Fractional CO₂ laser combined with topical compound betamethasone for Vitiligo-Associated Leukotrichia: a retrospective study of 13 patients with limited effectiveness

Fractional CO₂ laser combined with topical compound betamethasone for Vitiligo-Associated Leukotrichia: a retrospective study of 13 patients with limited effectiveness | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Fractional CO₂ laser combined with topical compound betamethasone for Vitiligo-Associated Leukotrichia: a retrospective study of 13 patients with limited effectiveness Xuhai Yuan, Juan Du, Xinxin Li, Yijie Sun, Xiaolan Ding, Hanlin Li, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8632638/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 6 You are reading this latest preprint version Abstract Purpose: To evaluate the effectiveness and safety of fractional CO₂ laser combined with topical compound betamethasone for treating vitiligo-associated leukotrichia (VAL). Methods: A total of 13 patients with VAL (a total of 20 lesions) were enrolled; patients who were in rapid-progressing phase (VIDA=4) were excluded. Patients received fractional CO₂ laser following immediate topical application of compound betamethasone every 4 weeks. All patients underwent a minimum of 3 laser treatment sessions, with the number of sessions ranging from 3 to 8 per patient. Treatment outcomes were assessed using global photograph assessment (GPA)-scale, standardized repigmentation grading (G0–G5), and dermoscopic evaluations of hair density and type. Adverse events were also assessed during the 4 weeks post each session. Results: Only 1 patient (7.7%) achieved significant hair repigmentation (grade G4), while 2 others showed mild repigmentation in the vitiligo patches (grade G1). No significant changes in hair counts or densities were observed on dermoscopy after treatment (all p > 0.2). Transient erythema and pain occurred in all patients, and mild desquamation in 15%, all resolving within 2 weeks. No cases of skin atrophy were noted. Conclusion: In this small cohort, fractional CO₂ laser plus topical betamethasone produced minimal hair repigmentation in VAL but was well tolerated. The poor effectiveness may reflect depletion of follicular melanocyte reserves or suboptimal treatment parameters; further controlled studies are needed. Vitiligo leukotrichia fractional CO₂ laser betamethasone laser-assisted drug delivery hair depigmentation Figures Figure 1 Figure 2 Introduction Vitiligo is a chronic pigmentary disorder characterized by cutaneous and mucosal depigmentation due to melanocyte destruction with a global prevalence of 0.5–1.6% [ 1 ]. The disfiguring nature of the condition frequently leads to profound psychosocial consequences, including stigmatization, anxiety, and depression [ 2 ]. Current therapeutic approaches for vitiligo encompass immunomodulators (e.g., corticosteroids, calcineurin inhibitors, JAK inhibitors), phototherapy (e.g., narrowband UVB, 308nm excimer laser), and surgical interventions in stable stage. Leukotrichia in vitiliginous skin (Vitiligo-Associated Leukotrichia, VAL) occurs in 42.14% of cases and is often resistant to both pharmacological and phototherapeutic interventions [ 3 , 4 ]. Surgical transplantation demonstrated certain therapeutic effectiveness for VAL, however, its application remains contraindicated in progressive stage of vitiligo. This highlights the urgent need for innovative therapies with improved effectiveness and safety profiles [ 5 ]. Fractional lasers, including the non-ablative 1550nm erbium-glass and ablative 2940nm Er:YAG/10,600-nm CO₂ systems, promote hair regeneration during the anagen phase and restoration of pigmentation through trauma-induced wound healing mechanisms [ 6 , 7 ]. These lasers primarily exert their effects by activating hair follicle stem cells and enhancing skin re-epithelialization following controlled microscopic thermal injury [ 7 ]. These devices leverage water as their chromophore to achieve selective photothermolysis, enabling precise tissue coagulation or vaporization while stimulating skin-remodeling processes [ 8 ]. Current evidence supports their effectiveness in hair diseases, including androgenetic alopecia (AGA) and alopecia areata (AA), vitiligo, and hypopigmentation in scars [ 6 , 9 ]. Fractional lasers, particularly ablative fractional CO₂ laser therapy, enhance transdermal drug delivery by creating microthermal treatment zones (MTZs). These MTZs form vertical epidermal and dermal channels, facilitating uniform penetration of topical agents in skin and hair follicle-rich regions[ 8 ]. Simultaneously, these lasers demonstrate synergistic effects with adjunctive therapies, including topical corticosteroids, tacrolimus, platelet-rich plasma (PRP), and narrowband UVB—which amplify follicular stimulation [ 10 ]. This suggests that combinatorial approaches may yield superior outcomes in hair disorders and vitiligo compared to monotherapy [ 7 , 11 ]. The combined use of 10600 nm CO₂ fractional laser and compound betamethasone has shown excellent responder rate in vitiligo patches [ 12 ]. The combined use of CO₂ fractional laser and compound betamethasone enhances vitiligo treatment effectiveness by modulating cytotoxic T-cell activity, promoting melanocyte migration, and improves the levels of inflammatory factors (↓IL-17/IFN-γ, ↑IL-10), resulting in superior repigmentation rate, reduced the risk of relapse, compared to monotherapy [ 12 ]. To date, the effectiveness of CO 2 fractional laser in the management of VAL remains largely unknown. In this study, we investigated the effectiveness of CO₂ fractional laser in combination with topical compound betamethasone for VAL. Patients and Methods This retrospective cohort study (conducted in accordance with STROBE guidelines) was carried out from April 2021 to November 2024 with approval from the institutional ethics committee. Patients diagnosed with VAL, which was confirmed by two experienced dermatologists using Wood’s lamp and Dermoscopic examinations, were identified from paper and electronic medical records. Written informed consent was obtained from all participants. For minors, consent was provided by guardians. Vitiligo patients with leukotrichia who received CO₂ fractional laser combined with topical compound betamethasone were included. Patients who had vitiliginous skin > 5 mm with VAL and underwent at least 3 sessions of laser and topical steroid combination therapy were included. Patients in the rapid-progressive phase (​​defined by a ​​Vitiligo Disease Activity [VIDA] score of + 4​​, indicating new lesions or lesion expansion within the past 6 weeks), or those with a history of hair dyeing, immune-compromised condition, history of keloids or with incomplete demographic or imaging data, were excluded from the study. Demographic characteristics and medical histories were collected for all patients. The assessment began with macroscopic imaging of the target lesions, followed by dermoscopic evaluations utilizing the Fotofinder system (Fotofinder ATBM Systems GmbH, Germany) at 20-fold magnification. After applying 5% compound lidocaine cream (Ziguang, H20063466) for topical anesthesia, the target lesions were cleaned and treated with CO₂ fractional laser (AcuPulse, Lumenis, USA, wavelength 10600 nm) at the standardized setting (spot size 4 mm, deep mode 15-22.5 mJ with a density of 10%, superficial mode 60–70 mJ with a density of 40%, one pulse, square shape). The laser was delivered to the vitiliginous skin with leukotrichia, including a 3 mm extending depigmented margin. Therapeutic interventions were administered to avoid damage to hair shafts. Immediately following the laser procedure, topical compound betamethasone (5 mg dipropionate + 2 mg sodium phosphate solution, Diprospan, Merck Sharp & Dohme) was applied with an occlusive dressing maintained for 30 minutes. All patients received at least three treatment sessions at 4-week intervals. The total number of sessions varied between patients (range: 3–8) according to individual clinical response and patient preference, reflecting real-world treatment prctice in refractory cases. Patients were instructed to avoid water contact and sun exposure to the treated regions for a minimum of 2 days post-procedure. Concurrent systemic and topical medications were recorded. Treatment effectiveness was assessed using the Global photograph assessment (GPA)-scale through serial macroscopic images. Repigmentation of VAL was categorized into six grades: G0 (no change), G1 (1–25%, minimal improvement), G2 (26–50%, moderate improvement), G3 (51–75%, marked improvement), G4 (75–99%, excellent improvement), and G5 (100%, complete improvement)[ 13 ]. The evaluating dermatologist was blinded to the timepoint sequence but was aware of the treatment. Overall responder rate was calculated as (number of patients with G1-G5)/(total number of patients) × 100%. Repigmentation grades for the basal vitiliginous patches were also defined using the GPA scale as G0 (no repigmentation), G1 (1–25% improvement), G2 (26–50%), G3 (51–75%), G4 (76–99%), and G5 (100% repigmentation).A dermatologist evaluated the dermoscopic characteristics using Fotofinder Trichoscale Pro. Assessment included total hair density (hairs/cm²) before and after treatment, white/black hair density, proportion of vellus and terminal hairs, and diameter diversity of leukotrichia. All adverse events were systematically documented, including erythema, pain, itching, telangiectasia, folliculitis, desquamation, and transient hair shedding. For each event, precise onset-to-resolution timelines were recorded. All reported adverse events were graded by severity (mild, moderate, severe). Data were analyzed using IBM SPSS Statistics software (version 24.0; Armonk, NY, USA). Normally distributed data were expressed as ​​mean ± standard deviation (SD)​​ (e.g., age: 30.0 ± 9.8 years), while skewed distributions were presented as ​​median (interquartile range, IQR)​​. Categorical variables were described using ​​absolute frequencies and percentages​​ (e.g., 7/13 female patients, 53.8%). Paired t-tests were applied to normally distributed parameters when comparing baseline versus final measurements. Missing data at the variable level were minimal due to the exclusion of incomplete demographic or imaging data. No imputation was performed for any missing outcomes. Results Demographic and disease characteristics Of all 13 patients included (7 females and 6 males), the mean age was 