Long-term efficacy of fractional microneedle radiofrequency versus botulinum toxin-A in primary axillary hyperhidrosis: a randomized controlled trial

Primary axillary hyperhidrosis is an idiopathic disorder that creates severe psycho-social burden due to excessive uncontrolled sweating. Various therapeutic agents have been described, but each has its own limitations. The use of fractional microneedling radiofrequency has emerged lately with promising results. This study aimed to determine the efficacy and safety of fractional microneedle radiofrequency in comparison to Botulinum toxin-A (BT-A) in patients with primary axillary hyperhidrosis. In this randomized controlled clinical trial, 20 patients (40 sides) were randomized to either fractional microneedle radiofrequency (4 sessions at 3-week intervals) or BT-A (single session), where each side received one of the treatment modalities. Efficacy was measured at 3, 6 and 12 months using Minor’s starch iodine test, HDSS score, Hqol questionnaire, and patient satisfaction. Fractional microneedle radiofrequency, although showed moderate efficacy, is inferior to BT-A regarding longitudinal efficacy at 12 months, as well as patients’ satisfaction. Both treatment modalities showed to be equally safe, but fractional microneedle radiofrequency procedure was substantially more painful. In conclusion, fractional microneedle radiofrequency does not offer a better substitute to BT-A in primary axillary hyperhidrosis. BT-A shows higher efficacy, is less painful, less expensive, and needs a smaller number of sessions.


Introduction
Primary axillary hyperhidrosis is a distressing disorder that can result in skin maceration and secondary bacterial and fungal infections, in addition to appreciable social problems in both private and professional life [1].Many therapeutic modalities have been tried for this condition, ranging from topical therapies to surgery, but each has its own limitations and side effects [2].
BT-A works by temporarily inhibiting the release of acetylcholine from the neuromascular junction; thus decreasing sweat production [3].Onabotulinum toxin-A was FDA approved in 2004 for the treatment of axillary hyperhidrosis

Methods
The protocol for this randomized controlled clinical trial (RCT) was approved by Kasr Al-Ainy Ethical Committee and was published on www.pactr.org(PACTR201808213089174).The study protocol is conformed to the ethical guidelines of the 1975 Declaration of Helsinki.Reporting of data followed the CONSORT checklist for reporting of RCTs [10].
Patients were asked to give a score for the severity of their hyperhidrosis condition according to hyperhidrosis disease severity score (HDSS) score [11]; Responses are rendered on a four-point scale: 1 = never noticeable, never interferes with daily activities; 2 = tolerable, sometimes interferes with daily activities; 3 = barely tolerable, frequently interferes with daily activities; 4 = intolerable, always interferes with daily activities.
Twenty patients older than 18 years presenting with primary axillary hyperhidrosis grades 3 and 4 HDSS and approving the study protocol were included and signed informed consent.Exclusion criteria included any history of surgery for hyperhidrosis, history of BT-A therapy within the previous 12 months, history of pacemaker implantation or any other electronic implants for incompatibility with radiofrequency apparatus, known hypersensitivity from BT-A, known neuromuscular disease (e.g.myasthenia gravis), auto immune diseases, tendency for keloid formation, and pregnancy or breastfeeding.
Patients' axillae were randomized to receive one of both treatments using the closed envelope method, where patients were allowed to choose between two envelopes, enclosing either 'right' or 'left'.The side chosen randomly by the patient was treated by BT-A, while the other side was treated by FMR.The BT-A group received a single session of BT-A intradermal injection (Refinex ® , Shandong Bioresearch institute, China) using a 50IU vial injected in standard procedure [3].The FMR group received 4 sessions at 3-week intervals using Vivace ® device (Shenb co., Seoul, Korea) with 3.5 mm length non-insulated needles: power Level 7, exposure time 600 msec, frequency 1 Hz.A single pass over the whole hyperhidrotic area was performed while the skin being adequately stretched, and the device handpiece firmly pressured on the skin.In both groups, the hyperhidrotic area revealed by Minors starch iodine test was marked by a surgical pen.Local anesthetic cream was applied under occlusion 30-60 min prior to the session.
Patients were assessed at baseline then after 3, 6 and 12 months from baseline for both efficacy and safety outcomes.Efficacy outcomes included the following: Safety outcomes included monitoring of side effects as pain, bruising, infection, compensatory hyperhidrosis.Pain was evaluated on a visual analogue scale 1 to 10, where 1 is the least and 10 is the most severe pain.
Since this is the first study to be conducted on these parameters, sample size was calculated (using G*Power 3.1.9.2.) based on a pilot run of 5 patients that revealed a moderate to large effect size corresponding to Cohen's d = 0.76, that was assumed to be clinically significant.Analysis was performed with a two tailed alpha error probability set at 0.05, the projected sample size needed for the aforementioned effect size (d = 0.76) was 17 patients to be able to reject the null hypothesis that this difference is zero with probability (power) 0.80.To account for expected 10% drop-outs and to allow for sub-group analysis, a sample of 20 patients was recruited.Data were coded and entered using the statistical package for the Social Sciences (SPSS) version 25 (IBM Corp., Armonk, NY, USA).P-values less than 0.05 were considered as statistically significant.Treatment success (2024) 39:177 data were analyzed based on intention-to-treat, while other data were submitted to per protocol analysis.

