张倩 张金娥 郭森 宋璞 高琳 李春英
空军军医大学西京皮肤医院，西安 710032
通讯作者: 李春英 E-mail : l ichying@fmmu.edu.cn
【摘要】 目的 探讨CO2点阵激光联合氟尿嘧啶或联合复方倍他米松注射液导入治疗白癜风的临床疗效。方法 回顾性分析2018年10月至2023年5月在空军军医大学西京皮肤医院美容中心采用CO2点阵激光辅助药物传输治疗的94例局限性、非节段型、稳定期白癜风患者的临床资料，其中CO2点阵激光联合氟尿嘧啶导入组40例，CO2点阵激光联合复方倍他米松注射液导入组54例。每月治疗1次共5次。采用4级评估法比较两组的临床疗效，同时分析其安全性。组间比较采用卡方检验、Fisher确切概率法和t检验。结果 CO2点阵激光联合氟尿嘧啶导入组中，男22例，女18例，年龄（21.95 ± 12.88）岁，病程（25.46 ± 11.42）个月；CO2点阵激光联合复方倍他米松注射液导入组中，男36例，女18例，年龄（22.26 ± 8.79）岁，病程（26.51 ± 12.81）个月。第1次治疗后1个月，两组间疗效差异无统计学意义（χ2 = 1.39，P = 0.238）。第5次治疗后1个月，CO2点阵激光联合氟尿嘧啶导入组2例（5.0%）治疗反应优秀，4例（10.0%）反应良好，12例（30.0%）反应一般，22例（55.0%）反应不佳；CO2点阵激光联合复方倍他米松注射液导入组中，8例（14.8%）反应良好，8例（14.8%）反应一般，38例（70.4%）反应不佳；5次治疗后两组间疗效差异无统计学意义（χ2 = 2.35，P = 0.125）。第1次及第5次治疗后两种治疗方案在面颈部、躯干四肢及手足各部位的疗效差异均无统计学意义（均P > 0.05）。比较同一种治疗方案在不同发病部位的疗效显示，第1次治疗后CO2点阵激光联合氟尿嘧啶治疗面颈部皮损的疗效优于手足部位（P = 0.039）；5次治疗后，两种治疗方案对面部皮损的疗效均优于手足部皮损，差异有统计学意义（P = 0.005、0.049）。两组间不良反应如色素沉着、感染及瘢痕等发生情况未见明显差异。结论 CO2点阵激光联合氟尿嘧啶和联合复方倍他米松注射液治疗白癜风有相似的疗效与安全性，均可作为白癜风的治疗选择方法之一。
关键词:白癜风, 激光疗法, 氟尿嘧啶, 治疗结果, CO2点阵激光, 复方倍他米松注射液
基金项目:国家自然科学基金数学天元基金——琶洲实验室（黄埔）“数学与医疗健康交叉重点专项”（PZLABHP-02-2023K0605）；国家自然科学基金（12126606）
DOI:10.35541/cjd.20230412
Comparison of the efficacy of fractional CO2 laser combined with topical delivery offluorouracil versus compound betamethasone injections in the treatment of vitiligo: a clinical observation
Zhang Qian, Zhang Jin′e, Guo Sen, Song Pu, Gao Lin, Li Chunying
Department of Dermatology, Xijing Hospital, Air Force Medical University, Xi′an 710032, China
Corresponding author li Chunying ,Email l ichying@fmmu.edu.cn
【Abstract】 Objective To compare the efficacy of fractional CO2 laser combined with topical delivery of fluorouracil versus compound betamethasone injections in the treatment of vitiligo. Methods Clinical data were collected from 94 patients with localized, non-segmental, and stable vitiligo, who received fractional CO2 laser combined with drug delivery at the Cosmetological Center, Xijing Hospital, Air Force Medical University from October 2018 to May 2023, and were retrospectively analyzed. Among them, there were 40 cases in the fractional CO2 laser combined with fluorouracil injection group, and 54 cases in the fractional CO2 laser combined with compound betamethasone injection group. All the patients received the above treatment once a month for 5 sessions. A 4-level grading scale was used to evaluate the