首頁資訊斑禿的免疫發(fā)病機(jī)制與靶向治療進(jìn)展

斑禿的免疫發(fā)病機(jī)制與靶向治療進(jìn)展

來源：泰然健康網(wǎng) 時間：2024年12月07日 23:32

斑禿(alopecia areata,AA)是臨床上常見的一種非瘢痕性脫發(fā)性疾病,常表現(xiàn)為圓形或者橢圓型的斑片狀脫發(fā),嚴(yán)重者出現(xiàn)全禿-頭發(fā)全部脫落,甚至普禿-累及全身的毛發(fā)脫落。作為一種自身免疫性疾病[1],其發(fā)病機(jī)制涉及多種炎癥反應(yīng)[2-3],發(fā)病原因涉及遺傳、精神壓力、情緒應(yīng)激、感染等多種因素,治療面臨諸多困難。傳統(tǒng)治療方式如糖皮質(zhì)激素、免疫抑制劑等對中重度及頑固性斑禿的治療欠佳,不同的斑禿患者因發(fā)病機(jī)制不同存在療效差異,治療效果很好的普禿患者也面臨著斑禿脫發(fā)復(fù)發(fā)的風(fēng)險[4]。患者常因損容病情、療效不佳以及疾病復(fù)發(fā)等加重心理壓力,甚至導(dǎo)致焦慮、抑郁[5]。近年來,生物制劑及小分子藥物廣泛應(yīng)用于特應(yīng)性皮炎、銀屑病等許多自身免疫性炎癥性皮膚病中,取得了較好的臨床療效,靶向治療也正成為斑禿的重要治療手段。本文綜述斑禿的免疫發(fā)病機(jī)制,并結(jié)合目前靶向治療在斑禿中的應(yīng)用現(xiàn)狀,探討靶向治療斑禿新思路。

1 斑禿的免疫發(fā)病機(jī)制

1.1 炎癥信號通路及相關(guān)細(xì)胞因子在斑禿發(fā)病機(jī)制中的作用

包括Th1、Th2、Th17在內(nèi)的多條炎癥信號通路參與AA發(fā)病,其中細(xì)胞因子的紊亂在AA發(fā)病中有重要作用(

表1

),但是其與AA臨床嚴(yán)重程度和病程之間的關(guān)系,仍有待進(jìn)一步研究[9-10]。其中IFN-γ是毛囊IP崩潰的關(guān)鍵因子,可誘導(dǎo)細(xì)胞MHC-I類分子的表達(dá)上調(diào)、招募CD8+NKG2D+T細(xì)胞的聚集從而破壞毛囊[7-8]。調(diào)節(jié)T細(xì)胞分泌IL-10(也可以由Th1型細(xì)胞分泌)和TGF-β。IL-10能抑制T細(xì)胞的增殖、炎癥細(xì)胞因子的生產(chǎn)和降低CD8+T細(xì)胞的活性,TGF-β可下調(diào)T細(xì)胞的MHC-I表達(dá),二者均可以維持IP的免疫抑制環(huán)境,發(fā)揮“毛囊IP衛(wèi)士”的作用[11-12]。

表1 細(xì)胞因子在AA中的水平變化

Table 1 Changes in cytokine levels in AA

分類 AA患者與健康對照組血清中細(xì)胞因子水平變化發(fā)病相關(guān)細(xì)胞因子 Th1型 IFN-γ:升高[6]
IL-2:升高[6-7]
IL-10: 無明顯差異[7];升高[8] Th2型 IL-4、IL-13、IL-33和IL-17E/25:升高[9-10] Th17型 IL-17,IL-21,TNF-α:升高[9-10] 維護(hù)IP相關(guān)細(xì)胞因子/分子神經(jīng)肽/神經(jīng)激素 P物質(zhì)[12] 調(diào)節(jié)T細(xì)胞 IL-10:無明顯差異[6]; 升高[10]TGF-β:升高[6];降低[10] 神經(jīng)肽/神經(jīng)激素降鈣素基因相關(guān)肽(CGRP)、黑素細(xì)胞刺激激素(α-MSH)和血管活性腸肽(VIP)[13] 其他 MIF(巨噬細(xì)胞遷移抑制因子)、吲哚胺2,3-雙加氧酶(IDO)、血栓反應(yīng)素1(TSP1)和Red/IK[12,14]