30.0 ± 9.8 years (range: 13–47 years) and average disease duration was 55.77 ± 74.86 months (range: 2–252 months). Among the patients, 4 (30.77%) were diagnosed with non-segmental vitiligo, 4 (30.77%) with segmental vitiligo, and 5 (38.46%) with undefined vitiligo. Twenty vitiliginous patches with leukotrichia were observed in these 13 patients, 15 patches (75%) were located on the scalp, 3 patches (15%) on the eyebrow, and 2 patches (10%) on the legs (Table 1 ). Family history of vitiligo and thyroid disorders were reported in 1 (7.69%) and 3 (23.07%) patients, respectively. Table 1 Demographic and disease characteristics of vitiligo patients with leukotrichia (N = 13) No Age(years) Sex Type of vitiligo VIDA Disease duration (month) location Hair type Comorbid Autoimmune Diseases Concomitant Treatments 1 34 F UD 0 252 Scalp Long None None 2 27 F UD 3 5 Scalp Long Subacute thyroiditis Oral Total Glucosides of White Paeony Capsules, Compound Betamethasone (IM) 3 47 F NSV 3 24 Scalp Long Hashimoto’s thyroiditis Compound Betamethasone (IM), Oral Total Glucosides of White Paeony Capsules, Oral Extract of Ginkgo Biloba Leaves Injection 4 17 M NSV 2 84 Scalp Long None Oral Compound Glycyrrhizin Tablets 5 43 M UD 3 10 Eyebrow Long None Prednisone15mg Oral, Oral Extract of Ginkgo Biloba Leaves Injection, Tacrolimus Ointment 6 39 M SV 3 12 Eyebrow Long None Tacrolimus Ointment, Travoprost​​ Eye Drops 7 26 M SV 3 2 Eyebrow Long None Methylprednisolone 16mg QD (Oral), Mometasone Furoate Cream, Tacrolimus Ointment 8 24 M UD 1 12 Scalp Vellus None UVB 9 36 F NSV 3 36 Scalp Long None Prednisone15mg Oral 10 34 M NSV 3 168 Leg Long Hyperthyroidism Prednisone 15mg Oral, Halometasone Cream 11 25 F SV 3 12 Scalp Long None Compound Betamethasone (IM), Pimecrolimus Cream 12 23 F UD 2 36 Scalp Long None Compound Betamethasone (IM) 13 13 F SV 2 72 Scalp Long None Compound Betamethasone (IM) M: Male, F: Female, SV: segmental vitiligo, NSV: non-segmental vitiligo, UD: Undetermined Type of Vitiligo, VIDA: Vitiligo Disease Activity score, IM: intramuscula Therapeutic Effect Evaluation The results of GPA-scale were provided in Fig. 1 . All 13 patients included in the study underwent at least three laser treatment sessions, with the number of sessions ranging from 3 to 8 over a period of 6 to 38 weeks. Only one patient (1/13, 7.69%, patient 2, on scalp) achieved G4 repigmentation of leukotrichia (Fig. 1 A). The rest of the patients (12/13, 92.31%) showed no improvement nor deterioration of leukotrichia. Evaluation of basal vitiliginous patches demonstrated G4 repigmentation (75–99%) in 1 patient (patient 2, on scalp) and G1 repigmentation (1–25%) in 2 patients (patient 3 and patient 6, on scalp and eyebrow respectively), yielding an overall responder rate of 23.08% (3/13) (Fig. 1 B). Macroscopic imaging and dermoscopic photographs from selected patients were shown in Fig. 2 . Dermoscopic Analysis Before and After Treatment Dermoscopic analysis before and after treatment is summarized in Table 2 .​ Quantitative dermoscopic analysis using Fotofinder Trichoscale Pro revealed no statistically significant changes in hair characteristics after the treatment. The mean black hair count remained stable, with pretreatment values of 67 ± 45.52/cm² versus posttreatment values of 66 ± 44.52/cm² ( p = 0.225). White hair density was also similar, from 87 ± 56.56/cm² to 86 ± 66.69/cm² ( p = 0.545). Total hair count (154.67 ± 22.74/cm² vs. 148.67 ± 34.85/cm², p = 0.494), thick hair count (51 ± 37.58/cm² vs. 51 ± 42.93/cm², p = 1.000), and vellus hair count (29 ± 19.00/cm² vs. 17.67 ± 3.05/cm², p = 0.441) exhibited no significant alterations. Follicular density decreased numerically from 70.1 ± 16.6/cm² to 62 ± 23.08/cm² ( p = 0.303). Notably, hair shaft thickness demonstrated a marginal increase from 51.3 ± 18.9 µm to 57.7 ± 19.8 µm ( p = 0.049). Table 2 Dermoscopic Analysis Before and After Treatment Hair type Before Treatment (mean ± SD) After Treatment (mean ± SD) P value* Total hair 154.67 ± 22.74 148.67 ± 34.85 0.494 Black hair 67 ± 45.52 66 ± 44.52 0.225 White hair 87 ± 56.56 86 ± 66.69 0.545 Thick hair 51 ± 37.58 51 ± 42.93 1.000 Vellus hair 29 ± 19.00 17.67 ± 3.05 0.441 Thickness of hair shaft (µm) 51.3 ± 18.9 57.7 ± 19.8 0.049 *P value was calculated using t-test Safety Evaluation The main adverse events included transient erythema (reported in 4/13 within 7 days, 5/13 between 7 and 14 days, and 1/13 lasting longer than 14 days), pain (13/13, 100%, tolerable), folliculitis (1,7.69%), desquamation (2(15.38%) and transient hair shedding (13/13, 100%, recover in 2 weeks) (Table 3 ). These adverse events were all mild to moderate and most of them resolved spontaneously within 1–2 weeks after onset without requiring further medical treatment. Table 3 Adverse event in treatment site Adverse event, n (%) 14 days Erythema 4 (30.77%) 5 (38.47%) 1 (7.69%) Pain 13 (100%) 0 0 Itching 2 (15.38%) 0 0 Telangiectasia 0 1 (7.69%) 0 Folliculitis 1 (7.69%) 1 (7.69%) 0 Desquamation 2 (15.38%) 2 (15.38%) 0 Transient hair shedding 13 (100%) 0 0 The intervention demonstrated a favorable safety profile, with complete resolution of most adverse events achieved within 7–14 days post-procedure. Notably, no case of cutaneous atrophy was observed among patients during the follow-up period. Discussion VAL is a therapeutically resistant variant of vitiligo, exhibiting significantly higher prevalence in segmental vitiligo (SV: 77.4%) compared to nonsegmental subtypes (NSV: 39.1%; P < 0.05) [ 14 ]. Immunohistochemical studies confirm functionally impaired Melanocyte Stem Cells (McSCs) and active melanocytes within vitiliginous white hair by attenuated melanogenic markers (HMB-45↓, tyrosinase↓) and abrogated SCF/c-Kit paracrine signaling [ 15 , 16 ]. The depletion of McSCs creates a significant therapeutic challenge, as the repigmentation of VAL and vitiliginous patches depends on the activation and migration of residual McSCs to depigmented hair shafts and epidermal basement membrane [ 17 ]. Current treatments available for vitiligo include steroids, tacrolimus, cyclosporine, phototherapy, and surgical transplantation, as well the emerging treatments of Janus kinase (JAK) inhibitors, afamelanotide, phosphodiesterase 4 inhibitors, basic fibroblast growth factor, tumor necrosis factor (TNF) inhibitors, and pseudocatalase [ 18 ]. Currently, no universally effective therapeutic modality exists for vitiligo. Those cases with VAL demonstrate even poorer response to existing treatments. Previous studies have confirmed that leukotrichia serves as a critical negative prognostic factor for both UV phototherapy and tacrolimus outcomes [ 14 ]. Fractional laser (non-ablative or ablative CO₂ laser) combined with drug delivery has demonstrated effectiveness in the treatment of vitiliginous patches, AA, and AGA [ 9 , 10 , 19 ]; however, its application VAL cases has not been reported. Fractional photothermolysis generates controlled arrays of MTZs, each comprising vertically aligned thermal columns (depth: 200–1200 µm) that induce confined dermal coagulation. Re-epithelialization typically commences within 24 hours post-laser intervention, driven by accelerated keratinocyte migration from adjacent unaffected epidermis toward MTZs. Subsequent dermal remodeling usually persists for longer than 90 days, characterized by progressive collagen III/I ratio normalization and elastin reorganization. This reparative cascade also enhances the production of growth factor (e.g., fibroblast growth factor, epidermal growth factor, insulin growth factor, and hepatocyte growth factor, VEGF)-which stimulate dermal papilla cell proliferation and activate hair follicle stem cell [ 10 ]. Another study demonstrated that fractional CO₂ laser significantly enhances melanocyte viability, melanin synthesis, and tyrosinase activity in human melanocytes ( P < 0.05 )[ 20 ]. In mouse model, fractional CO₂ laser-treated lesions showed increased perifollicular melanin deposition, indicating potential activation of follicular McSCs[ 20 ]. Fractional laser treatment (18 mJ/spot, 361 spots/cm²) has been shown to induce hair follicular telogen-to-anagen conversion by triggering transient inflammatory responses and subsequent regenerative processes. These events culminate in progressive hair regrowth from day 5 onward, as demonstrated by histopathological, molecular, and immunohistochemical analyses [ 21 ]. Fractional laser combined with topical corticosteroids or other medications, aiming to promote the delivery of medications, has achieved excellent effectiveness in the cure of both vitiligo white patches and other hair diseases. Ablative laser therapy could help with the effective delivery and uniform distribution of topical agents to the dermis and the hair site. A histological study of AGA patients treated with fractional Erbium:YAG 2940nm laser demonstrated progressive microchannel closure within 24 hours and complete epidermal re-epithelialization by 48 hours post-procedure, offering the first human scalp evidence on transient channel patency critical for laser-assisted drug delivery (LADD) effectiveness [ 22 ]. Guo’s research indicates fractional CO₂ laser induces transient suppression of epidermal tight junction proteins (claudins, occludins) for ≤ 7 days post-treatment, establishing a prolonged therapeutic window for enhanced LADD [ 23 ]. In a comparative trial involving 20 AA patients with multiple patches, fractional CO₂ laser therapy (3–6 biweekly sessions) demonstrated better sustained hair regrowth rates and fewer adverse events compared to monthly intralesional corticosteroid injections (≤ 3 sessions), suggesting its potential as a safer and more effective alternative therapy [ 24 ]. In Halim DA et.al’ randomized controlled trial of 30 AA patients, fractional CO₂ laser either alone or combined with betamethasone valerate cream demonstrated significantly improvement of SALT scores, terminal hair regrowth, and patient satisfaction compared to betamethasone monotherapy [ 19 ]. Further evidence of fractional CO₂ laser and LADD function in AGA, another hair related disease, demonstrated that fractional CO₂ laser combined with topical dutasteride yielded superior clinical improvement in both global photographic assessments and dermoscopic parameters compared to fractional CO₂ laser monotherapy. A randomized controlled trial of 48 stable non-segmental vitiligo patients revealed low-energy and low-density fractional CO₂ laser (60 mJ, 8% coverage) combined with NB-UVB and