They could increase this during flares of their rosacea. The treatment was applied for 8 weeks, and the primary outcome was ‘treatment success’ at the end of the 8 weeks. The latter was defined as a score of 0 or 1 on the IGA.
The IGA scale evaluates overall rosacea severity by integrating both persistent facial erythema and inflammatory lesions (papules/pustules), consistent with the standard classification established by the National Rosacea Society Expert Committee.[3] The dermatologists who applied this scale were blind to group allocation, although how they did not notice the seed positions in not discussed.
IGA scale
- 0 – Clear: no clinical signs of rosacea; no erythema, papules or pustules
- 1 – Almost clear: barely perceptible erythema; no papules or pustules
- 2 – Mild: mild but definite erythema, with few scattered papules and/or pustules
- 3 – Moderate: moderate, clearly visible erythema, with several papules and/or pustules
- 4 – Severe: marked, deep erythema, with numerous papules and/or pustules
CEA scale (CEA score was the primary outcome in the taVNS study mentioned above). This scale specifically assesses the severity of persistent central facial erythema.
- 0 – Clear: no detectable erythema
- 1 – Almost clear: faint, barely perceptible erythema
- 2 – Mild: light red, clearly identifiable erythema
- 3 – Moderate: bright red, prominent erythema with well-defined distribution
- 4 – Severe: deep, intense red erythema with extensive facial involvement
At week 8 (end of the treatment phase) the IGA score treatment success (0 or 1) rate was 56.9% (58 of 102) in the concha AA group and 35.3% (36 of 102) in the active control, which was highly significant (p=0.003 for the difference).
I have to admit that I was rather surprised by this result. Most of the secondary outcomes followed the same pattern, ie a significant change over time in both groups and a significantly greater change in the concha AA group.
As well as a variety of clinical outcome measures, the research team also measured several biomarkers from fasting blood samples: CGRP; IL-6; LL-37; and TNFα. The results from these also followed the same pattern as the primary outcome, which is astonishing.
I should now own up to the fact that I have never heard of LL-37 before.
LL-37 is a naturally occurring antimicrobial and immunomodulatory peptide that forms part of the innate immune system.[4] It is particularly important in host defence against infection, inflammation, wound healing and regulation of immune responses. It is the only human member of the cathelicidin family of antimicrobial peptides.
LL-37 has been implicated in several conditions, including of course, rosacea. In rosacea, abnormal processing of the LL-37 precursor hCAP18 generates peptides with exaggerated pro-inflammatory and vasoactive properties.
I guess it should not be a surprise to me, that despite this being the first time for me to hear about LL-37, its role in rosacea was first reported nearly 2 decades ago in a letter to Nature Medicine [IF 52.5].[5]
References
1 Xu B, Chu J, Wang Y, et al. Device-Free Auricular Acupressure for Rosacea: A Randomized Clinical Trial. JAMA Dermatol. Published Online First: 14 October 2026. doi: 10.1001/jamadermatol.2026.3999
2 Li J, Wei J, Zhang M, et al. Transcutaneous Auricular Vagus Nerve Stimulation Treatment for Erythematotelangiectatic Rosacea: A Randomized Clinical Trial. JAMA Dermatol. 2025;161:1229–37. doi: 10.1001/jamadermatol.2025.3796
3 Gallo RL, Granstein RD, Kang S, et al. Standard classification and pathophysiology of rosacea: The 2017 update by the National Rosacea Society Expert Committee. J Am Acad Dermatol. 2018;78:148–55. doi: 10.1016/j.jaad.2017.08.037
4 Svensson D, Nilsson B-O. Human antimicrobial/host defense peptide LL-37 may prevent the spread of a local infection through multiple mechanisms: an update. Inflamm Res. 2025;74:36. doi: 10.1007/s00011-025-02005-8
5 Yamasaki K, Di Nardo A, Bardan A, et al. Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nat Med. 2007;13:975–80. doi: 10.1038/nm1616
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