另外,毛囊中的感覺神經(jīng)末梢分泌各種神經(jīng)肽和神經(jīng)激素也參與毛囊IP的崩潰或者維護(hù)。毛囊神經(jīng)末梢分泌的P物質(zhì)參與IP崩潰,而降鈣素基因相關(guān)肽(CGRP)、黑素細(xì)胞刺激激素(α-MSH)、和血管活性腸肽(VIP)均作為毛囊IP的“安全衛(wèi)士”,可維持正常IP和恢復(fù)毛囊崩潰的IP[13]。

其他細(xì)胞因子如巨噬細(xì)胞遷移抑制因子(MIF)、吲哚胺2,3-雙加氧酶(IDO)、血栓反應(yīng)素1(TSP1)、和Red/IK等因子也通過免疫調(diào)節(jié)作用來維護(hù)毛囊的免疫特權(quán)[11,14]。

1.2 免疫細(xì)胞在斑禿發(fā)病機(jī)制中作用

T細(xì)胞及其各種亞型在AA發(fā)病中作用突出,體現(xiàn)在AA發(fā)病、AA的IP恢復(fù)以及AA復(fù)發(fā)的全過程。首先,CD8+NKG2D+T細(xì)胞在AA的發(fā)病中起主要作用,Gilhar等人已經(jīng)證明,NKG2D+/CD56+T細(xì)胞、NK細(xì)胞即能單獨在SCID小鼠上的健康人皮膚移植處誘導(dǎo)AA樣皮損[15],這提示了NKG2D受體陽性的T細(xì)胞是AA發(fā)病的充分條件。另外,樹突狀表皮T細(xì)胞(DETC,也稱為γδT細(xì)胞)在激活狀態(tài)下可促進(jìn)NKG2D表達(dá)和IFN-γ分泌而引發(fā)毛囊IP破壞[16]。其次,調(diào)節(jié)T細(xì)胞(Tregs)和iNKT細(xì)胞(一種非傳統(tǒng)的T細(xì)胞亞型) 參與毛囊IP的調(diào)節(jié),促進(jìn)AA的恢復(fù)。調(diào)節(jié)T細(xì)胞可通過分泌細(xì)胞因子TGF-β、IL-10或者高表達(dá)CD25(IL-2受體α)消耗IL-2等多種機(jī)制來發(fā)揮免疫抑制效應(yīng)[6,17],其免疫抑制功能受損可促進(jìn)AA發(fā)展[6],而在小鼠模型中增加其數(shù)量可促進(jìn)AA皮損恢復(fù)[18]。iNKT10細(xì)胞可以直接或間接抑制CD8+/NKG2D+T細(xì)胞,其激活物-半乳糖神經(jīng)酰胺(a-GalCer)以IL-10依賴的方式阻止小鼠AA的發(fā)展[11]。最后,AA的復(fù)發(fā)常見在原脫發(fā)部位,提示其局部可能具有免疫記憶。一項關(guān)于瘢痕性脫發(fā)的研究,發(fā)現(xiàn)斑禿患者皮損中CD103+CD69+TRM(組織駐留記憶T細(xì)胞)細(xì)胞出現(xiàn)上調(diào)狀態(tài)[19],并且使用Janus激酶(JAK)信號通路的抑制劑(如tofacitinib)治療后的AA小鼠,其病變T細(xì)胞克隆不會完全消失,直接或間接提示了TRM細(xì)胞可能參與AA復(fù)發(fā)[5]。TRM細(xì)胞能夠在遇到同源抗原時快速反應(yīng),大量分泌AA的重要驅(qū)動因子IFN-γ,以及腫瘤壞死因子-α(TNFα))等[20],以此促進(jìn)AA復(fù)發(fā),但是具體機(jī)制仍待進(jìn)一步驗證。

除T細(xì)胞以外,樹突狀細(xì)胞(DCs)中的漿細(xì)胞樣DC(pDCs)也能分泌I型IFN從而啟動毛囊自身免疫反應(yīng)[21]。肥大細(xì)胞在AA患者皮損中表現(xiàn)為促炎表型,可通過脫顆粒和增加與CD8+T細(xì)胞的接觸促進(jìn)炎癥反應(yīng)[12]。