topical betamethasone achieved superior repigmentation effectiveness at 3 and 6 months compared to higher-density protocols with optimized tolerability. These evidences confirmed the micro-destruction and reconstruction process and that LADD facilitates hair growth and melanocyte activation. No prior study has investigated the effectiveness of fractional CO₂ laser combined with topical steroids for treating VAL. To address this gap, we conducted this retrospective study of 13 patients (20 VAL patches) to evaluate the effectiveness of this combined therapy in managing refractory phenotype. Despite the acceptable safety, the therapeutic outcomes were markedly limited with only 7.69% (1/13) patients achieving partial repigmentation (G4) in VAL and 23.08% patients showing some extent of recovering (G1-G4) basal vitiliginous patches. Notably, the only responsive case ( with both G4 repigmentation in VAL and basal vitiliginous patches) had a short disease duration (5 months), contrasting with the suboptimal majority (mean disease duration: 55.77 months) who exhibited nearly no improvement of VAL, even when combined with systemic therapies and the lower responder rate in basal vitiligo patches is much lower (23.08%) compared to previous study(92.73%​​) [ 12 ]. Early intervention and optimized laser parameters targeting the hair bulge niche are warranted. This finding should be interpreted with caution due to the sample size but may inform future study designs.These two phenomena suggest possible depletion of follicular melanocyte stem cells and highlight the need for early intervention before irreversible McSCs reservoir depletion. Previous transcriptomic and histological studies have demonstrated that stable vitiligo lesions are typically characterized by sparse inflammatory infiltrates and low immune activation status, especially in fully depigmented areas [ 25 , 26 ]. Since compound betamethasone exerts its effect mainly via anti-inflammatory and immunosuppressive mechanisms, the limited effectiveness observed in long-standing vitiligo-associated leukotrichia in this study may partially reflect the lack of ongoing immune activity in stable disease. Accordingly, alternative approaches aimed at directly stimulating melanocyte regeneration may prove more effective in such refractory cases. For instance, the use of laser-assisted delivery of agents that promote melanocyte differentiation—such as WNT pathway agonists—deserves further investigation. The limited effectiveness observed may also be related to suboptimal laser parameters. The determination of the necessary depth and density in hair region, and maximizing therapeutic benefits while ensuring safety with CO₂ fractional lasers, remains a significant challenge. The variable settings used in our study, deep mode (15-22.5mJ/cm², 10% in density) with a penetration depth of 550–700µm in the reticular dermis, and the superficial mode (15-22.5mJ/cm², 40% in density) with a penetration depth of 40–50µm into epidermal layer, might have contributed to insufficient melanocyte activation in the hair bulge. In future attempts, higher parameters of energy and density levels and more frequent laser session can be conducted, but caution should be exercised to avoid permanent damage to the hair follicle bulge caused by CO₂ ablative lasers. The alternative utility of fractional Er:YAG laser (2,940 nm) still warrants critical evaluation, as its exceptionally high water-absorption fundamentally restricts penetration to hair bulge deep. The limited effectiveness of fractional CO₂ laser with topical long-lasting steroids likely reflects the irreversible depletion or dysfunction of the follicular melanocyte reservoir, where even aggressive physical enhancement methods fail to reactivate melanogenesis. Surgical interventions, especially follicular unit extraction (FUE) transplantation, emerge as a promising definitive intervention for stable VAL patients. Limitations This study has several limitations to acknowledge. First, the retrospective design, small-sample size, and lack of a control group substantially limit the reliability of our conclusions and preclude definitive causal inferences regarding the effectiveness of the combined therapy. The limited sample size (N = 13) was a result of halted enrollment due to limited effectiveness without pre-specified power calculation. This resulted in insufficient statistical power and a heightened risk of Type II error. Second, the interpretation of treatment effects is confounded by the heterogeneous concomitant therapies (e.g., systemic corticosteroids, immunomodulators, phototherapy) received by some patients, an inherent challenge in real-world studies of refractory conditions. Third, our study is potentially subject to selection bias. The requirement for a minimum of three treatment sessions excluded patients who discontinued therapy early, potentially due to inefficacy or adverse events, which may skew our results toward a more favorable outcome. Furthermore, the cohort also likely represents a highly motivated subgroup with refractory disease, limiting generalizability. Fourth, although the evaluation was blinded to the timepoint sequence of photographs, the lack of blinding to the treatment may have introduced measurement bias in the repigmentation grading. Finally, the heterogeneity in VAL subtypes and disease duration limited our ability to perform meaningful stratified analyses. The finding that the only responder had a short disease duration should be interpreted as hypothesis-generating rather than conclusive. In conclusion, in this retrospective small-sample study, CO₂ fractional laser combined with topical betamethasone demonstrated an extremely low repigmentation rate for VAL, with acceptable safety. The insufficient effectiveness may be related to depletion of follicular melanocyte stem cell reserves and inadequate parameters/frequency, requiring validation through prospective controlled studies. Given the small sample size, formal subgroup analysis was not feasible. However, we descriptively summarized outcomes by VAL subtype and disease duration. The only patient achieving G4 repigmentation (Patient 2) had non-segmental vitiligo and a short disease duration (5 months). Among the other patients with disease duration ≤ 12 months (n = 5), none achieved repigmentation in VAL. No clear pattern emerged across subtypes (segmental, non-segmental or undetermined), though the limited number precludes definitive conclusions. Declarations The author(s) report no conflicts of interest in this work. Ethics approval: This study was conducted in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Approval was granted by the Ethics Committee of Peking University People’s Hospital (No. 2024PHB598-001). Consent to participate: Written informed consent to participate in the study was obtained from all individual participants included in the study. For minor participants, consent was obtained from their legal guardians. Consent for publication: Not applicable. The manuscript does not contain any personal data or identifiable images. Competing interests: The authors have no relevant financial or non-financial interests to disclose. Clinical trial number Not applicable. Funding: This study was funded by the National Natural Science Foundation of China (NSFC No. 82173403). Author Contribution Juan Du, Fang Wang, and Xiaolan Ding were involved in the study conception and design. Xuhai Yuan, Xinxin Li, Hanlin Li, and Fang Wang performed data collection and analysis. The initial draft of the manuscript was written by Xuhai Yuan and Yijie Sun. Critical revision and editing of the manuscript for important intellectual content were carried out by Fang Wang, and Juan Du. 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(2023) Vitiligo: Pathogenesis and New and Emerging Treatments. Int J Mol Sci 24:17306. https://doi.org/10.3390/ijms242417306 Halim DA, et al. (2023) Evaluation of fractional carbon dioxide laser alone versus its combination with betamethasone valerate in treatment of alopecia areata, a clinical and dermoscopic study. Arch Dermatol Res 315:505-511. https://doi.org/10.1007/s00403-022-02393-5 Tang H, et al. (2024) The Effect of Fractional Carbon Dioxide Laser on Melanogenesis in Human Melanocytes and Vitiligo Mouse Models. Clin Cosmet Investig Dermatol 17:1729-1737. https://doi.org/10.2147/CCID.S445131 Zhuo F-L, et al. (2019) Effects of CO2 fractional laser on hair growth in C57BL/6 mice and potential underlying mechanisms. Chin Med J (Engl) 132:1257-1260. https://doi.org/10.1097/CM9.0000000000000220 Pidal C, et al. (2021) Fractional-assisted drug delivery performed with erbium yag laser in androgenic alopecia: Histological aspects. Dermatol Ther 34:e14730. https://doi.org/10.1111/dth.14730 Guo H, et al. (2023) Dynamic panoramic presentation of skin function after fractional CO2 laser treatment. iScience 26:107559. https://doi.org/10.1016/j.isci.2023.107559 El-Husseiny R, Elframawy S, Abdallah M (2020) Comparative study between fractional carbon dioxide laser vs intralesional steroid injection in treatment of alopecia areata. Dermatol Ther 33:e13742. https://doi.org/10.1111/dth.13742 Regazzetti C, et al. (2015) Transcriptional Analysis of Vitiligo Skin Reveals the Alteration of WNT Pathway: A Promising Target for Repigmenting Vitiligo Patients. J Invest Dermatol 135:3105-3114. https://doi.org/10.1038/jid.2015.335 Shiu J, et al. (2022) Multimodal analyses of vitiligo skin identify tissue characteristics of stable disease. JCI Insight 7:e154585. https://doi.org/10.1172/jci.insight.154585 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 11 Mar, 2026 Reviewers agreed at journal 17 Feb, 2026 Reviewers invited by journal 17 Feb, 2026 Editor assigned by journal 16 Feb, 2026 Submission checks completed at journal 29 Jan, 2026 First submitted to journal 18 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8632638","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":592995767,"identity":"0132e8c5-4844-4016-9cca-380bee9f5464","order_by":0,"name":"Xuhai Yuan","email":"","orcid":"","institution":"Peking University People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xuhai","middleName":"","lastName":"Yuan","suffix":""},{"id":592995768,"identity":"ca47633b-c5a5-4794-b871-6aeec2101cef","order_by":1,"name":"Juan Du","email":"","orcid":"","institution":"Peking University People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Juan","middleName":"","lastName":"Du","suffix":""},{"id":592995769,"identity":"7b2a2bdd-6e6a-47f4-b229-aa316dfd36fa","order_by":2,"name":"Xinxin