作者投稿
专家审稿
编辑办公
主编办公
Progress in the Diagnosis and Treatment and the Establishment of Care System for Rare Skin Diseases
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摘要:
皮肤罕见病种类多样，诊疗中面临诸多挑战及困难。近年来皮肤罕见病的诊断水平不断提高，以二代测序技术为代表的分子诊断工具，可有效辅助临床建立罕见病精准诊断。孤儿药研发及基因治疗不断取得突破和进步，为皮肤罕见病患者带来了曙光。建立科学的疾病管理体系、分级转诊网络及规范化的诊疗路径对提高皮肤罕见病的诊治水平至关重要。本文总结了目前皮肤罕见病的诊疗进展，并对未来发展做出展望。
Abstract:Rare skin diseases are various in kinds facing many challenges and difficulties in diagnosis and treatment. Recently, the diagnosis of rare skin diseases has improved continuously. Molecular diagnostic tool, a representation of the next generation sequencing technology, can effectively assist the accuracy of clinical diagnosis for rare diseases. The research and development of orphan drugs and gene therapy have made continuous breakthroughs and progress, bringing hope to patients with rare skin diseases. It is crucial to establish scientific disease management system of the disease, layered referral networks, and the standardized clinical pathways to improve the diagnosis and treatment level of rare skin diseases.This article provides a brief overview of the progress in the diagnosis and treatment of rare skin diseases and explore the future possibilities.
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Keywords:
- dermatosis /
- rare diseases /
- diagnosis /
- treatment /
- management
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张波
北京协和医院药剂科主任
本期执行主编
“诊断难、药物少、负担重”是罕见病患者面临的三大困难，罕见病也是全球面临的重要公共卫生挑战。全球超过7000多种罕见病，有药可治的比例不足5%。由于大多数罕见病的诊断、发病机制和自然病史尚未阐明，罕见病药物研发仍面临很大挑战，药物的作用靶点及药物疗效的评估指标尚不明确；另一方面，罕见病患者人数少，临床试验受试者的招募困难，开展药物临床试验的难度和周期都比较长。此外，罕见病患者人数少、市场小，但药物研发的难度和投入大，人均研发成本高。因此，目前全球批准的罕见病药物相对较少。截至2023年12月31日，美国共批准上市的罕见病药物749种，欧盟批准的罕见病药物260种。在我国，“境外有药，境内无药”“境内有药，但尚无获批罕见病适应证”及“境内有药，但保障不足”等问题，仍是导致罕见病患者用药困境的主要原因。
关注罕见病、研究罕见病是一个国家经济发展、社会文明和科技发展的重要标志之一。为了切实解决罕见病患者“药物少”和“用药难”的困境，我国多部门联动，陆续出台一系列罕见病药物保障激励政策，鼓励药物研发，对罕见病药物实施优先审评，加速罕见病药物在国内上市。通过两批罕见病目录的发布，显著提升了目录内207种罕见病的诊疗能力和药物保障能力。通过建立多种政策性引进模式，如“临床急需药品临时进口工作方案”、海南博鳌乐城国际医疗旅游先行区和北京天竺综合保税区罕见病药物先行区等，让更多中国罕见病患者能够在药品未在我国上市的情况下，尽早使用到国外新药。通过国家谈判的方式积极推动落实罕见病药物进入医保目录，实现高值药物进入医保的重大突破。一系列支持性政策的颁布和落地，体现出国家对于保障罕见病患者用药的决心，进一步提升了罕见病药品可负担性。道阻且长，行则将至，药物研发和用药保障的每一次推进，都为罕见病患者打开一道“希望之门”。
罕见病药物研发已成为目前药物研发的热点，据统计，2011—2022年美国FDA批准上市的孤儿药占新药总数的46.3%。虽然近年来我国罕见病药品供应保障已取得积极进展，但罕见病药物研发和用药保障仍有诸多困境待解，需要多部门和医药产业全流程的协同发力。由于我国人口基数大，罕见病患者数量相对较多，这为罕见病药物研究创造了有利环境。面向未来，我们呼吁更多的专家和学者聚焦罕见病药物研究，以罕见病目录为抓手，以全国罕见病诊疗协作网和罕见病注册登记平台为依托，打造“政产学研医”协同创新平台，推动罕见病药物研究高质量发展。
本期《罕见病研究》杂志聚焦罕见病药物。我们非常荣幸地邀请到了深耕罕见病药物研究的专家学者，为读者奉上该领域前沿进展、政策分析、研究技术和发展方向。内容包括罕见病药物研发的审评审批、伦理审查、临床试验开展，罕见病药物治疗进展、临床实践和经验分享，罕见病用药保障及服务模式的创新等。近年来我国罕见病药物研究领域优秀的成果层出不穷，但由于篇幅有限不能收录更多。因此也期待未来再组专刊展示成果，以飨读者。我们期待广大同仁把握时机，迎难而上，携手同行，为提升我国罕见病药物的研究水平不懈努力！
2024年4月 作者贡献：刘晓涵收集和整理皮肤罕见病的诊断和治疗资料，撰写文章；晋红中设计选题并对本文的撰写进行指导、修改及审核。利益冲突：所有作者均声明不存在利益冲突。 -
[1] 张抒扬, 张学. 近年中国罕见病相关政策和实践探索[J]. 罕见病研究, 2022, 1(1): 1-6. doi: 10.12376/j.issn.2097-0501.2022.01.001 [2] Feng S, Liu S, Zhu C, et al. National rare diseases registry system of China and related cohort studies: vision and roadmap[J]. Hum Gene Ther, 2018, 29(2): 128-135. doi: 10.1089/hum.2017.215
[3] 张学军. 罕见性遗传性皮肤病的研究现状及展望[J]. 皮肤科学通报, 2020, 37(1): 1-4. https://www.cnki.com.cn/Article/CJFDTOTAL-ZYXW202001001.htm [4] He PP, He CD, Cui Y, et al. Refined localization of dyschromatosis symmetrica hereditaria gene to a 9.4-cM region at 1q21-22 and a literature review of 136 cases reported in China[J]. Br J Dermatol, 2004, 150(4): 633-639. doi: 10.1111/j.0007-0963.2004.05861.x