2 生物制劑治療AA及其潛在靶點

2.1 Th1型

2.1.1 IFN-γ

IFN-γ作為Th1型細(xì)胞因子,是AA發(fā)病的關(guān)鍵因子。目前阻斷IFN-γ作用通路的研究主要有2個方面:1.阻斷IFN誘導(dǎo)型趨化因子(CXCL9/10/11)及其受體CXCR3,可抑制CD8+NKG2D+T細(xì)胞向AA小鼠模型中遷移,從而抑制AA的發(fā)展[22];2.細(xì)胞因子信號傳導(dǎo)抑制劑3(SOCS3)-可以阻斷產(chǎn)生IFN-γ的CD8+T細(xì)胞在AA皮損中的積累[23]。雖然以上兩個方面可作為生物治療AA的潛在靶點,但是由于IFN-γ作為Th1型炎癥通路的關(guān)鍵信號因子,臨床上尚無應(yīng)用于治療的生物制劑。

2.1.2 低劑量IL-2

IL-2在AA患者的血清中水平升高,但是多項研究表明IL-2在血清中的水平與AA患者的病情嚴(yán)重程度、疾病持續(xù)時間無關(guān)[7,24]。然而,低劑量IL-2能夠通過募集Tregs細(xì)胞而增加其數(shù)量,從而有望治療重度AA。一項包含5例受試者的前瞻性研究通過皮下注射IL-2,實現(xiàn)了4名受試者的血清Tregs細(xì)胞數(shù)量增加和毛發(fā)再生,而樣本量更大的多中心前瞻性安慰劑對照研究雖證實了低劑量IL-2對Tregs細(xì)胞的招募效果,卻沒有實現(xiàn)受試者毛發(fā)再生[25-26]。低劑量IL-2對AA的治療作用研究需要進(jìn)一步明確IL-2對Tregs細(xì)胞的招募作用的機(jī)制和其對Tregs細(xì)胞功能的影響。

2.2 Th2型

度普利尤單抗(Dupilumab)是一種通過結(jié)合IL-4R受體a亞基(IL-4和IL-13共有的受體亞基)從而抑制Th2型炎癥反應(yīng)的單克隆抗體。目前該藥物廣泛應(yīng)用于特應(yīng)性皮炎(AD)。在其臨床應(yīng)用過程中,多項病例報告/系列發(fā)現(xiàn),Dupilumab治療AD的同時,可能緩解AA,也可能誘發(fā)AA樣脫發(fā)甚至加重AA[27]。一項關(guān)于Dupilumab治療AA的隨機(jī)、安慰劑對照臨床研究表明,在治療的24周后,Dupilumab的治療反應(yīng)與血清總IgE水平相關(guān),IgE水平越高,對Dupilumab治療反應(yīng)越好[28]。出現(xiàn)以上度普利尤單抗治療AA的臨床效果差異性的原因究其根本在于AA患者的臨床表型差異性:在血清中IgE水平高的AA患者中,Th2炎癥通路可能在AA的發(fā)病中占據(jù)著相對較重要的地位,當(dāng)使用Dupilumab阻斷該炎癥通路,AA能得到緩解;然而對于非以Th2型炎癥反應(yīng)為主的AA患者,抑制該通路不僅達(dá)不到治療效果,反而加強(qiáng)了Th1炎癥反應(yīng),從而誘發(fā)或者加重AA。值得注意的是,有學(xué)者認(rèn)為,度普利尤單抗治療AD過程中脫發(fā)的誘發(fā)或者AA加重(同TNF-α抑制劑引起的脫發(fā)一樣)是由于藥物反應(yīng)所致,藥物誘導(dǎo)了皮脂腺的萎縮和非瘢痕性的脫發(fā)[29]。度普利尤單抗治療AA需要明確的臨床評價指標(biāo),IgE水平是否可以做為該指標(biāo),需要進(jìn)一步的臨床隨機(jī)對照試驗證實。