Li","email":"","orcid":"","institution":"Peking University People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xinxin","middleName":"","lastName":"Li","suffix":""},{"id":592995771,"identity":"df33890a-fc18-4f0e-98cd-8975cfaa4b61","order_by":3,"name":"Yijie Sun","email":"","orcid":"","institution":"Peking University People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yijie","middleName":"","lastName":"Sun","suffix":""},{"id":592995772,"identity":"08f35b01-3cbf-4dd0-ad69-39ec1d62ae25","order_by":4,"name":"Xiaolan Ding","email":"","orcid":"","institution":"Peking University People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiaolan","middleName":"","lastName":"Ding","suffix":""},{"id":592995776,"identity":"a7c4b67f-0b65-42cb-853b-6766d09a3303","order_by":5,"name":"Hanlin Li","email":"","orcid":"","institution":"Peking University People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hanlin","middleName":"","lastName":"Li","suffix":""},{"id":592995780,"identity":"fc283cb2-beaf-4d19-bad4-c2fefee3c143","order_by":6,"name":"Fang Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0ElEQVRIiWNgGAWjYDAC5gMgUoKBjb2B4QBxWtgSoFp4DpCmBaQrAY8qZGBwjPnZw69tFol9ks8fHi6oYZDnFyNgmcExNnNjmTMSxmzSOQaHZxxjMJw5m4B1ZvcbzKQlKiTkgFoYDvOwMSQY3Cak5Rj7N2kJAwkeNsnjDw7z/CNKC4+Z5AeQLRIMBod524jQYn+Mp0yaAeQXHqBfePskCPtFso19m+TPtrrE+e3HH3/m+WYjzy9NQAsIMPMg2BKElYMA4w/i1I2CUTAKRsFIBQBEizujgBtPAAAAAABJRU5ErkJggg==","orcid":"","institution":"Peking University People's Hospital","correspondingAuthor":true,"prefix":"","firstName":"Fang","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2026-01-18 16:38:27","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8632638/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8632638/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":103168102,"identity":"65df11ad-821d-49d9-b398-b02527bda45a","added_by":"auto","created_at":"2026-02-22 12:57:36","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":141424,"visible":true,"origin":"","legend":"\u003cp\u003eRepigmentation outcomes for Vitiligo-Associated Leukotrichia (VAL) evaluated using the GPA-scale (A) Repigmentation in VAL; (B) Repigmentation in Basal vitiliginous patches\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8632638/v1/e37c8922d64e447a0516fd10.png"},{"id":103168103,"identity":"7d09f6f2-e026-4428-ba62-dd5f20046c8e","added_by":"auto","created_at":"2026-02-22 12:57:36","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1207050,"visible":true,"origin":"","legend":"\u003cp\u003eDermoscopic photographs and macroscopic imaging and of selected patients before and after treatment\u003c/p\u003e\n\u003cp\u003e(A-B) Dermoscopic photographs from patient 2 before (A) and after (B) receiving CO₂ fractional laser combined with topical compound betamethasone demonstrated G4 repigmentation (75-90% improvement) following 5 treatments in 16 weeks. The outcome achieved through concurrent administration of oral total glucosides of paeony (TGP) capsules and 3 times of intramuscular compound betamethasone treatment. (C-D) Dermoscopic photographs from patient 1 before (C) and after (D) therapy demonstrated no clinical improvement (G0) after 6 treatments in 18 weeks, suggesting limited effectiveness in refractory cases. (E-F) Clinical photographs from patient 7 exhibited no repigmentation (G0) in the left eyebrow following 4 treatments in 15 weeks despite concurrent administration of oral methylprednisolone (16 mg/d), topical mometasone furoate cream (0.1% bid), and tacrolimus ointment (0.1% bid). (G-H) Clinical photographs from a 13-year-old female patient with scalp leukotrichia (VIDA score = 2) before (G) and after (H) receiving 3 sessions of CO₂ fractional laser combined with topical compound betamethasone demonstrated no clinical improvement (G0) following treatment\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8632638/v1/1ad30b7c1d010bde61343956.png"},{"id":103168110,"identity":"b1bdfbd3-54dd-457e-afc6-bff39079181d","added_by":"auto","created_at":"2026-02-22 12:57:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2681907,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8632638/v1/0134b21f-3500-41b0-a169-ea1c19c17214.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Fractional CO₂ laser combined with topical compound betamethasone for Vitiligo-Associated Leukotrichia: a retrospective study of 13 patients with limited effectiveness","fulltext":[{"header":"Introduction","content":"\u003cp\u003eVitiligo is a chronic pigmentary disorder characterized by cutaneous and mucosal depigmentation due to melanocyte destruction with a global prevalence of 0.5\u0026ndash;1.6% [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The disfiguring nature of the condition frequently leads to profound psychosocial consequences, including stigmatization, anxiety, and depression [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Current therapeutic approaches for vitiligo encompass immunomodulators (e.g., corticosteroids, calcineurin inhibitors, JAK inhibitors), phototherapy (e.g., narrowband UVB, 308nm excimer laser), and surgical interventions in stable stage. Leukotrichia in vitiliginous skin (Vitiligo-Associated Leukotrichia, VAL) occurs in 42.14% of cases and is often resistant to both pharmacological and phototherapeutic interventions [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Surgical transplantation demonstrated certain therapeutic effectiveness for VAL, however, its application remains contraindicated in progressive stage of vitiligo. This highlights the urgent need for innovative therapies with improved effectiveness and safety profiles [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFractional lasers, including the non-ablative 1550nm erbium-glass and ablative 2940nm Er:YAG/10,600-nm CO₂ systems, promote hair regeneration during the anagen phase and restoration of pigmentation through trauma-induced wound healing mechanisms [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. These lasers primarily exert their effects by activating hair follicle stem cells and enhancing skin re-epithelialization following controlled microscopic thermal injury [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. These devices leverage water as their chromophore to achieve selective photothermolysis, enabling precise tissue coagulation or vaporization while stimulating skin-remodeling processes [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Current evidence supports their effectiveness in hair diseases, including androgenetic alopecia (AGA) and alopecia areata (AA), vitiligo, and hypopigmentation in scars [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFractional lasers, particularly ablative fractional CO₂ laser therapy, enhance transdermal drug delivery by creating microthermal treatment zones (MTZs). These MTZs form vertical epidermal and dermal channels, facilitating uniform penetration of topical agents in skin and hair follicle-rich regions[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Simultaneously, these lasers demonstrate synergistic effects with adjunctive therapies, including topical corticosteroids, tacrolimus, platelet-rich plasma (PRP), and narrowband UVB\u0026mdash;which amplify follicular stimulation [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. This suggests that combinatorial approaches may yield superior outcomes in hair disorders and vitiligo compared to monotherapy [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The combined use of 10600 nm CO₂ fractional laser and compound betamethasone has shown excellent responder rate in vitiligo patches [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe combined use of CO₂ fractional laser and compound betamethasone enhances vitiligo treatment effectiveness by modulating cytotoxic T-cell activity, promoting melanocyte migration, and improves the levels of inflammatory factors (\u0026darr;IL-17/IFN-γ, \u0026uarr;IL-10), resulting in superior repigmentation rate, reduced the risk of relapse, compared to monotherapy [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo date, the effectiveness of CO\u003csub\u003e2\u003c/sub\u003e fractional laser in the management of VAL remains largely unknown. In this study, we investigated the effectiveness of CO₂ fractional laser in combination with topical compound betamethasone for VAL.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cp\u003e This retrospective cohort study (conducted in accordance with STROBE guidelines) was carried out from April 2021 to November 2024 with approval from the institutional ethics committee. Patients diagnosed with VAL, which was confirmed by two experienced dermatologists using Wood\u0026rsquo;s lamp and Dermoscopic examinations, were identified from paper and electronic medical records. Written informed consent was obtained from all participants. For minors, consent was provided by guardians. Vitiligo patients with leukotrichia who received CO₂ fractional laser combined with topical compound betamethasone were included. Patients who had vitiliginous skin\u0026thinsp;\u0026gt;\u0026thinsp;5 mm with VAL and underwent at least 3 sessions of laser and topical steroid combination therapy were included. Patients in the rapid-progressive phase (​​defined by a ​​Vitiligo Disease Activity [VIDA] score of +\u0026thinsp;4​​, indicating new lesions or lesion expansion within the past 6 weeks), or those with a history of hair dyeing, immune-compromised condition, history of keloids or with incomplete demographic or imaging data, were excluded from the study.\u003c/p\u003e \u003cp\u003eDemographic characteristics and medical histories were collected for all patients. The assessment began with macroscopic imaging of the target lesions, followed by dermoscopic evaluations utilizing the Fotofinder system (Fotofinder ATBM Systems GmbH, Germany) at 20-fold magnification. After applying 5% compound lidocaine cream (Ziguang, H20063466) for topical anesthesia, the target lesions were cleaned and treated with CO₂ fractional laser (AcuPulse, Lumenis, USA, wavelength 10600 nm) at the standardized setting (spot size 4 mm, deep mode 15-22.5 mJ with a density of 10%, superficial mode 60\u0026ndash;70 mJ with a density of 40%, one pulse, square shape). The laser was delivered to the vitiliginous skin with leukotrichia, including a 3 mm extending depigmented margin. Therapeutic interventions were administered to avoid damage to hair shafts. Immediately following the laser procedure, topical compound betamethasone (5 mg dipropionate\u0026thinsp;+\u0026thinsp;2 mg sodium phosphate solution, Diprospan, Merck Sharp \u0026amp; Dohme) was applied with an occlusive dressing maintained for 30 minutes. All patients received at least three treatment sessions at 4-week intervals. The total number of sessions varied between patients (range: 3\u0026ndash;8) according to individual clinical response and patient preference, reflecting real-world treatment prctice in refractory cases. Patients were instructed to avoid water contact and sun exposure to the treated regions for a minimum of 2 days post-procedure. Concurrent systemic and topical medications were recorded.