杨婧懿;徐倩玥;余红;
YANG Jingyi;XU Qianyue;YU Hong;Department of Dermatology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine;

• 1:上海交通大学医学院附属新华医院皮肤科

摘要(Abstract)：

青少年局限性硬皮病(juvenile localized scleroderma, JLS)是一种罕见的儿童自身免疫性疾病,早期缺乏特异性症状,易被误诊、漏诊而导致病变加剧,甚至造成机体功能损害和生长障碍等严重后果。为明确JLS病因,指导有效治疗药物的开发和应用,本文综述近年来JLS发病机制相关学说,总结其传统治疗方案和相关新型治疗药物研究进展,以提高临床医生对JLS的认识。
Juvenile localized scleroderma(JLS) is a rare autoimmune disease in children. The lack of specificity in the early symptoms of JLS makes it easy to be misdiagnosed and missed, which leads to the continuous progression of the lesions, and even causes systemic malfunction and growth disorder. For identifying the etiology of JLS and guiding the development and application of effective therapeutic drugs, we reviewed recent theories about the pathogenesis of JLS and summarized the traditional treatment options and relevant new therapeutic drugs, aiming to further enhance the fundamental understanding of JLS and its therapeutic progress.

关键词(KeyWords)： 青少年局限性硬皮病;发病机制;治疗;研究进展
juvenile localized scleroderma;pathogenesis;treatment;research progress

Abstract:

Keywords:

基金项目(Foundation):

作者(Authors): 杨婧懿;徐倩玥;余红;
YANG Jingyi;XU Qianyue;YU Hong;Department of Dermatology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine;

