Dual-wavelength long-pulsed 755-nm alexandrite/1,064-nm Nd:YAG laser versus Nd:YAG alone for treatment of palmoplantar verruca

ABSTRACT We compared the effectiveness and safety of the long-pulsed neodymium-doped yttrium-aluminum-garnet (Nd:YAG) laser alone and combined with a 755-nm alexandrite laser for treating palmoplantar warts. We divided patients into two groups to receive up to four monthly treatments with Nd:YAG alone (single-wavelength) or combined with the alexandrite laser (dual-wavelength). We assessed treatment responses (according to clearance rate), vascular/hyperkeratosis grades, and patient satisfaction and pain ratings. The differences in treatment response (p = .348), patient satisfaction (p = .560), and pain ratings (p = .728) between the groups were not significant. The single- and dual-wavelength treatment options were equally effective in treating recalcitrant palmoplantar warts.


Introduction
Common warts (verruca vulgaris) are benign epidermal hyperplasia caused by human papillomavirus.Palmoplantar warts are commonly encountered in dermatology clinics and are often resistant to treatments.There is currently no specific antiviral therapy for human papillomavirus; therefore, treatments focus on destroying hyperkeratotic lesions or inducing cytotoxicity against affected keratinocytes.Traditionally, palmoplantar warts have been cured by topical fluorouracil, topical imiquimod, cryotherapy, curettage, or laser ablation.However, some lesions are recalcitrant to multiple sessions of these treatments.
The pulsed dye laser (PDL) has been widely studied since the early 1990s for its efficacy on recalcitrant viral warts (1)(2)(3).Through selective photothermolysis, PDL therapy destroys superficial dermal vessels (4), which are typically more numerous in warts.In an early randomized controlled trial, the PDL showed a treatment success rate comparable to that of conventional therapy (3).The complete cure rate of PDL therapy ranges from 5.1% to 89% in clinical trials, including for palmoplantar warts (5).The overall clearance rate of plantar warts by the PDL has been reported to be 47.6% (6).
The long-pulsed 1,064-nm neodymium-doped yttriumaluminum-garnet (Nd:YAG) laser is also used for various vascular lesions (7-9) because its wavelength is included in the absorption spectrum of hemoglobin and rather weakly absorbed by melanin and water (10).Although it requires more energy than the PDL, the strength of the long-pulsed Nd:YAG laser lies in its deep penetration.With an extended continuous wave, Nd:YAG laser hyperthermia results in the clearance of HPV viral particles (11).In a randomized controlled trial, the cure rate and the number of sessions required to completely cure plantar warts were equivalent for the longpulsed Nd:YAG laser and PDL (12).However, the report showed that the Nd:YAG laser was more painful and resulted in significantly more complications (12).
The 755-nm alexandrite laser is traditionally indicated for dermal hyperpigmented lesions, such as nevus of Ota or melasma (13,14).Because its main target chromophore is melanin, the alexandrite laser is also popular for hair removal (15).Recently, its use has expanded to treating dermal vascular lesions, such as port-wine stains and venous lakes (16,17).To our knowledge, the application of the alexandrite laser for cutaneous warts has only been reported in one case report of recalcitrant hand warts (18).
In this randomized controlled trial, we compared the safety and efficacy of the long-pulsed Nd:YAG laser alone versus in combination with the lower-energy alexandrite laser for palmoplantar warts.