[5] Xing QH, Wang MT, Chen XD, et al. A gene locus responsible for dyschromatosis symmetrica hereditaria (DSH) maps to chromosome 6q24.2-q25.2[J]. Am J Hum Genet, 2003, 73(2): 377-382. doi: 10.1086/377007
[6] Zhang Z, Niu Z, Yuan W, et al. Fine mapping and identification of a candidate gene SSH1 in disseminated superficial actinic porokeratosis[J]. Hum Mutat, 2004, 24(5): 438.
[7] Zhang ZH, Niu ZM, Yuan WT, et al. A mutation in SART3 gene in a Chinese pedigree with disseminated superficial actinic porokeratosis[J]. Br J Dermatol, 2005, 152(4): 658-663. doi: 10.1111/j.1365-2133.2005.06443.x
[8] Lin Z, Chen Q, Lee M, et al. Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome[J]. Am J Hum Genet, 2012, 90(3): 558-564. doi: 10.1016/j.ajhg.2012.02.006
[9] Wu Y, Li G, Zhu X. A novel homozygous point mutation in the COL17A1 gene in a Chinese family with generalized atrophic benign epidermolysis bullosa[J]. J Dermatol Sci, 2002, 28(3): 181-186. doi: 10.1016/S0923-1811(01)00163-3
[10] Feng YG, Xiao SX, Ren XR, et al. Keratin 17 mutation in pachyonychia congenita type 2 with early onset sebaceous cysts[J]. Br J Dermatol, 2003, 148(3): 452-455. doi: 10.1046/j.1365-2133.2003.05152.x
[11] He PP, Zhang XJ, Yang Q, et al. Refinement of a locus for Marie Unna hereditary hypotrichosis to a 1.1-cM interval at 8p21.3[J]. Br J Dermatol, 2004, 150(5): 837-842. doi: 10.1111/j.1365-2133.2004.05913.x
[12] Yang Y, Wang Y, Li S, et al. Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia[J]. J Med Genet, 2004, 41(3): 171-174. doi: 10.1136/jmg.2003.012153
[13] Wang B, Yang W, Wen W, et al. Gamma-secretase gene mutations in familial acne inversa[J]. Science, 2010, 330(6007): 1065. doi: 10.1126/science.1196284
[14] Wei A, Zhang T, Yuan Y, et al. Spectrum analysis of albinism genes in a large cohort of Chinese index patients[J]. J Invest Dermatol, 2022, 142(6): 1752-1755. e3. doi: 10.1016/j.jid.2021.11.014
[15] Has C, Bauer JW, Bodemer C, et al. Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility[J]. Br J Dermatol, 2020, 183(4): 614-627. doi: 10.1111/bjd.18921
[16] Chen F, Wei R, Deng D, et al. Genotype and phenotype correlations in 441 patients with epidermolysis bullosa from China[J]. J Eur Acad Dermatol Venereol, 2023, 37(2): 411-419. doi: 10.1111/jdv.18692
[17] Chen C, Hou G, Zeng C, et al. Metabolomic profiling reveals amino acid and carnitine alterations as metabolic signatures in psoriasis[J]. Theranostics, 2021, 11(2): 754-767. doi: 10.7150/thno.51154
[18] Chiu CY, Lin G, Wang CJ, et al. Metabolomics reveals microbial-derived metabolites associated with immunoglobulin E responses in filaggrin-related atopic dermatitis[J]. Pediatr Allergy Immunol, 2021, 32(8): 1709-1717. doi: 10.1111/pai.13570
[19] Huang Y, Chen G, Liu X, et al. Serum metabolomics study and eicosanoid analysis of childhood atopic dermatitis based on liquid chromatography-mass spectrometry[J]. J Proteome Res, 2014, 13(12): 5715-5723. doi: 10.1021/pr5007069
[20] Lee SJ, Woo SI, Ahn SH, et al. Functional interpretation of metabolomics data as a new method for predicting long-term side effects: treatment of atopic dermatitis in infants[J]. Sci Rep, 2014, 4: 7408. doi: 10.1038/srep07408
[21] Xing L, Wu T, Yu L, et al. Exploration of biomarkers of psoriasis through combined multiomics analysis[J]. Mediators Inflamm, 2022, 2022: 7731082.