\u003c/p\u003e \u003cp\u003eTreatment effectiveness was assessed using the Global photograph assessment (GPA)-scale through serial macroscopic images. Repigmentation of VAL was categorized into six grades: G0 (no change), G1 (1\u0026ndash;25%, minimal improvement), G2 (26\u0026ndash;50%, moderate improvement), G3 (51\u0026ndash;75%, marked improvement), G4 (75\u0026ndash;99%, excellent improvement), and G5 (100%, complete improvement)[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The evaluating dermatologist was blinded to the timepoint sequence but was aware of the treatment. Overall responder rate was calculated as (number of patients with G1-G5)/(total number of patients) \u0026times; 100%. Repigmentation grades for the basal vitiliginous patches were also defined using the GPA scale as G0 (no repigmentation), G1 (1\u0026ndash;25% improvement), G2 (26\u0026ndash;50%), G3 (51\u0026ndash;75%), G4 (76\u0026ndash;99%), and G5 (100% repigmentation).A dermatologist evaluated the dermoscopic characteristics using Fotofinder Trichoscale Pro. Assessment included total hair density (hairs/cm\u0026sup2;) before and after treatment, white/black hair density, proportion of vellus and terminal hairs, and diameter diversity of leukotrichia.\u003c/p\u003e \u003cp\u003eAll adverse events were systematically documented, including erythema, pain, itching, telangiectasia, folliculitis, desquamation, and transient hair shedding. For each event, precise onset-to-resolution timelines were recorded. All reported adverse events were graded by severity (mild, moderate, severe).\u003c/p\u003e \u003cp\u003eData were analyzed using IBM SPSS Statistics software (version 24.0; Armonk, NY, USA). Normally distributed data were expressed as ​​mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD)​​ (e.g., age: 30.0\u0026thinsp;\u0026plusmn;\u0026thinsp;9.8 years), while skewed distributions were presented as ​​median (interquartile range, IQR)​​. Categorical variables were described using ​​absolute frequencies and percentages​​ (e.g., 7/13 female patients, 53.8%). Paired t-tests were applied to normally distributed parameters when comparing baseline versus final measurements.\u003c/p\u003e \u003cp\u003eMissing data at the variable level were minimal due to the exclusion of incomplete demographic or imaging data. No imputation was performed for any missing outcomes.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eDemographic and disease characteristics\u003c/h2\u003e \u003cp\u003eOf all 13 patients included (7 females and 6 males), the mean age was 30.0\u0026thinsp;\u0026plusmn;\u0026thinsp;9.8 years (range: 13\u0026ndash;47 years) and average disease duration was 55.77\u0026thinsp;\u0026plusmn;\u0026thinsp;74.86 months (range: 2\u0026ndash;252 months). Among the patients, 4 (30.77%) were diagnosed with non-segmental vitiligo, 4 (30.77%) with segmental vitiligo, and 5 (38.46%) with undefined vitiligo. Twenty vitiliginous patches with leukotrichia were observed in these 13 patients, 15 patches (75%) were located on the scalp, 3 patches (15%) on the eyebrow, and 2 patches (10%) on the legs (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Family history of vitiligo and thyroid disorders were reported in 1 (7.69%) and 3 (23.07%) patients, respectively.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic and disease characteristics of vitiligo patients with leukotrichia (N\u0026thinsp;=\u0026thinsp;13)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAge(years)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eType of vitiligo\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eVIDA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eDisease duration\u003c/p\u003e \u003cp\u003e(month)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003elocation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eHair type\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eComorbid Autoimmune Diseases\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eConcomitant Treatments\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eUD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e252\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eScalp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLong\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e2\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eUD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eScalp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLong\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eSubacute thyroiditis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eOral Total Glucosides of White Paeony Capsules, Compound Betamethasone (IM)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e3\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNSV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eScalp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLong\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eHashimoto\u0026rsquo;s thyroiditis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eCompound Betamethasone (IM), Oral Total Glucosides of White Paeony Capsules, Oral Extract of Ginkgo Biloba Leaves Injection\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e4\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNSV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eScalp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLong\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eOral Compound Glycyrrhizin Tablets\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e5\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eUD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eEyebrow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLong\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003ePrednisone15mg Oral, Oral Extract of Ginkgo Biloba Leaves Injection, Tacrolimus Ointment\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e6\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eEyebrow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLong\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eTacrolimus Ointment, Travoprost​​ Eye Drops\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e7\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eEyebrow\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLong\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eMethylprednisolone 16mg QD (Oral), Mometasone Furoate Cream, Tacrolimus Ointment\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e8\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eUD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eScalp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eVellus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eUVB\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e9\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNSV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eScalp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLong\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003ePrednisone15mg Oral\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e10\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNSV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e168\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLeg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLong\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eHyperthyroidism\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003ePrednisone 15mg Oral, Halometasone Cream\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e11\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eScalp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLong\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eCompound Betamethasone (IM), Pimecrolimus Cream\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e12\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eUD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eScalp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLong\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eCompound Betamethasone (IM)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e13\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eScalp\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLong\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eCompound Betamethasone (IM)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003eM: Male, F: Female, SV: segmental vitiligo, NSV: non-segmental vitiligo, UD: Undetermined Type of Vitiligo, VIDA: Vitiligo Disease Activity score, IM: intramuscula\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eTherapeutic Effect Evaluation\u003c/h3\u003e\n\u003cp\u003eThe results of GPA-scale were provided in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. All 13 patients included in the study underwent at least three laser treatment sessions, with the number of sessions ranging from 3 to 8 over a period of 6 to 38 weeks. Only one patient (1/13, 7.69%, patient 2, on scalp) achieved G4 repigmentation of leukotrichia (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). The rest of the patients (12/13, 92.31%) showed no improvement nor deterioration of leukotrichia. Evaluation of basal vitiliginous patches demonstrated G4 repigmentation (75\u0026ndash;99%) in 1 patient (patient 2, on scalp) and G1 repigmentation (1\u0026ndash;25%) in 2 patients (patient 3 and patient 6, on scalp and eyebrow respectively), yielding an overall responder rate of 23.08% (3/13) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). Macroscopic imaging and dermoscopic photographs from selected patients were shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eDermoscopic Analysis Before and After Treatment\u003c/h3\u003e\n\u003cp\u003eDermoscopic analysis before and after treatment is summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.