Methods
From March 2021 to January 2022, patients with palmoplantar warts aged 19 to 65 who agreed to discontinue any treatments other than the laser treatment were recruited for this trial.The study was conducted in two medical institutions with a protocol approved by the Institutional Review Board of Severance Hospital (IRB No. 1-2020-0085).The study was also registered with the Clinical Research Information Service (CRIS, https://cris.nih.go.kr) (KCT 0005876).
The subjects were randomized into two groups: the longpulsed 1,064-nm Nd:YAG laser -only group (single-wavelength group) or the combined long-pulsed 755-nm alexandrite and subjects received laser treatments monthly for up to 4 months or until all lesions disappeared and were followed up with 1 month after the final treatment.A laser device with dual-wavelength beams (1,064 nm and 755 nm; Clarity II ™ , Lutronic Corp., Goyang, Korea) was used for both groups.Clinical photographs and dermoscopic images were taken for each lesion at each visit.Before laser irradiation, topical lidocaine (25 mg/g) plus prilocaine (25 mg/g) cream was applied for 30 minutes, and then the lesions were pared with double-edged razor blades.In the singlewavelength group, each lesion received two passes of Nd:YAG with the following parameters: fluence 130 ~ 160 J/cm 2 , spot size 5 mm, pulse width 30 msec.In the dual-wavelength group, each lesion received one pass of Nd:YAG with the same parameters and one pass of the alexandrite laser with 60-J/cm 2 fluence, 5-mm spot size, and 1-msec pulse width.After the final visit, the investigators assessed the treatment response for each lesion by comparing the initial and final photographs.If the lesion diameter was reduced by more than 75%, treatment was considered to have an excellent response.If the clearance was 50% ~75%, 25%~50%, or less than 25%, the treatment response was considered good, fair, or poor, respectively.The lesions were also graded on a scale of 0 to 4 by their degree of vascularity and hyperkeratosis.The prototype of each grade is depicted in Supplementary figure S1.
At the final visit, patients rated their overall satisfaction as very much satisfied, satisfied, somewhat satisfied, or not satisfied.At each treatment session, patients documented their pain level on a 10-point scale.Any serious adverse event was documented at all visits.
Data were analyzed using IBM SPSS Statistics for Windows, Version 25.0.(Armonk, NY: IBM Corp).The Chi-square test was used to compare the investigator assessment of treatment response and patient satisfaction score between the dual-and single-wavelength groups.The independent t-test was performed to compare the pain scores between the two groups.We used a linear mixed model to compare the vascular and hyperkeratosis grading scores of the two groups.Statistical significance was defined as p < .05.

Results
Thirty patients with 102 palmoplantar warts were included in the study.Among them, 15 patients with 52 lesions were allocated to the dual-wavelength group and the remaining 15 patients with 50 lesions were assigned to the single-wavelength group.Characteristics of the subjects in each group are presented in Table 1.The average age of the subjects was 31.4 ± 10.8 years and the numbers of male and female patients were 15 each.The number of warts ranged from two to seven per patient.Most lesions were on the foot (85 lesions, 83.3%).
The treatment response, patient satisfaction questionnaire results, and average pain score are listed in Table 2.The investigator-assessed treatment response revealed that 21 lesions (40.4%) showed an excellent response, 8 lesions (15.4%) showed a good response, 9 lesions (17.3%) showed a fair response, and 14 lesions (26.9%) showed a poor response in the dual-wavelength group.In the single-wavelength group, 26 lesions (52.0%) showed an excellent response, 10 lesions (20.0%) showed a good response, 7 lesions (14.0%) showed a fair response, and 7 lesions (14.0%) showed a poor response.There was no correlation between the treatment method and treatment response (p = .348,Chi-square test) (Figure 1).
Serial photographs of a dual-wavelength treated patient and a single-wavelength patient are shown in Figure 2. Table 3 presents the results of the vascular and hyperkeratosis gradings.The differences between the initial and final treatment grades were statistically significant for both the vascular and hyperkeratosis scores regardless of the treatment methods.We used a linear mixed model to compare the change in average vascular and hyperkeratosis scores between the two treatment groups (Figure 3) and found no significant difference in the rate of improvement for either score (hyperkeratosis p = .191,vascular p = .158).
In the dual-wavelength group, 7 patients (46.7%) reported being very much satisfied, 4 patients (26.7%) were satisfied, 3 patients (20.0%) were somewhat satisfied, and 1 patient (6.7%) was not satisfied 1 month after the final treatment.In the single-wavelength group, 9 patients (60.0%) were very  much satisfied, 2 patients (13.3%) were satisfied, 4 patients (26.7%) were somewhat satisfied, and none were not satisfied.The difference between the distributions was not statistically significant (p = .560,Chi-square test) (Figure 4).When satisfaction scores were rated on a scale of 1 to 4, with 1 being the lowest and 4 being the highest, the average score for the dual-wavelength group was 3.13 ± 0.99 and the average score for the single-wavelength group was 3.33 ± 0.90 (p = .567,independent t-test).
At every treatment session, patients graded their maximum pain on a scale of 1 to 10.The average pain score of the dualwavelength group was 7.12 ± 1.74 and that of the singlewavelength group was 7.00 ± 1.92.The difference was not statistically significant (p = .728,independent t-test).However, the dual-wavelength group largely attributed the maximum pain to the long-pulsed Nd:YAG laser, which irradiated at a higher fluence than the alexandrite laser.One patient in the dual-wavelength group experienced plantar hematoma after laser treatment.There were no serious adverse events in the single-wavelength group.