[22] Leng L, Liu Z, Ma J, et al. Proteomic identification of new diagnostic biomarkers of early-stage cutaneous mycosis fungoides[J]. Cancer Commun (Lond), 2022, 42(6): 558-562. doi: 10.1002/cac2.12266
[23] Xu C, Zhou D, Luo Y, et al. Tissue and serum lipidome shows altered lipid composition with diagnostic potential in mycosis fungoides[J]. Oncotarget, 2017, 8(29): 48041-48050. doi: 10.18632/oncotarget.18228
[24] Wang L, Yu X, Wu C, et al. RNA sequencing-based longitudinal transcriptomic profiling gives novel insights into the disease mechanism of generalized pustular psoriasis[J]. BMC Med Genomics, 2018, 11(1): 52. doi: 10.1186/s12920-018-0369-3
[25] 弓孟春, 焦塬石, 马武仁, 等. 人工智能支持罕见病诊疗的研究进展[J]. 罕见病研究, 2022, 1(2): 101-109. doi: 10.12376/j.issn.2097-0501.2022.02.003 [26] Kakkis ED, Muenzer J, Tiller GE, et al. Enzyme-replacement therapy in mucopolysaccharidosis I[J]. N Engl J Med, 2001, 344(3): 182-188. doi: 10.1056/NEJM200101183440304
[27] Germain DP, Charrow J, Desnick RJ, et al. Ten-year outcome of enzyme replacement therapy with agalsidase beta in patients with Fabry disease[J]. J Med Genet, 2015, 52(5): 353-358. doi: 10.1136/jmedgenet-2014-102797
[28] Longhurst H, Cicardi M, Craig T, et al. Prevention of hereditary angioedema attacks with a subcutaneous C1 inhibitor[J]. N Engl J Med, 2017, 376(12): 1131-1140. doi: 10.1056/NEJMoa1613627
[29] French JA, Lawson JA, Yapici Z, et al. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study[J]. Lancet, 2016, 388(10056): 2153-2163. doi: 10.1016/S0140-6736(16)31419-2
[30] Bissler JJ, McCormack FX, Young LR, et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis[J]. N Engl J Med, 2008, 358(2): 140-151. doi: 10.1056/NEJMoa063564
[31] Langendonk JG, Balwani M, Anderson KE, et al. Afamelanotide for erythropoietic protoporphyria[J]. N Engl J Med, 2015, 373(1): 48-59. doi: 10.1056/NEJMoa1411481
[32] Donadieu J, Larabi IA, Tardieu M, et al. Vemurafenib for refractory multisystem langerhans cell histiocytosis in children: an international observational study[J]. J Clin Oncol, 2019, 37(31): 2857-2865. doi: 10.1200/JCO.19.00456
[33] Bachelez H, Choon SE, Marrakchi S, et al. Trial of spesolimab for generalized pustular psoriasis[J]. N Engl J Med, 2021, 385(26): 2431-2440. doi: 10.1056/NEJMoa2111563
[34] Iznardo H, Puig L. Exploring the role of IL-36 cytokines as a new target in psoriatic disease[J]. Int J Mol Sci, 2021, 22(9): 4344.
[35] Gurevich I, Agarwal P, Zhang P, et al. In vivo topical gene therapy for recessive dystrophic epidermolysis bullosa: a phase 1 and 2 trial[J]. Nat Med, 2022, 28(4): 780-788.
[36] Leachman SA, Hickerson RP, Schwartz ME, et al. First-in-human mutation-targeted siRNA phase Ib trial of an inherited skin disorder[J]. Mol Ther, 2010, 18(2): 442-446.
[37] Mendell JR, Rodino-Klapac LR, Sahenk Z, et al. Eteplirsen for the treatment of Duchenne muscular dystrophy[J]. Ann Neurol, 2013, 74(5): 637-647.
[38] Darras BT, Chiriboga CA, Iannaccone ST, et al. Nusiner-sen in later-onset spinal muscular atrophy: long-term results from the phase 1/2 studies[J]. Neurology, 2019, 92(21): e2492-e2506.
[39] Ablinger M, Lettner T, Friedl N, et al. Personalized development of antisense oligonucleotides for exon skipping restores type XVⅡ collagen expression in junctional epidermolysis bullosa[J]. Int J Mol Sci, 2021, 22(7): 3326.
[40] Ma J, Li W, Cao R, et al. Application of an iPSC-derived organoid model for localized scleroderma therapy[J]. Adv Sci (Weinh), 2022, 9(16): e2106075.
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