2.3 Th17型

2.3.1 TNF-α抑制劑

TNF-α抑制劑治療AA并沒有在臨床上取得較好的療效,相反,其可能加重或者誘發(fā)AA。一項20例病例的前瞻性研究表明依那西普在治療中度至重度斑禿、全禿或全身性脫發(fā)中無效[30]。阿達(dá)木單抗治療AA的3例病例報告也提示其不能誘導(dǎo)毛發(fā)的再生[31]。甚至,有病例報告提示在阿達(dá)木單抗治療銀屑病后出現(xiàn)了斑禿[32]。出現(xiàn)這些結(jié)果的原因可能與TNF-α失去對漿細(xì)胞樣樹突狀細(xì)胞所產(chǎn)生的干擾素的抑制有關(guān)[33],也可能是上文所述的藥物反應(yīng)。但同時,也有阿達(dá)木單抗成功治療了斑禿的案例,治療效果不一致可能與AA復(fù)雜的發(fā)病機(jī)制和AA患者個體差異有關(guān)。

2.3.2 IL-17抑制劑

IL-17抑制劑包括了司庫奇優(yōu)單抗(Secukinumab)、依奇珠單抗(ixekizumab )和布羅達(dá)魯單抗(brodalumab,)。鑒于IL-17在AA中的重要作用,其在靶向治療AA上頗有潛力,但目前尚缺乏有力的臨床隨機(jī)對照試驗證實它在促進(jìn)毛發(fā)再生中的作用。一項包括11名受試者的RCT表明在接受24周皮下注射蘇金單抗治療的AA患者的毛發(fā)無明顯再生[34]。同時,也有病例報告表明在司庫奇優(yōu)單抗治療銀屑病合并全禿患者時,患者毛發(fā)有一定程度再生,停藥后毛發(fā)再次脫落[35]。與之相反,有個案報道的銀屑病患者經(jīng)過司庫奇優(yōu)單抗治療后出現(xiàn)多毛[36]。以上IL-17抑制劑治療AA成功或者失敗的例子不能完全說明其有效和無效,需要樣本量更大的RCT來證實。

2.3.3 IL-12/23抑制劑

烏司奴單抗(Ustekinumab)是抑制IL-12/23的共有P40亞基的的全人源化單克隆抗體,IL-12、IL-23分別是誘導(dǎo)T細(xì)胞向Th17細(xì)胞、Th1細(xì)胞分化的重要細(xì)胞因子。烏司奴單抗主要應(yīng)用于中重度斑塊狀銀屑病。在Emma Guttman-Yassky的病例系列報告中,3例經(jīng)烏司奴單抗治療的患者在20周后出現(xiàn)不同程度的毛發(fā)再生,且患者皮膚活檢中炎癥標(biāo)志物水平也降低[37]。但是,Ortolan LS等人進(jìn)一步小鼠試驗表明,中和IL-12、IL-23的共有P40亞基和IL-23的特異性P19亞基不會抑制AA的發(fā)展;并且4例AA患者使用烏司奴單抗治療均失敗[38]。此外,也有病例報告顯示在烏司奴單抗治療銀屑病期間出現(xiàn)了AA的發(fā)展[39]。總體來說,目前尚無臨床隨機(jī)對照研究來證明烏司奴單抗在治療AA的臨床效果。

3 小分子藥物靶向治療AA現(xiàn)狀

3.1 JAK抑制劑

JAK通路是某些干擾素和白介素類細(xì)胞因子的共同下游通路,通過抑制此通路,不僅可以阻斷IFN-γ信號傳導(dǎo),還可以阻斷其他細(xì)胞因子介導(dǎo)的炎癥反應(yīng)。JAK抑制劑治療AA頗具潛力。

3.1.1 非選擇性JAK抑制劑

非選擇性JAK抑制劑在臨床上可應(yīng)用于治療AA的有托法替尼(tofacitinib)、魯索替尼(ruxolitinib)、巴瑞替尼(baricitinib)。托法替尼是JAK1/3抑制劑,魯索替尼、巴瑞替尼是JAK1/2抑制劑,它們在臨床試驗中顯示出良好的治療效果及安全性[40-41]。需注意的是目前少有臨床試驗證實兒童口服JAK抑制劑的療效和安全性,但有研究證實了外用JAK抑制劑在AA兒童患者中的療效。一項針對6名兒童患者的研究中,使用1%~2%濃度的托法替尼和魯索替尼外用制劑進(jìn)行治療后,6例患者中有4例出現(xiàn)毛發(fā)再生[42]。