​ Quantitative dermoscopic analysis using Fotofinder Trichoscale Pro revealed no statistically significant changes in hair characteristics after the treatment. The mean black hair count remained stable, with pretreatment values of 67\u0026thinsp;\u0026plusmn;\u0026thinsp;45.52/cm\u0026sup2; versus posttreatment values of 66\u0026thinsp;\u0026plusmn;\u0026thinsp;44.52/cm\u0026sup2; (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.225). White hair density was also similar, from 87\u0026thinsp;\u0026plusmn;\u0026thinsp;56.56/cm\u0026sup2; to 86\u0026thinsp;\u0026plusmn;\u0026thinsp;66.69/cm\u0026sup2; (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.545). Total hair count (154.67\u0026thinsp;\u0026plusmn;\u0026thinsp;22.74/cm\u0026sup2; vs. 148.67\u0026thinsp;\u0026plusmn;\u0026thinsp;34.85/cm\u0026sup2;, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.494), thick hair count (51\u0026thinsp;\u0026plusmn;\u0026thinsp;37.58/cm\u0026sup2; vs. 51\u0026thinsp;\u0026plusmn;\u0026thinsp;42.93/cm\u0026sup2;, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.000), and vellus hair count (29\u0026thinsp;\u0026plusmn;\u0026thinsp;19.00/cm\u0026sup2; vs. 17.67\u0026thinsp;\u0026plusmn;\u0026thinsp;3.05/cm\u0026sup2;, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.441) exhibited no significant alterations. Follicular density decreased numerically from 70.1\u0026thinsp;\u0026plusmn;\u0026thinsp;16.6/cm\u0026sup2; to 62\u0026thinsp;\u0026plusmn;\u0026thinsp;23.08/cm\u0026sup2; (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.303). Notably, hair shaft thickness demonstrated a marginal increase from 51.3\u0026thinsp;\u0026plusmn;\u0026thinsp;18.9 \u0026micro;m to 57.7\u0026thinsp;\u0026plusmn;\u0026thinsp;19.8 \u0026micro;m (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.049).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDermoscopic Analysis Before and After Treatment\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHair type\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBefore Treatment\u003c/p\u003e \u003cp\u003e(mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAfter Treatment\u003c/p\u003e \u003cp\u003e(mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value*\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTotal hair\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e154.67\u0026thinsp;\u0026plusmn;\u0026thinsp;22.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e148.67\u0026thinsp;\u0026plusmn;\u0026thinsp;34.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.494\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBlack hair\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e67\u0026thinsp;\u0026plusmn;\u0026thinsp;45.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e66\u0026thinsp;\u0026plusmn;\u0026thinsp;44.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.225\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eWhite hair\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e87\u0026thinsp;\u0026plusmn;\u0026thinsp;56.56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e86\u0026thinsp;\u0026plusmn;\u0026thinsp;66.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.545\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eThick hair\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e51\u0026thinsp;\u0026plusmn;\u0026thinsp;37.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e51\u0026thinsp;\u0026plusmn;\u0026thinsp;42.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eVellus hair\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e29\u0026thinsp;\u0026plusmn;\u0026thinsp;19.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e17.67\u0026thinsp;\u0026plusmn;\u0026thinsp;3.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.441\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eThickness of hair shaft (\u0026micro;m)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e51.3\u0026thinsp;\u0026plusmn;\u0026thinsp;18.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e57.7\u0026thinsp;\u0026plusmn;\u0026thinsp;19.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.049\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e*P value was calculated using t-test\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eSafety Evaluation\u003c/h3\u003e\n\u003cp\u003eThe main adverse events included transient erythema (reported in 4/13 within 7 days, 5/13 between 7 and 14 days, and 1/13 lasting longer than 14 days), pain (13/13, 100%, tolerable), folliculitis (1,7.69%), desquamation (2(15.38%) and transient hair shedding (13/13, 100%, recover in 2 weeks) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). These adverse events were all mild to moderate and most of them resolved spontaneously within 1\u0026ndash;2 weeks after onset without requiring further medical treatment.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAdverse event in treatment site\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdverse event, n (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;7 days\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7\u0026thinsp;~\u0026thinsp;14 days\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;14 days\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eErythema\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (30.77%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (38.47%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (7.69%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePain\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eItching\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (15.38%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTelangiectasia\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (7.69%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFolliculitis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (7.69%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (7.69%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDesquamation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (15.38%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (15.38%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTransient hair shedding\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe intervention demonstrated a favorable safety profile, with complete resolution of most adverse events achieved within 7\u0026ndash;14 days post-procedure. Notably, no case of cutaneous atrophy was observed among patients during the follow-up period.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eVAL is a therapeutically resistant variant of vitiligo, exhibiting significantly higher prevalence in segmental vitiligo (SV: 77.4%) compared to nonsegmental subtypes (NSV: 39.1%; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Immunohistochemical studies confirm functionally impaired Melanocyte Stem Cells (McSCs) and active melanocytes within vitiliginous white hair by attenuated melanogenic markers (HMB-45\u0026darr;, tyrosinase\u0026darr;) and abrogated SCF/c-Kit paracrine signaling [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The depletion of McSCs creates a significant therapeutic challenge, as the repigmentation of VAL and vitiliginous patches depends on the activation and migration of residual McSCs to depigmented hair shafts and epidermal basement membrane [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCurrent treatments available for vitiligo include steroids, tacrolimus, cyclosporine, phototherapy, and surgical transplantation, as well the emerging treatments of Janus kinase (JAK) inhibitors, afamelanotide, phosphodiesterase 4 inhibitors, basic fibroblast growth factor, tumor necrosis factor (TNF) inhibitors, and pseudocatalase [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Currently, no universally effective therapeutic modality exists for vitiligo. Those cases with VAL demonstrate even poorer response to existing treatments.\u003c/p\u003e \u003cp\u003ePrevious studies have confirmed that leukotrichia serves as a critical negative prognostic factor for both UV phototherapy and tacrolimus outcomes [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Fractional laser (non-ablative or ablative CO₂ laser) combined with drug delivery has demonstrated effectiveness in the treatment of vitiliginous patches, AA, and AGA [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]; however, its application VAL cases has not been reported. Fractional photothermolysis generates controlled arrays of MTZs, each comprising vertically aligned thermal columns (depth: 200\u0026ndash;1200 \u0026micro;m) that induce confined dermal coagulation. Re-epithelialization typically commences within 24 hours post-laser intervention, driven by accelerated keratinocyte migration from adjacent unaffected epidermis toward MTZs. Subsequent dermal remodeling usually persists for longer than 90 days, characterized by progressive collagen III/I ratio normalization and elastin reorganization. This reparative cascade also enhances the production of growth factor (e.g., fibroblast growth factor, epidermal growth factor, insulin growth factor, and hepatocyte growth factor, VEGF)-which stimulate dermal papilla cell proliferation and activate hair follicle stem cell [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Another study demonstrated that fractional CO₂ laser significantly enhances melanocyte viability, melanin synthesis, and tyrosinase activity in human melanocytes (\u003cem\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/em\u003e)[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In mouse model, fractional CO₂ laser-treated lesions showed increased perifollicular melanin deposition, indicating potential activation of follicular McSCs[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Fractional laser treatment (18 mJ/spot, 361 spots/cm\u0026sup2;) has been shown to induce hair follicular telogen-to-anagen conversion by triggering transient inflammatory responses and subsequent regenerative processes. These events culminate in progressive hair regrowth from day 5 onward, as demonstrated by histopathological, molecular, and immunohistochemical analyses [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFractional laser combined with topical corticosteroids or other medications, aiming to promote the delivery of medications, has achieved excellent effectiveness in the cure of both vitiligo white patches and other hair