pigmentation improvement, and the clinical efficacy and safety of the two therapeutic regimens were compared. Comparisons between groups were performed using chi-square test, Fisher′s exact test, and t test. Results In the fractional CO2 laser combined with fluorouracil injection group, there were 22 males and 18 females, their ages were 21.95 ± 12.88 years, and the disease duration was 25.46 ± 11.42 months; in the fractional CO2 laser combined with compound betamethasone injection group, there were 36 males and 18 females, their ages were 22.26 ± 8.79 years, and the disease duration was 26.51 ± 12.81 months. One month after the first treatment, no significant difference was observed in the efficacy between the two groups （χ2 = 1.39, P = 0.238）. One month after the fifth treatment, 2 （5.0%） patients showed an excellent response, 4 （10.0%） showed a good response, 12 （30.0%） showed a mild response, and 22 （55.0%） showed a poor response in the fractional CO2 laser combined with fluorouracil injection group; in the fractional CO2 laser combined with compound betamethasone injection group, 8 （14.8%） patients showed a good response, 8 （14.8%） showed a mild response, and 38 （70.4%） showed a poor response; there was no significant difference in the efficacy between the two groups after 5 sessions of treatment （χ2 = 2.35, P = 0.125）. After either 1 or 5 sessions of treatment, there were no significant differences in the efficacy for lesions on the face and neck, trunk and limbs, hands and feet between the two therapeutic regimens （all P > 0.05）. Comparisons of the efficacy for skin lesions on different body sites showed that one session of the fractional CO2 laser combined with fluorouracil injection was more effective for the treatment of skin lesions on the face and neck compared with those on the hands and feet （P = 0.039）; after 5 sessions of treatment, the two therapeutic regimens both showed better efficacy for facial skin lesions compared with hand and foot skin lesions （P = 0.005, 0.049）. There was no significant difference in the occurrence of adverse reactions such as pigmentation, infection and scarring between the two groups. Conclusion The fractional CO2 laser combined with topical delivery of fluorouracil and compound betamethasone injections showed similar efficacy and safety in the treatment of vitiligo, and both can be used as treatment options for vitiligo.