據(jù)各種臨床研究顯示,使用JAK抑制劑最常見的不良反應(yīng)是上呼吸道感染,頭痛,痤瘡,疲勞等,實驗室檢查指標(biāo)上少數(shù)患者可出現(xiàn)肝酶異常、脂質(zhì)異常,白細(xì)胞計數(shù)減少等,未見嚴(yán)重不良反應(yīng)[43]。但是停藥后復(fù)發(fā)是目前治療面臨的重要問題,預(yù)防疾病復(fù)發(fā)可予藥物的維持治療,可以選擇口服藥物維持,或者改用外用藥物,但目前尚缺乏明確具體維持治療方案的研究[40,43]。在選擇口服或者外用給藥方面,需考慮患者皮損的累及范圍及年齡,同時考慮長期使用藥物的不良反應(yīng)。一般來說,局限性的AA和兒童患者選擇外用制劑更好,以求更高的局部浸潤濃度和更好的安全性,雖然并沒有明確的研究證實外用制劑和口服用藥在不良反應(yīng)上的差別。對皮損廣泛且成年AA患者來說,口服用藥是更好的選擇。Phan等[43]的研究也顯示,口服JAK抑制劑比局部外用治療效果好。

3.1.2 選擇性JAK抑制劑

選擇性JAK抑制劑有更高的選擇性和安全性。一些選擇性JAK抑制劑已經(jīng)應(yīng)用于臨床,如選擇性JAK1抑制劑厄帕替尼(upadacitinib)已獲批上市用于治療類風(fēng)濕關(guān)節(jié)炎(RA)。一些選擇性Jak抑制劑治療AA進(jìn)入II-III期臨床階段[44]。

3.2 T細(xì)胞調(diào)劑

阿巴西普(Abatacept)是細(xì)胞毒性T淋巴細(xì)胞相關(guān)抗原 4(Cytotoxic T lymphocyte associate protein-4,CTLA-4)和部分IgG1(CTLA-4Ig)組成的融合蛋白。其可阻斷T細(xì)胞上CD28的共刺激作用,從而廣泛抑制T細(xì)胞,減少關(guān)鍵炎癥細(xì)胞因子如FN-γ、TNF-α的產(chǎn)生[45]。目前有一項開放標(biāo)簽單臂臨床試驗顯示了阿巴西普對AA的治療潛力[46]。

3.3 磷酸二酯酶(PDE4)抑制劑

阿普斯特(Apremilast)是一種口服磷酸二酯酶4(PDE4)抑制劑,其可通過升高細(xì)胞內(nèi)cAMP水平,降低TNF-α、IL-12、17、23等多種細(xì)胞因子的表達(dá),提高IL-10等的表達(dá),降低炎癥反應(yīng)水平,從而治療AA。目前少量小樣本臨床研究證實了其對AA患者毛發(fā)再生的作用[47]。

4 結(jié)語與展望

AA的發(fā)病機(jī)制比較復(fù)雜,涉及眾多炎癥通路和免疫細(xì)胞,這造成了不同AA患者的異質(zhì)性,也為靶向治療AA取得滿意的療效帶來了一定的困難。但是,在進(jìn)一步明確AA發(fā)病機(jī)制基礎(chǔ)上的靶向治療,可為提升AA患者療效帶來更多可能。因此,針對AA發(fā)病機(jī)制的研究和針對AA發(fā)病過程中失衡的細(xì)胞因子或者免疫細(xì)胞的靶點藥物研究仍需深入開展。關(guān)于AA的靶向治療可以考慮同時將阻斷炎癥通路和恢復(fù)毛囊IP的治療相結(jié)合,這樣更可能在AA患者自身異質(zhì)性的情況下,達(dá)到理想的治療效果和防止復(fù)發(fā)的效果。

=2" class="main_content_center_left_zhengwen_bao_erji_title main_content_center_left_one_title" style="font-size: 16px;">{{custom_sec.title}}{{custom_sec.content}}[1]SIMAKOU T

BUTCHER J P

REID S

, et al. Alopecia areata:a multifactorial autoimmune condition[J]. J Autoimmun, 2019, 98:74-85.

ITO N

TAKIGAWA M

, et al. The hair follicle and immune privilege[J]. J Investig Dermatol Symp Proc, 2003, 8(2):188-194.

GILHAR A

PAUS R

. Alopecia areata as a model for T cell-dependent autoimmune diseases[J]. Exp Dermatol, 2012, 21(6):477-479.