diseases. Ablative laser therapy could help with the effective delivery and uniform distribution of topical agents to the dermis and the hair site. A histological study of AGA patients treated with fractional Erbium:YAG 2940nm laser demonstrated progressive microchannel closure within 24 hours and complete epidermal re-epithelialization by 48 hours post-procedure, offering the first human scalp evidence on transient channel patency critical for laser-assisted drug delivery (LADD) effectiveness [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Guo\u0026rsquo;s research indicates fractional CO₂ laser induces transient suppression of epidermal tight junction proteins (claudins, occludins) for \u0026le;\u0026thinsp;7 days post-treatment, establishing a prolonged therapeutic window for enhanced LADD [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In a comparative trial involving 20 AA patients with multiple patches, fractional CO₂ laser therapy (3\u0026ndash;6 biweekly sessions) demonstrated better sustained hair regrowth rates and fewer adverse events compared to monthly intralesional corticosteroid injections (\u0026le;\u0026thinsp;3 sessions), suggesting its potential as a safer and more effective alternative therapy [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. In Halim DA et.al\u0026rsquo; randomized controlled trial of 30 AA patients, fractional CO₂ laser either alone or combined with betamethasone valerate cream demonstrated significantly improvement of SALT scores, terminal hair regrowth, and patient satisfaction compared to betamethasone monotherapy [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Further evidence of fractional CO₂ laser and LADD function in AGA, another hair related disease, demonstrated that fractional CO₂ laser combined with topical dutasteride yielded superior clinical improvement in both global photographic assessments and dermoscopic parameters compared to fractional CO₂ laser monotherapy. A randomized controlled trial of 48 stable non-segmental vitiligo patients revealed low-energy and low-density fractional CO₂ laser (60 mJ, 8% coverage) combined with NB-UVB and topical betamethasone achieved superior repigmentation effectiveness at 3 and 6 months compared to higher-density protocols with optimized tolerability. These evidences confirmed the micro-destruction and reconstruction process and that LADD facilitates hair growth and melanocyte activation.\u003c/p\u003e \u003cp\u003eNo prior study has investigated the effectiveness of fractional CO₂ laser combined with topical steroids for treating VAL. To address this gap, we conducted this retrospective study of 13 patients (20 VAL patches) to evaluate the effectiveness of this combined therapy in managing refractory phenotype. Despite the acceptable safety, the therapeutic outcomes were markedly limited with only 7.69% (1/13) patients achieving partial repigmentation (G4) in VAL and 23.08% patients showing some extent of recovering (G1-G4) basal vitiliginous patches. Notably, the only responsive case ( with both G4 repigmentation in VAL and basal vitiliginous patches) had a short disease duration (5 months), contrasting with the suboptimal majority (mean disease duration: 55.77 months) who exhibited nearly no improvement of VAL, even when combined with systemic therapies and the lower responder rate in basal vitiligo patches is much lower (23.08%) compared to previous study(92.73%​​) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Early intervention and optimized laser parameters targeting the hair bulge niche are warranted. This finding should be interpreted with caution due to the sample size but may inform future study designs.These two phenomena suggest possible depletion of follicular melanocyte stem cells and highlight the need for early intervention before irreversible McSCs reservoir depletion. Previous transcriptomic and histological studies have demonstrated that stable vitiligo lesions are typically characterized by sparse inflammatory infiltrates and low immune activation status, especially in fully depigmented areas [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Since compound betamethasone exerts its effect mainly via anti-inflammatory and immunosuppressive mechanisms, the limited effectiveness observed in long-standing vitiligo-associated leukotrichia in this study may partially reflect the lack of ongoing immune activity in stable disease. Accordingly, alternative approaches aimed at directly stimulating melanocyte regeneration may prove more effective in such refractory cases. For instance, the use of laser-assisted delivery of agents that promote melanocyte differentiation\u0026mdash;such as WNT pathway agonists\u0026mdash;deserves further investigation. The limited effectiveness observed may also be related to suboptimal laser parameters. The determination of the necessary depth and density in hair region, and maximizing therapeutic benefits while ensuring safety with CO₂ fractional lasers, remains a significant challenge. The variable settings used in our study, deep mode (15-22.5mJ/cm\u0026sup2;, 10% in density) with a penetration depth of 550\u0026ndash;700\u0026micro;m in the reticular dermis, and the superficial mode (15-22.5mJ/cm\u0026sup2;, 40% in density) with a penetration depth of 40\u0026ndash;50\u0026micro;m into epidermal layer, might have contributed to insufficient melanocyte activation in the hair bulge. In future attempts, higher parameters of energy and density levels and more frequent laser session can be conducted, but caution should be exercised to avoid permanent damage to the hair follicle bulge caused by CO₂ ablative lasers. The alternative utility of fractional Er:YAG laser (2,940 nm) still warrants critical evaluation, as its exceptionally high water-absorption fundamentally restricts penetration to hair bulge deep. The limited effectiveness of fractional CO₂ laser with topical long-lasting steroids likely reflects the irreversible depletion or dysfunction of the follicular melanocyte reservoir, where even aggressive physical enhancement methods fail to reactivate melanogenesis. Surgical interventions, especially follicular unit extraction (FUE) transplantation, emerge as a promising definitive intervention for stable VAL patients.\u003c/p\u003e\n\u003ch3\u003eLimitations\u003c/h3\u003e\n\u003cp\u003eThis study has several limitations to acknowledge. First, the retrospective design, small-sample size, and lack of a control group substantially limit the reliability of our conclusions and preclude definitive causal inferences regarding the effectiveness of the combined therapy. The limited sample size (N\u0026thinsp;=\u0026thinsp;13) was a result of halted enrollment due to limited effectiveness without pre-specified power calculation. This resulted in insufficient statistical power and a heightened risk of Type II error. Second, the interpretation of treatment effects is confounded by the heterogeneous concomitant therapies (e.g., systemic corticosteroids, immunomodulators, phototherapy) received by some patients, an inherent challenge in real-world studies of refractory conditions. Third, our study is potentially subject to selection bias. The requirement for a minimum of three treatment sessions excluded patients who discontinued therapy early, potentially due to inefficacy or adverse events, which may skew our results toward a more favorable outcome. Furthermore, the cohort also likely represents a highly motivated subgroup with refractory disease, limiting generalizability. Fourth, although the evaluation was blinded to the timepoint sequence of photographs, the lack of blinding to the treatment may have introduced measurement bias in the repigmentation grading. Finally, the heterogeneity in VAL subtypes and disease duration limited our ability to perform meaningful stratified analyses. The finding that the only responder had a short disease duration should be interpreted as hypothesis-generating rather than conclusive.\u003c/p\u003e \u003cp\u003eIn conclusion, in this retrospective small-sample study, CO₂ fractional laser combined with topical betamethasone demonstrated an extremely low repigmentation rate for VAL, with acceptable safety. The insufficient effectiveness may be related to depletion of follicular melanocyte stem cell reserves and inadequate parameters/frequency, requiring validation through prospective controlled studies. Given the small sample size, formal subgroup analysis was not feasible. However, we descriptively summarized outcomes by VAL subtype and disease duration. The only patient achieving G4 repigmentation (Patient 2) had non-segmental vitiligo and a short disease duration (5 months). Among the other patients with disease duration\u0026thinsp;\u0026le;\u0026thinsp;12 months (n\u0026thinsp;=\u0026thinsp;5), none achieved repigmentation in VAL. No clear pattern emerged across subtypes (segmental, non-segmental or undetermined), though the limited number precludes definitive conclusions.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eThe author(s) report no conflicts of interest in this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Approval was granted by the Ethics Committee of Peking University People\u0026rsquo;s Hospital (No. 2024PHB598-001).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent to participate in the study was obtained from all individual participants included in the study. For minor participants, consent was obtained from their legal guardians.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. The manuscript does not contain any personal data or identifiable images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was funded by the National Natural Science Foundation of China (NSFC No. 82173403).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJuan Du, Fang Wang, and Xiaolan Ding were involved in the study conception and design. Xuhai Yuan, Xinxin Li, Hanlin Li, and Fang Wang performed data collection and analysis. The initial draft of the manuscript was written by Xuhai Yuan and Yijie Sun. Critical revision and editing of the manuscript for important intellectual content were carried out by Fang Wang, and Juan Du. All authors read and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available on request from the corresponding author.