Key words:Vitiligo, Laser therapy, Fluorouracil, Treatment outcome, Fractional CO2 laser, Compound betamethasone injection
Fund programs：National Natural Science Foundation of China, R&D Project of Pazhou Lab (Huangpu) under Grant （PZLABHP-02-2023K0605）; National Natural Science Foundation of China （12126606）
DOI:10.35541/cjd.20230412
白癜风是一种常见的由表皮黑色素细胞破坏导致的色素脱失性疾病,局部外用糖皮质激素和/或钙调磷酸酶抑制剂、抗氧化剂、小剂量口服糖皮质激素、光疗、手术和脱色治疗等均有一定疗效。与单一治疗相比,联合治疗方式往往会提高整体疗效,然而仍有10%~30%的白癜风患者对治疗无反应。剥脱性点阵激光作为透皮药物传递中常用的一种方式,不仅可增强局部应用药物如曲安奈德、氟尿嘧啶和他克莫司的吸收和使用效率,也可避免或减少系统用药可能出现的不良反应。本课题组前期大样本多中心研究证实,CO2点阵激光联合复方倍他米松注射液导入可有效改善肢端型白癜风皮损,已被广泛应用于临床。近年,氟尿嘧啶也被证实可用于白癜风复色,局部应用或病灶内注射均可增加局部色素,其作用机制可能为促进炎症介质和基质金属蛋白酶的释放,从而刺激和促进黑色素细胞的增殖和迁移。本研究中我们回顾性评价和对比CO2点阵激光联合氟尿嘧啶与联合复方倍他米松注射液治疗局限性、非节段型、稳定期白癜风的疗效和安全性。
对象与方法
一、研究对象
回顾性分析2018年10月至2023年5月在西京皮肤医院美容中心采用CO,点阵激光辅助药物传输治疗的局限性、非节段型、稳定期白癜风患者的临床资料及治疗前后照片。本研究经西京皮肤医院医学伦理委员会批准(批号:KY20232017-F-1),治疗前所有患者均签署知情同意书。
纳入标准:①为局限性、非节段型、稳定期白癜风;②均完成5次C0:点阵激光联合药物导人治疗，每月1次,且相关临床资料及照片完整;③对常规治疗如局部应用糖皮质激素、钙调磷酸酶抑制剂及光疗等疗效欠佳(近3个月常规治疗后复色面积小于25%),且停用相关治疗超过1个月。排除标准:①有活动性感染、近期暴晒史者;②既往有瘢痕疙瘩或出血倾向者;③孕妇或哺乳期妇女。
二、治疗方法
术前所有患者均予外用复方利多卡因乳膏(2.5%利多卡因+2.5%丙胺卡因,北京紫光制药有限公司)封包1h。术中选择CO:点阵激光(美国科医人医疗激光公司)治疗,治疗模式为Deep,能量17.5 mJ/cm²,密度5%,随后分别给予氟尿嘧啶注射液(天津金辉药业有限公司,规格:0.25 g/10 ml)或复方倍他米松注射液(重庆华邦制药有限公司,规格1ml:2 mg倍他米松磷酸钠+5mg二丙酸倍他米松)封包2h。所有患者于治疗结束后冰敷30 min。
三、疗效与不良反应评价
在基线和每次治疗前均由同一专业人员拍摄患者皮损照片,以评估治疗反应。色素改善程度由2名研究者在设盲的基础上采用4个等级评估:反应不佳(改善0%~25%);反应一般(改善26%~50%);反应良好(改善51%-75%);反应优秀(改善 76%~100%),评价术后有无色素沉着、瘢痕等不良反应。
四、统计学分析
采用Graphpad 9.5软件分析数据,正态分布的计量资料采用x±s表示,计数资料采用频数(百分比)来描述,组间比较采用卡方检验、Fisher确切概率法和t检验,P<0.05认为差异有统计学意义。
结果
一、两组患者基线资料对比
共纳入94例局限性、非节段型稳定期白癜风患者,男58例,女36例,皮损位于面颈部者居多(44例,46.8%),病程13~58个月,5例有白癜风家族史。CO2点阵激光联合氟尿嘧啶治疗40例,CO2点阵激光联合复方倍他米松导入治疗54例,两组患者在性别分布、年龄、皮损部位、皮损面积、病程及家族史等基线特征差异均无统计学意义(均P>0.05),见表1。
二、两组患者疗效对比
第1次治疗后1个月,CO2点阵激光联合氟尿嘧啶组34例(85.0%)对治疗反应不佳,4例(10.0%)反应一般,2例(5.0%)反应良好(图1);CO2点阵激光联合复方倍他米松组50例(92.6%)反应不佳,4例(7.4%)反应一般,无反应良好或反应优秀者。两组间疗效差异无统计学意义(x=139,P>0.05),
第5次治疗后1个月,C0-点阵激光联合氟尿嘧啶组22例(55.0%)治疗反应不佳,12例(30.0%)反应一般.4例(10.0%)反应良好,2例(5.0%)反应优秀,皮损复色面积超过75%(图2);00-点阵激光联合复方倍他米松组38例(70.4%)治疗反应不佳，8 例(14.8%)反应一般,8例(14.8%)反应良好(图3),无反应优秀者。5次治疗后两组间疗效差异无统计学意义(x=2.35,P>0.05)。
三,不同发病部位疗效比较
比较同一种治疗方案在不同发病部位的疗效差异,第1次治疗后CO联合氟尿嘧啶治疗面颈部皮损疗效优于手足部位(P=0.039);5次治疗后,两种治疗方案对面部皮损的疗效均优于手足部皮损，差异有统计学意义(P=0.005、0.049),见表2。