参考文献(References)：

• [1] Li SC.Scleroderma in children and adolescents:localized scleroderma and systemic sclerosis[J].Pediatr Clin North Am,2018,65:757- 781.
• [2] Zulian F,Athreya BH,Laxer R,et al.Juvenile localized scleroderma:clinical and epidemiological features in 750 children.An international study[J].Rheumatology (Oxford),2006,45:614- 620.
• [3] Li SC,Zheng RJ.Overview of Juvenile localized scleroderma and its management[J].World J Pediatr,2020,16:5- 18.
• [4] Jue MS,Kim MH,Ko JY,et al.Digital image processing for the acquisition of graphic similarity of the distributional patterns between cutaneous lesions of linear scleroderma and Blaschko's lines[J].J Dermatol,2011,38:778- 783.
• [5] Khatri S,Liu C,Mirizio E,et al.Autoantibodies in morphea:An update[J].Front Immunol,2019,10:1487.
• [6] Torok KS,Li SC,Jacobe HM,et al.Immunopathogenesis of Pediatric Localized Scleroderma[J].Front Immunol,2019,10:908.
• [7] Walker D,Susa JS,Currimbhoy S,et al.Histopathological changes in morphea and their clinical correlates:Results from the Morphea in Adults and Children Cohort V[J].J Am Acad Dermatol,2017,76:1124- 1130.
• [8] Stern EP,Denton CP.The Pathogenesis of Systemic Sclerosis[J].Rheum Dis Clin North Am,2015,41:367- 382.
• [9] Mirizio E,Marathi A,Hershey N,et al.Identifying the Signature Immune Phenotypes Present in Pediatric Localized Scleroderma[J].J Invest Dermatol,2019,139:715- 178.
• [10] Torok KS,Kurzinski K,Kelsey C,et al.Peripheral blood cytokine and chemokine profiles in juvenile localized scleroderma:T-helper cell-associated cytokine profiles[J].Semin Arthritis Rheum,2015,45:284- 293.
• [11] O'Brien JC,Rainwater YB,Malviya N,et al.Transcrip-tional and Cytokine Profiles Identify CXCL9 as a Biomarker of Disease Activity in Morphea[J].J Invest Dermatol,2017,137:1663- 1670.
• [12] Uziel Y,Feldman BM,Krafchik BR,et al.Increased serum levels of TGFbeta1 in children with localized scleroderma[J].Pediatr Rheumatol Online J,2007,5:22.
• [13] Budzyńska-W?odarczyk J,Michalska-Jakubus MM,Kowal M,et al.Evaluation of serum concentrations of the selected cytokines in patients with localized scleroderma[J].Postepy Dermatol Alergol,2016,33:47.
• [14] Kaushik A,Mahajan R,De D,et al.Paediatric morphoea:a holistic review.Part 1:epidemiology,aetiopathogenesis and clinical classification[J].Clin Exp Dermatol,2020,45:673- 678.
• [15] 黄婧，李梦涛，曾小峰.药物诱导硬皮病[J].协和医学杂志，2014,5:192- 196.Huang J,Li MT,Zeng XF.Drug-induced scleroderma[J].Xiehe Yixue Zazhi,2014,5:192- 196.
• [16] Saracino AM,Denton CP,Orteu CH.The molecular pathogenesis of morphoea:from genetics to future treatment targets[J].Br J Dermatol,2017,177:34- 46.
• [17] Condie D,Grabell D,Jacobe H.Comparison of outcomes in adults with pediatric-onset morphea and those with adult-onset morphea:a cross-sectional study from the morphea in adults and children cohort[J].Arthritis Rheumatol,2014,66:3496- 3504.
• [18] Foeldvari I.Update on the Systemic Treatment of Pediatric Localized Scleroderma[J].Paediatr Drugs,2019,21:461- 467.
• [19] Constantin T,Foeldvari I,Pain CE,et al.Development of minimum standards of care for juvenile localized scleroderma[J].Eur J Pediatr,2018,177:961- 977.
• [20] Do N,Ringold S,Sullivan E,et al.A retrospective study:Impact of consensus treatment plans on systemic therapy of pediatric morphea[J].Pediatr Dermatol,2020,37:278- 283.
• [21] Zulian F,Culpo R,Sperotto F,et al.Consensus-based recommendations for the management of juvenile localised scleroderma[J].Ann Rheum Dis,2019,78:1019- 1024.
• [22] Fett N,Werth VP.Update on morphea:part II.Outcome measures and treatment[J].J Am Acad Dermatol,2011,64:231- 244.
• [23] Hardy J,Boralevi F,Mallet S,et al.Clinical Profile of Methotrexate-resistant Juvenile Localised Scleroderma[J].Acta Derm Venereol,2019,99:539- 543.
• [24] Kreuter A,Krieg T,Worm M,et al.German guidelines for the diagnosis and therapy of localized scleroderma[J].J Dtsch Dermatol Ges,2016,14:199- 216.
• [25] Zulian F,Vallongo C,Patrizi A,et al.A long-term follow-up study of methotrexate in juvenile localized scleroderma (morphea)[J].J Am Acad Dermatol,2012,67:1151- 1156.
• [26] Lythgoe H,Almeida B,Bennett J,et al.Multi-centre national audit of juvenile localised scleroderma:describing current UK practice in disease assessment and management[J].Pediatr Rheumatol Online J,2018,16:80.
• [27] Asano Y,Fujimoto M,Ishikawa O,et al.Diagnostic criteria,severity classification and guidelines of localized scleroderma[J].J Dermatol,2018,45:755- 780.
• [28] Ozgen M,Koca SS,Dagli AF,et al.Mycophenolate mofetil and daclizumab targeting T lymphocytes in bleomycin-induced experimental scleroderma[J].Clin Exp Dermatol,2012,37:48- 54.
• [29] Mertens JS,Marsman D,van de Kerkhof PC,et al.Use of Mycophenolate Mofetil in Patients with Severe Localized Scleroderma Resistant or Intolerant to Methotrexate[J].Acta Derm Venereol,2016,96:510- 513.