Discussion
Palmoplantar warts are benign hyperkeratotic epidermal proliferative disorders brought on by the human papillomavirus.Laser therapy is a useful option for patients whose warts do not respond to traditional therapies, including intralesional bleomycin injection, cryotherapy, or topical salicylic acid (5).Hyperkeratotic verruca lesions can be removed by vaporizing the affected keratinocytes with ablative lasers, like carbon dioxide and erbium: yttrium-aluminum-garnet lasers.Verrucas can also be successfully treated with non-ablative lasers.The PDL has long been used to treat verruca by focusing on the dilated blood vessels within the dermal papillae (3,6,12,19).Longer-wavelength lasers, like the long-pulsed 1064-nm  Nd:YAG laser, have recently been developed for the treatment of verrucas and have slightly greater cure rates than that of the PDL (18,20).Additionally, the 755-nm alexandrite laser may be able to remove stubborn periungual warts (21).
In this study, we used a dual-wavelength alexandrite and Nd:YAG laser system to treat recalcitrant palmoplantar warts.Both wavelengths are absorbed by hemoglobin and thereby induce the coagulation and destruction of blood vessels.The removal of the feeder vessels then leads to necrotic changes in the virus-infected keratinocytes.The patients reported considerable intraoperative discomfort as a result of the Nd:YAG laser's extended pulse duration (30 msec) and high intensity.Furthermore, pulse-stacking is necessary to reach the desired outcome (slight blanching of the lesion), yet pulse-stacking with the 1,064-nm wavelength alone may result in unfavorable outcomes, such as bullae or burn.Notably, dermoscopy revealed that the long-pulsed alexandrite laser induced a comparable improvement in vascularity with lower patientreported pain scores.However, it is the limitation of our study that we did not separately investigate the pain score after each laser irradiation, thus being unable to quantify the difference in pain between Alexandrite and Nd:YAG laser treatments.

Conclusion
The combination of a 1064-nm Nd:YAG laser and a 755-nm alexandrite laser decreased overall pain, enhancing patient compliance.Therefore, we believe that combined Nd:YAG and alexandrite lasers are comparable to the Nd:YAG laser alone as a treatment option for recalcitrant palmoplantar warts.Additional research on alexandrite lasers is advised, particularly randomized controlled experiments contrasting the efficiency of alexandrite and Nd:YAG lasers.

Figure 2 .
Figure 2. Serial photographs of (a, f) initial, (b, g) on the second treatment day, (c, h) on the third treatment day, (d, i) on the fourth treatment day, and (e, j) one month after the final treatment of a patient treated with (a-e) dual-wavelength and (f-j) single-wavelength.

Figure 3 .
Figure3.The changes in average vascular and hyperkeratosis scores were compared using a linear mixed model.There was no significant difference in the rate of improvement between the dual-wavelength group and the single-wavelength group.

Table 1 .
Demographics and characteristics of patients.

Table 2 .
Investigator assessment, patient satisfaction, and pain score of the dual-wavelength and singlewavelength groups.

Table 3 .
The number of lesions in each vascular and hyperkeratosis grade in the initial and final visits.