Fisher 确切概率法分析显示,第1次及第5次治疗后两种治疗方案比较,在面颈部(P值分别为0.421和 0.060)、躯干四肢(P值分别为0.125和0.604)及手足各部位(P值分别为0.214和0.660)的疗效差异均无统计学意义。
四、不良反应评价
CO2点阵激光辅助药物传输治疗后常见红斑、肿胀、疼痛,多于24h内消退。CO2点阵激光联合氟尿嘧啶组6例(15.0%)出现色素沉着,CO2点阵激光联合复方倍他米松组4例(7.4%)出现色素沉着,两组间差异无统计学意义(x=0.71,P=0.400)。两组均未见术后感染或瘢痕形成。
讨论
近年,不同类型消融技术与常规治疗的联合应用逐渐受到关注,在难治性白癜风中取得良好疗效,如CO2点阵激光辅助复方倍他米松注射液导入并联合NB-UVB照射、Er:YAG激光辅助氟尿嘧啶导入并联合NB-UVB光疗、微针联合氟尿嘧啶导入、Er:YAG激光联合局部外用糖皮质激素及NB-UVB光疗,1565nm非剥脱点阵激光联合复方倍他米松注射液导人等。其中CO2点阵激光辅助复方倍他米松注射液导入并联NB-UVB因其损伤性及不良反应小、有效性优于单一CO2点阵激光治疗或非剥脱点阵激光联合治疗尤为受人关注,多项系统回顾及荟萃分析也证实,该联合治疗在白癜风尤其是肢端型白癜风治疗中有效性与安全性较高,其可能机制包括:①CO2点阵激光作用于皮肤产生直接的微热损伤区,所产生的多种炎症细胞可能会减弱细胞毒性CD8*T细胞对黑色素细胞的杀伤作用,并在损伤修复过程中产生多种细胞因子与生长因子,促进黑色素细胞从邻近的正常皮肤和毛囊迁移;②CO2点阵激光产生阵列排列的微孔道,利于药物以较高浓度向皮损深部渗透,使其直接作用于基底层黑色素细胞与真皮浅层炎症细胞,减少对黑色素细胞的破坏并促进其再生与迁移。
氟尿嘧啶已在许多研究中证实可促进白癜风色素减退斑的复色。既往研究报道,表皮磨削后局部外用氟尿嘧啶可使64%白癜风患者皮损完全或几乎完全复色。Mina等(3证实白癜风皮损内注射氟尿嘧啶的疗效明显优于局部外用0.03%他克莫司软膏。多项随机对照或开放性研究证实,消融治疗如CO.点阵激光、微晶磨削、Er:YAG激光等联合氟尿嘧啶的疗效优于单独外用氟尿嘧啶或皮损内注射氟尿嘧啶,且不良反应如烧灼感、水疱及色素沉着发生率较低。以上研究提示，氟尿嘧啶单独或联合治疗均对白癜风治疗有效。
本研究回顾性对比分析在相同治疗能量、治疗密度的CO2点阵激光作用下,两种不同辅助药物(复方倍他米松注射液与氟尿嘧啶)治疗白癜风的疗效与安全性。第1次治疗和5次治疗后两组间疗效差异均无统计学意义,提示CO2点阵激光联合氟尿嘧啶或复方倍他米松注射液均可用于治疗难治性白癜风。
白癜风不同发病部位对治疗反应不一。本研究结果显示,CO:点阵激光联合氟尿嘧啶与联合复方倍他米松注射液导入在白癜风相同发病部位的疗效未见明显差异;而同一治疗方案下探究不同皮损部位的疗效,我们发现两种方案治疗5次在面部皮损的疗效均优于手足部,该结果支持面颈部白癜风皮损经治疗后易于复色,而手足部皮损较为难治这一观点;且首次治疗后CO2联合氟尿喘啶组面颈部皮损也呈现更优疗效,可能倍他米松主要通过抗炎与免疫调节作用减少白癜风的免疫损伤,进而促进白癜风白斑复色,而氟尿嘧啶不仅可刺激角质形成细胞释放白三烯、基质金属蛋白酶2等炎症因子诱导黑色素细胞的增殖与迁移,还可通过免疫调节作用稳定白癜风的免疫状态。
此外,CO2点阵激光联合不同药物导人治疗白癜风术后可能出现一定程度的色素沉着,但两组间差异无统计学意义,且两组均未见术后感染、瘢痕形成等其他不良反应,表明这两种联合治疗安全性良好。
综上所述,本研究中我们尝试比较了CO2点阵激光联合氟尿嘧啶与联合复方倍他米松注射液导入治疗局限性、非节段型白癜风的疗效与安全性，结果显示,两种疗法疗效相似,均可用于对常规治疗效果不佳的白癜风患者,且安全性良好,为白癜风的临床治疗提供了新的选择方案。但本研究样本量小,缺乏长期随访以评估治疗反应的持久性，回顾性研究中存在选择偏倚和无法避免的混杂因素等。未来我们将进一步开展前瞻性、自身对照、大样本研究以深入探索CO2点阵激光联合不同药物治疗白癜风的疗效,为白癜风的治疗提供更多的临床证据。
利益冲突 所有作者均声明无利益冲突
作者贡献声明 张倩:文章撰写;张金娥:患者临床照片收集;郭森、宋璞:数据整理和统计学分析;高琳、李春英:研究指导、论文修改及经费支持
［1］中国中西医结合学会皮肤性病专业委员会色素病学组. 白癜风诊疗共识（2021版）［J］. 中华皮肤科杂志, 2021,54（2）:105⁃109. doi: 10.35541/cjd.20200785.
［2］Lei TC, Xu AE, Gao TW, et al. Consensus on the diagnosis and treatment of vitiligo in China （2021 revision）［J］. Int J Dermatol Venereol, 2021,4（1）:10⁃15. doi: 10.1097/JD9.0000000000000151.
［3］Qi SZ, Zeng XS, Hu SC. Efficacy and safety of 0.05% halometasone/1% triclosan cream versus 0.1% mometasone furoate cream in the treatment of truncal vitiligo: a retrospective study［J］. Int J Dermatol Venereol, 2021,4（4）:219⁃223. doi: 10.1097/JD9.0000000000000179.