Results
Three males (15%) and 17 females (85%) were included, with mean age 27.65 ± 9.39 (range: 18 to 48 years).Baseline Hqol was 53.65 ± 6.56.Both therapeutic arms were homogenous as regards baseline HDSS (p-value = 0.350).17/20 patients completed 12 months follow-up.Two patients dropped out after the 1st session, and 1 patient after his last session but he did not come for follow up.
In comparison to baseline HDSS, both BT-A and FMR groups showed a statistically significant difference of HDSS at 3, 6 and 12 months (Table 1).
At 3, 6 and 12 months, BT-A was found significantly more effective than FMR as demonstrated by a significantly lower mean HDSS score, lower mean Hqol, and higher mean percent patient satisfaction in comparison to baseline (Table 2).Figures 1 and 2 demonstrate the gradual decline of efficacy of both interventions and the superior efficacy of BT-A all through 12 months.Figure 3 shows starch iodine test in a representative side treated with FMR.The long-term maintenance of efficacy was demonstrated by a statistically significant difference between HDSS at baseline and HDSS at 3, 6 and 12 months in both BT-A and FMR groups.However, BT-A showed significantly higher treatment success at 6 months in comparison to FMR (75% of patients in BT-A group versus 30% of patients in FMR group).It seems that both procedures peak at 3 months, but the decline of efficacy is faster on the FMR side, reaching minimal efficacy at 6 months in comparison to BT-A.We defined treatment success based on a patient-oriented satisfactory success so as to ensure a realistic outcome.
The higher efficacy of BT-A was evidenced at 3, 6 and 12 months by a significantly lower mean HDSS score, lower mean Hqol (better quality of life), and higher mean percent patient satisfaction.Moreover, a significantly higher mean percent reduction of MSIT was recorded at 6 and 12 months in the BT-A group.
The superiority of BT-A over two sessions of FMR was previously reported in a three-months split-body comparative study in Thailand [14].At 3-months, BT-A demonstrated significantly lower HDSS, better quality of life (measured with DLQI), higher patient satisfaction and less transdermal water loss.Long-term efficacy was not studied.
The efficacy and safety of FMR was previously assessed in several studies with average results and high safety profile, as in the present study [7-9, 14, 15].Of note, most of treated patients were females, as in our study, denoting a higher distress and urge for treatment in this population [8,14].All the studies but one [7] applied 3 treatment sessions to their patients, compared to 4 sessions in the current Treatment success at 6 months was significantly better in BT-A versus FMR group: 15/20 (75%) and 6/20 (30%) respectively (p-value = 0.004).At 12 months, the significant difference was lost: 3/20 (15%) and 1/20 (5%) respectively achieved treatment success (p-value = 0.605).
Patients reported significantly higher mean pain score in FMR versus BT-A group (6.48 ± 0.93, 95% CI: 6.04-6.91 versus 4.00 ± 1.75, 95% CI: 3.18-4.82,p < 0.001).Compensatory hyperhidrosis manifested in 2 patients on the same side treated with BT-A.There was no bruising, infection or post-inflammatory pigmentation recorded in any group.One patient complained of itching on the side treated with FMR.
No significant correlation was found between age, baseline HDSS or HqoL and any of the outcomes.