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBibeau K, et al. (2022) \u003cem\u003eVitiligo prevalence and quality of life among adults in Europe, Japan and the USA. \u003c/em\u003eJ Eur Acad Dermatol Venereol 36:1831-1844. https://doi.org/10.1111/jdv.18257\u003c/li\u003e\n\u003cli\u003eEzzedine K, et al. (2021) \u003cem\u003ePsychosocial Effects of Vitiligo: A Systematic Literature Review. \u003c/em\u003eAm J Clin Dermatol 22:757-774. https://doi.org/10.1007/s40257-021-00631-6\u003c/li\u003e\n\u003cli\u003eLi M. B\u0026aacute;idi\u0026agrave;n Fēng B\u0026aacute;if\u0026agrave; de L\u0026iacute;nchu\u0026aacute;ng H\u0026eacute; M\u0026aacute;of\u0026agrave; J\u0026igrave;ng T\u0026egrave;zhēng, Chāowēi Ji\u0026eacute;g\u0026ograve;u Guānch\u0026aacute; j\u0026iacute; Zh\u0026igrave;li\u0026aacute;o Fāngfǎ T\u0026agrave;nsuǒ [Clinical and Trichoscopic Characteristics, Ultrastructural Observation, and Treatment Exploration of Vitiligo-Associated Leukotrichia]. Dissertation, Peking University; 2021\u003c/li\u003e\n\u003cli\u003eLi M, et al. (2023) \u003cem\u003eA Prospective Study of Dermoscopic and Ultrastructural Features of Vitiligo-Associated Leukotrichia. \u003c/em\u003eClin Cosmet Investig Dermatol 16:3673-3680. https://doi.org/10.2147/CCID.S435900\u003c/li\u003e\n\u003cli\u003eZhang J, et al. 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(2024) \u003cem\u003eThe role of laser and energy-assisted drug delivery in the treatment of alopecia. \u003c/em\u003eLasers Med Sci 39:73. https://doi.org/10.1007/s10103-024-04015-0\u003c/li\u003e\n\u003cli\u003eWenande E, Anderson RR, Haedersdal M (2020) \u003cem\u003eFundamentals of fractional laser-assisted drug delivery: An in-depth guide to experimental methodology and data interpretation. \u003c/em\u003eAdv Drug Deliv Rev 153:169-184. https://doi.org/10.1016/j.addr.2019.10.003\u003c/li\u003e\n\u003cli\u003eShen Y, et al. (2023) \u003cem\u003eEffect of fractional laser alone or in combination on alopecia areata: A systematic review and meta-analysis. \u003c/em\u003eJ Cosmet Dermatol 22:1528-1535. https://doi.org/10.1111/jocd.15630\u003c/li\u003e\n\u003cli\u003eHanthavichai S, Archavarungson N, Wongsuk T (2022) \u003cem\u003eA study to assess the efficacy of fractional carbon dioxide laser with topical platelet-rich plasma in the treatment of androgenetic alopecia. \u003c/em\u003eLasers Med Sci 37:2279-2286. https://doi.org/10.1007/s10103-021-03496-7\u003c/li\u003e\n\u003cli\u003eMansouri P, et al. (2023) \u003cem\u003eExploring the Efficacy of Fractional Carbon Dioxide Laser as an Add-on Combination to Conventional Therapies for Treatment-Resistant Vitiligo (A Review Article). \u003c/em\u003eJ Lasers Med Sci 14:e51. https://doi.org/10.34172/jlms.2023.51\u003c/li\u003e\n\u003cli\u003eZhang L, et al. (2024) \u003cem\u003eClinical efficacy of CO2 fractional laser combined with compound betamethasone in treating vitiligo and its impact on inflammatory factors. \u003c/em\u003eFront Med (Lausanne) 11:1408409. https://doi.org/10.3389/fmed.2024.1408409\u003c/li\u003e\n\u003cli\u003eRenert-Yuval Y, et al. (2024) \u003cem\u003eA Review of the Vitiligo Literature to Standardize Expression of Disease Severity. \u003c/em\u003eJ Drugs Dermatol 23:842-846. https://doi.org/10.36849/JDD.2024.8049\u003c/li\u003e\n\u003cli\u003eKim MS, et al. (2016) \u003cem\u003eEffect of excimer laser treatment on vitiliginous areas with leukotrichia after confirmation by dermoscopy. \u003c/em\u003eInt J Dermatol 55:886-892. https://doi.org/10.1111/ijd.12972\u003c/li\u003e\n\u003cli\u003eSeleit I, et al. (2015) \u003cem\u003eImmunohistochemical evaluation of vitiliginous hair follicle melanocyte reservoir: is it retained? \u003c/em\u003eJ Eur Acad Dermatol Venereol 29:444-451. https://doi.org/10.1111/jdv.12573\u003c/li\u003e\n\u003cli\u003eSong HJ, Choi GS, Shin JH (2011) \u003cem\u003ePreservation of melanoblasts of white hair follicles of segmental vitiligo lesions: A preliminary study. \u003c/em\u003eJ Eur Acad Dermatol Venereol 25:240-242. https://doi.org/10.1111/j.1468-3083.2010.03710.x\u003c/li\u003e\n\u003cli\u003eZhou Y, et al. (2024) \u003cem\u003ePathogenesis and regenerative therapy in vitiligo and alopecia areata: focus on hair follicle. \u003c/em\u003eFront Med (Lausanne) 11:1510363. https://doi.org/10.3389/fmed.2024.1510363\u003c/li\u003e\n\u003cli\u003ePerez-Bootello J, et al. (2023) \u003cem\u003eVitiligo: Pathogenesis and New and Emerging Treatments. \u003c/em\u003eInt J Mol Sci 24:17306. https://doi.org/10.3390/ijms242417306\u003c/li\u003e\n\u003cli\u003eHalim DA, et al. (2023) \u003cem\u003eEvaluation of fractional carbon dioxide laser alone versus its combination with betamethasone valerate in treatment of alopecia areata, a clinical and dermoscopic study. \u003c/em\u003eArch Dermatol Res 315:505-511. https://doi.org/10.1007/s00403-022-02393-5\u003c/li\u003e\n\u003cli\u003eTang H, et al. (2024) \u003cem\u003eThe Effect of Fractional Carbon Dioxide Laser on Melanogenesis in Human Melanocytes and Vitiligo Mouse Models. \u003c/em\u003eClin Cosmet Investig Dermatol 17:1729-1737. https://doi.org/10.2147/CCID.S445131\u003c/li\u003e\n\u003cli\u003eZhuo F-L, et al. (2019) \u003cem\u003eEffects of CO2 fractional laser on hair growth in C57BL/6 mice and potential underlying mechanisms. \u003c/em\u003eChin Med J (Engl) 132:1257-1260. https://doi.org/10.1097/CM9.0000000000000220\u003c/li\u003e\n\u003cli\u003ePidal C, et al. (2021) \u003cem\u003eFractional-assisted drug delivery performed with erbium yag laser in androgenic alopecia: Histological aspects. \u003c/em\u003eDermatol Ther 34:e14730. https://doi.org/10.1111/dth.14730\u003c/li\u003e\n\u003cli\u003eGuo H, et al. (2023) \u003cem\u003eDynamic panoramic presentation of skin function after fractional CO2 laser treatment. \u003c/em\u003eiScience 26:107559. https://doi.org/10.1016/j.isci.2023.107559\u003c/li\u003e\n\u003cli\u003eEl-Husseiny R, Elframawy S, Abdallah M (2020) \u003cem\u003eComparative study between fractional carbon dioxide laser vs intralesional steroid injection in treatment of alopecia areata. \u003c/em\u003eDermatol Ther 33:e13742. https://doi.org/10.1111/dth.13742\u003c/li\u003e\n\u003cli\u003eRegazzetti C, et al. (2015) \u003cem\u003eTranscriptional Analysis of Vitiligo Skin Reveals the Alteration of WNT Pathway: A Promising Target for Repigmenting Vitiligo Patients. \u003c/em\u003eJ Invest Dermatol 135:3105-3114. https://doi.org/10.1038/jid.2015.335\u003c/li\u003e\n\u003cli\u003eShiu J, et al. (2022) \u003cem\u003eMultimodal analyses of vitiligo skin identify tissue characteristics of stable disease. \u003c/em\u003eJCI Insight 7:e154585. https://doi.org/10.1172/jci.insight.154585\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"lasers-in-medical-science","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"lims","sideBox":"Learn more about [Lasers in Medical Science](https://link.springer.com/journal/10103)","snPcode":"10103","submissionUrl":"https://submission.springernature.com/new-submission/10103/3","title":"Lasers in Medical Science","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Vitiligo, leukotrichia, fractional CO₂ laser, betamethasone, laser-assisted drug delivery, hair depigmentation","lastPublishedDoi":"10.21203/rs.3.rs-8632638/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8632638/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose: \u003c/strong\u003eTo evaluate the effectiveness and safety of fractional CO₂ laser combined with topical compound betamethasone for treating vitiligo-associated leukotrichia (VAL).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eA total of 13 patients with VAL (a total of 20 lesions) were enrolled; patients who were in rapid-progressing phase (VIDA=4) were excluded. Patients received fractional CO₂ laser following immediate topical application of compound betamethasone every 4 weeks. All patients underwent a minimum of 3 laser treatment sessions, with the number of sessions ranging from 3 to 8 per patient. Treatment outcomes were assessed using global photograph assessment (GPA)-scale, standardized repigmentation grading (G0–G5), and dermoscopic evaluations of hair density and type. Adverse events were also assessed during the 4 weeks post each session.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eOnly 1 patient (7.7%) achieved significant hair repigmentation (grade G4), while 2 others showed mild repigmentation in the vitiligo patches (grade G1). No significant changes in hair counts or densities were observed on dermoscopy after treatment (all p \u0026gt; 0.2). Transient erythema and pain occurred in all patients, and mild desquamation in 15%, all resolving within 2 weeks. No cases of skin atrophy were noted.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eIn this small cohort, fractional CO₂ laser plus topical betamethasone produced minimal hair repigmentation in VAL but was well tolerated. The poor effectiveness may reflect depletion of follicular melanocyte reserves or suboptimal treatment parameters; further controlled studies are needed.\u003c/p\u003e","manuscriptTitle":"Fractional CO₂ laser combined with topical compound betamethasone for Vitiligo-Associated Leukotrichia: a retrospective study of 13 patients with limited effectiveness","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-22 12:57:17","doi":"10.21203/rs.3.rs-8632638/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-03-11T20:05:05+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"123563004932363898438785565334706527222","date":"2026-02-17T23:00:00+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-17T15:28:09+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-17T03:30:13+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-29T13:11:06+00:00","index":"","fulltext":""},{"type":"submitted","content":"Lasers in Medical Science","date":"2026-01-18T16:32:57+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"lasers-in-medical-science","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"lims","sideBox":"Learn more about [Lasers in Medical Science](https://link.springer.com/journal/10103)","snPcode":"10103","submissionUrl":"https://submission.springernature.com/new-submission/10103/3","title":"Lasers in Medical Science","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"7d01699f-fd70-425e-9956-01ee981b2d0f","owner":[],"postedDate":"February 22nd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-02-22T12:57:17+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-22 12:57:17","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8632638","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8632638","identity":"rs-8632638","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}