［4］Speeckaert R, van Geel N. Vitiligo: an update on pathophysiology and treatment options［J］. Am J Clin Dermatol, 2017,18（6）:733⁃744. doi: 10.1007/s40257⁃017⁃0298⁃5.
［5］Kim HJ, Hong ES, Cho SH, et al. Fractional carbon dioxide laser as an "add⁃on" treatment for vitiligo: a meta⁃analysis with systematic review［J］. Acta Derm Venereol, 2018,98（2）:180⁃184. doi: 10.2340/00015555⁃2836.
［6］Liu L, Wu Y, Zhang J, et al. Ablative fractional CO2 laser aided delivery of long⁃acting glucocorticoid in the treatment of acral vitiligo: a multicenter, prospective, self⁃bilateral controlled study［J］. J Dermatolog Treat, 2019,30（4）:320⁃327. doi: 10.1080/09546634.2018.1509048.
［7］Searle T, Al⁃Niaimi F, Ali FR. 5⁃Fluorouracil in dermatology: the diverse uses beyond malignant and premalignant skin disease［J］. Dermatol Surg, 2021,47（3）:e66⁃e70. doi: 10.1097/DSS.00 00000000002879.
［8］Mohammadi S, Amiri R, Khalili M, et al. Treatment protocols and efficacy of combined laser with medical treatment modalities in vitiligo［J］. J Cosmet Dermatol, 2022,21（8）:3272⁃3291. doi: 10.1111/jocd.14602.
［9］Anbar TS, Westerhof W, Abdel⁃Rahman AT, et al. Effect of one session of ER:YAG laser ablation plus topical 5⁃fluorouracil on the outcome of short⁃term NB⁃UVB phototherapy in the treatment of non⁃segmental vitiligo: a left⁃right comparative study［J］. Photodermatol Photoimmunol Photomed, 2008,24（6）:322⁃329. doi: 10.1111/j.1600⁃0781.2008.00385.x.
［10］Chhabra S, Chahar YS, Singh A. A comparative study of microneedling combined with topical 5⁃fluorouracil versus microneedling alone in treatment of localized stable vitiligo［J］. Indian J Dermatol, 2021,66（5）:574. doi: 10.4103/ijd.ijd_130_21.
［11］Yan R, Yuan J, Chen H, et al. Fractional Er:YAG laser assisting topical betamethasone solution in combination with NB⁃UVB for resistant non⁃segmental vitiligo［J］. Lasers Med Sci, 2017,32（7）:1571⁃1577. doi: 10.1007/s10103⁃017⁃2282⁃y.
［12］Doghaim NN, El⁃Tatawy RA, Ismail MA, et al. Study the effect of erbium:YAG laser plus topical 5⁃flurouracil in stable vitiligo resistant to NB⁃UVB phototherapy［J］. J Cosmet Dermatol, 2020,19（1）:122⁃130. doi: 10.1111/jocd.13134.
［13］Chiu YJ, Perng CK, Ma H. Fractional CO2 laser contributes to the treatment of non⁃segmental vitiligo as an adjunct therapy: a systemic review and meta⁃analysis［J］. Lasers Med Sci, 2018,33（7）:1549⁃1556. doi: 10.1007/s10103⁃018⁃2516⁃7.
［14］Tsuji T, Hamada T. Topically administered fluorouracil in vitiligo［J］. Arch Dermatol, 1983,119（9）:722⁃727.
［15］Mina M, Elgarhy L, Al⁃Saeid H, et al. Comparison between the efficacy of microneedling combined with 5⁃fluorouracil vs microneedling with tacrolimus in the treatment of vitiligo［J］. J Cosmet Dermatol, 2018,17（5）:744⁃751. doi: 10.1111/jocd.12440.
［16］Elgarhy LH, El⁃Tatawy RA, Ali DM, et al. Treatment of stable nonsegmental vitiligo using transdermal delivery of 5⁃fluorouracil by fractional CO2 laser versus intralesional injection of 5⁃fluorouracil, both followed by narrow⁃band type ultraviolet B （UVB）: a comparative study［J］. J Cosmet Dermatol, 2022,21（9）:3832⁃3841. doi: 10.1111/jocd.14691.
［17］Jha AK, Sonthalia S. 5⁃Fluorouracil as an adjuvant therapy along with microneedling in vitiligo［J］. J Am Acad Dermatol, 2019,80（4）:e75⁃e76. doi: 10.1016/j.jaad.2018.12.008.