• [30] Martini G,Saggioro L,Culpo R,et al.Mycophenolate mofetil for methotrexate-resistant juvenile localized sclero-derma[J].Rheumatology (Oxford),2021,60:1387- 1391.
• [31] Li SC,Torok KS,Pope E,et al.Development of consensus treatment plans for juvenile localized scleroderma:a roadmap toward comparative effectiveness studies in juvenile localized scleroderma[J].Arthritis Care Res(Hoboken),2012,64:1175- 1185.
• [32] Dytoc M,Wat H,Cheung-Lee M,et al.Evaluation of the efficacy and safety of topical imiquimod 5% for plaque-type morphea:a multicenter,prospective,vehicle-controlled trial[J].J Cutan Med Surg,2015,19:132- 139.
• [33] Pope E,Doria AS,Theriault M,et al.Topical imiquimod 5% cream for pediatric plaque morphea:a prospective,multiple-baseline,open-label pilot study[J].Dermatology,2011,223:363- 369.
• [34] Kroft EB,Groeneveld TJ,Seyger MM,et al.Efficacy of topical tacrolimus 0.1% in active plaque morphea:rando-mized,double-blind,emollient-controlled pilot study[J].Am J Clin Dermatol,2009,10:181- 187.
• [35] Bali G,Frühauf J,Wutte N,et al.Cyclosporine Reduces Sclerosis in Morphea:a Retrospective Study in 12 Patients and a Literature Review[J].Dermatology,2016,232:503- 510.
• [36] Ogawa T,Okiyama N,Takamuki R,et al.Juvenile case of multiple morphea profunda resulting in joint contracture that was successfully treated with cyclosporin A:A case report and review of the published works[J].J Dermatol,2019,46:354- 357.
• [37] Aranegui B,Jiménez-Reyes J.Morphea in Childhood:An Update[J].Actas Dermosifiliogr (Engl Ed),2018,109:312- 322.
• [38] Hulshof MM,Bouwes Bavinck JN,Bergman W,et al.Double-blind,placebo-controlled study of oral calcitriol for the treatment of localized and systemic scleroderma[J].J Am Acad Dermatol,2000,43:1017- 1023.
• [39] Frumholtz L,Roux J,Bagot M,et al.Treatment of Generalized Deep Morphea with Everolimus[J].JAMA Dermatol,2016,152:1170- 1172.
• [40] Kumar AB,Blixt EK,Drage LA,et al.Treatment of morphea with hydroxychloroquine:A retrospective review of 84 patients at Mayo Clinic,1996—2013[J].J Am Acad Dermatol,2019,80:1658- 1663.
• [41] Inamo Y,Ochiai T.Successful combination treatment of a patient with progressive juvenile localized scleroderma (morphea) using imatinib,corticosteroids,and methotrexate[J].Pediatr Dermatol,2013,30:e191-e193.
• [42] Foeldvari I,Anton J,Friswell M,et al.Tocilizumab is a promising treatment option for therapy resistant juvenile localized scleroderma patients[J].J Scleroderma Relat Disord,2017,2:203- 207.
• [43] Lythgoe H,Baildam E,Beresford MW,et al.Tocilizumab as a potential therapeutic option for children with severe,refractory juvenile localized scleroderma[J].Rheumatology (Oxford),2018,57:398- 401.
• [44] Kalampokis I,Yi BY,Smidt AC.Abatacept in the treatment of localized scleroderma:A pediatric case series and systematic literature review[J].Semin Arthritis Rheum,2020,50:645- 656.
• [45] Stausb?l-Gr?n B,Olesen AB,Deleuran B,et al.Abatacept is a promising treatment for patients with disseminated morphea profunda:presentation of two cases[J].Acta Derm Venereol,2011,91:686- 688.
• [46] Fage SW,Arvesen KB,Olesen AB.Abatacept Improves Skin-score and Reduces Lesions in Patients with Localized Scleroderma:A Case Series[J].Acta Derm Venereol,2018,98:465- 466.
• [47] Li SC,Torok KS,Ishaq SS,et al.Preliminary evidence on abatacept safety and efficacy in refractory juvenile localized scleroderma[J].Rheumatology(Oxford),2021,60:3817- 3825.
• [48] Ferguson ID,Weiser P,Torok KS.A Case Report of Successful Treatment of Recalcitrant Childhood Localized Scleroderma with Infliximab and Leflunomide[J].Open Rheumatol J,2015,9:30- 35.
• [49] Kim SR,Charos A,Damsky W,et al.Treatment of generalized deep morphea and eosinophilic fasciitis with the Janus kinase inhibitor tofacitinib[J].JAAD Case Rep,2018,4:443- 445.
• [50] Chimenti MS,Teoli M,Di Stefani A,et al.Resolution with rituximab of localized scleroderma occurring during etanercept treatment in a patient with rheumatoid arthritis[J].Eur J Dermatol,2013,23:273- 274.
• [51] 刘志锋，赵慧男，聂绍良.积雪草苷药理作用及其机制的研究进展[J].广东医学，2009,30:649- 651.Liu ZF,Zhao HN,Nie SL.Progress of Study on Pharmaceutical Activities and Mechanisms of Asiaticoside[J].Guangdong Yixue,2009,30:649- 651.
• [52] 田菲，高娟，张国强.积雪草苷联合曲尼司特治疗局限性硬皮病疗效观察[J].现代中西医结合杂志，2016,25:3649- 3651.Tian F,Gao J,Zhang GQ.Observe on effect of asiaticoside combined with tranilast in treatment of localized scleroderma[J].Xiandai Zhongxiyi Jiehe Zazhi,2016,25:3649- 3651.
• [53] 胡南，肖志平，温云鹏，等.积雪草苷联合曲尼司特治疗局限性硬皮病的临床疗效观察[J].皮肤病与性病，2019,41:469- 471.Hu N,Xiao ZP,Wen YP,et al.Clinical observation of asiaticoside combined with tranilast in the treatment of localized scleroderma[J].Pifubing Yu Xingbing,2019,41:469- 471.