Discussion
The results of this long-term study show that a single session of BT-A injection is more effective in management of PAH and yield higher patient satisfaction than four sessions of FMR, with the microneedle type and parameters used in the present study.Both interventions show best efficacy after 3 months, then a gradual decline is observed, although some efficacy is still preserved in a few patients up to 12 months.This study is the first to compare both procedures in a longitudinal follow-up for 12 months.Both treatment modalities were shown to be equally safe, but FMR procedure was more painful compared to BT-A injection.[18].Quantitative assessment of effectiveness was additionally performed in some studies using gravimetry [18,20,23].Similar to our results, a significant effectiveness was achieved by BT-A at 3 months, as evidenced by a mean reduction of 2 points in HDSS [21], in approximation to our 3-months results (mean HDSS score reduced from 3.50 to 1.41).Mild and transient side effects were reported in 6% [22] and 11% [19] of patients, namely compensatory hyperhidrosis which was similarly manifested by 11.8% of our study patients on the same treated side.

Conclusions
Fractional microneedle radiofrequency does not offer a better substitute to BT-A in primary axillary hyperhidrosis, even if the number of sessions is increased to four sessions.BT-A shows better efficacy up to 12 months, is less painful, less expensive, and needs less number of sessions.The results of a single-pass technique using non-insulated needles for FMR, as in this work, gives comparable results to previous studies using multiple pass method with insulated needles, but with less prolonged efficacy.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material.If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.To view a copy of this licence, visit http://creativecommons. org/licenses/by/4.0/.study.While most of studies did not clarify, the use of insulated needles at 3 depths (2, 3 and 3.5 mms) was previously reported in one study [15] in contrast with our work where non-insulated needles were used at 3.5 mm depth, and the results are comparable (80% of patients achieved ≥ 50% reduction in sweat production at 6 months, versus 70.5% of our study patients).This suggests that the use of noninsulated needles in a single-pass method, first applied in the current work, might offer a more practical alternative to the several passes method with insulated needles, minding a higher pain with non-insulated needles.Nevertheless, the long-term effectiveness of FMR reported by a shamcontrolled study from Iran [9] is better than the one we achieved (mean HDSS score at 12 months 2.5 versus 3.18, respectively).This difference might be attributed to different parameters used, operator-dependent factors, or genetic susceptibility among different ethnic populations.The use of insulated needles in the latter study with 3 passes targeting 3 different depths might account for the better long-term efficacy demonstrated, due to cumulative destruction of sweat glands by the delivered thermal energy.
The depth of sweat glands, both eccrine and apocrine, was evaluated in the axilla using post-mortem histological analysis [16] and ultrahigh frequency ultrasound in Japanese patients [16,17].The secretory coils were found located at the boundary between dermis and subcutaneous tissue, and the vertical depth ranged from 1.5 to 3 mm.Therefore, the use of FMR needles with full length (3.5 mm) and good coaptation of the handpiece with the stretched skin should deliver the necessary energy to the full length of the sweat glands.But it seems that the regenerative power of the glands or the lack of adequate power might compromise the permanent efficacy of FMR.This aspect warrants further investigation with clinicopathological study of the effects of FMR on the sweat glands destruction.Unfortunately, we could not obtain patient consent for skin biopsies to study the histological response to treatment in this work.
It is of interest that we observed a better result achieved by thin patients than overweight patients receiving FMR treatment (based on clinical observation).A significant correlation between HDSS change and body mass index was previously documented after FMR sessions [9].Also of interest, the skin tightness noticed after FMR sessions contributed to patient satisfaction in one of our patients, emphasizing the role of FMR in cosmesis.Previously reported adverse events include pain and hyperpigmentation [7].The latter did not occur in our hands.
The results of the non-comparative studies conducted on BT-A came consistent with the current study as regards outcomes, safety and patient satisfaction for BT-A in hyperhidrosis.[5,[18][19][20][21][22][23]

Fig. 2 Fig. 1
Fig. 2 Line chart showing a declining mean percent patient satisfaction (Pt sat) of both groups at 3, 6 then 12 months, with constant superior satisfaction in botulinum toxin (BT-A) group in comparison to fractional microneedle radiofrequency (FMR) group

Fig. 3
Fig. 3 Minor's starch iodine test in a side treated by fractional microneedling radiofrequency: Excellent response at 3 and 6 months, 50% relapse at 12 months

Hyperhidrosis Quality of life questionnaire (Hqol),
1. Investigator's global assessment of improvementfrom baseline based on photographic assessment of