JABBARI A

DAI Z

, et al. High-throughput T cell receptor sequencing identifies clonally expanded CD8+ T cell populations in alopecia areata[J]. JCI insight, 2018, 3(19):e121949.doi:10.1172/jci.insight.121949.

MARKS D H

MANATIS-LORNELL A

, et al. Association between alopecia areata, anxiety, and depression: a systematic review and meta-analysis[J]. Am Acad Dermatol, 2019, 1:S0190-9622(19)30890-4.doi:10.1016/j.jaad.2019.05.086.

SHARMA V K

. T-helper and regulatory T-cell cytokines in the peripheral blood of patients with active alopecia areata[J]. Br J Dermatol, 2013, 169(3):543-548.

Alteration in T-lymphocyte function and cytokines secreted by T-cell subsets has been proposed in the immunopathogenesis of alopecia areata (AA). The role of T-helper and regulatory T-cell cytokines in the pathogenesis of active AA has not been established.To assess the role of hallmark cytokines of T-helper cells (Th1, Th2 and Th17) and regulatory T cells (Tregs) in the pathogenesis of AA, and its clinical correlation.Fifty-one patients with AA and 45 age- and sex-matched healthy control subjects were included in the study. Serum interleukin (IL)-2, interferon (IFN)-γ, IL-10, IL-13, IL-17A and transforming growth factor (TGF)-β1 were measured by enzyme-linked immunosorbent assay in both groups. Correlation of serum cytokine levels with age, sex, disease subtype and duration, number of patches on the scalp, associated autoimmune disorders and atopy was studied.The serum cytokine levels of IL-2, IFN-γ, IL-13 and IL-17A were significantly increased, and serum TGF-β1 levels were significantly decreased (P < 0·05) in patients with AA compared with controls. Serum IL-2 levels were significantly different among AA subgroups (P < 0·05). IL-2 levels were positively correlated with the total disease duration and the number of patches on the scalp.The increased levels of serum IL-2, IFN-γ, IL-13 and IL-17A suggested altered T-helper cell function, and reduced serum TGF-β1 levels suggested a defect in Treg function. Therefore, enhanced T-cell-mediated immunity and breakdown of immune tolerance due to deficiency in Tregs may facilitate the occurrence of AA.? 2013 The Authors BJD ? 2013 British Association of Dermatologists.

CAVALJUGA S

OVCINA-KURTOVIC N

, et al. Serum levels of interleukin-2 in patients with alopecia areata: relationship with clinical type and duration of the disease[J]. Skin Appendage Disor, 2018, 4(4):286-290.

Background: Alopecia areata (AA) is a disease characterized by focally, nonscarring hair loss on the scalp or any hair-bearing surface. The etiology is unknown, although the evidence suggests that AA is an immunologically mediated disease. In the pathogenesis of AA, Th1 immune response is predominant. A special cytokine profile is created by Th1 cells, which disturbs the natural balance of the cytokine networks and leads to inflammatory reaction and follicle damage. Objective: The aim of our study was to evaluate serum concentrations of IL-2 in patients with AA and healthy subjects. We also examined a possible association between serum levels of IL-2, disease severity, and duration of AA. Methods: Sixty patients with AA and 20 healthy controls were enrolled in the study. Serum concentrations of IL-2 were measured using enzyme-linked immunoassay techniques. Results: Comparison of mean values of IL-2 has showed that serum concentrations of this cytokine are significantly higher in serum samples of AA patients in relation to the control group (22.2 ± 1.19 vs. 21.1 ± 2.68 pg/mL, respectively; p = 0.0142). No correlations were found between clinical type, duration of the disease, and serum levels of IL-2. Conclusion: Our findings support the evidence that elevation of serum IL-2 is associated with AA. The exact role of serum IL-2 in AA should be additionally investigated in future studies.

SINGH Y

GUPTA A

, et al. The profile of cytokines (IL-2, IFN-γ, IL-4, IL-10, IL-17A, and IL-23) in active alopecia areata[J]. J Cosmet Dermtol, 2020, 19(1):234-240.

MCDONALD E

MOFFAT F

, et al. Alopecia areata is characterized by dysregulation in systemic type 17 and type 2 cytokines, which may contribute to disease-associated psychological morbidity[J]. Br J Dermatol, 2020, 182(1):130-137.

Alopecia areata (AA) is a common autoimmune disease, causing patchy hair loss that can progress to involve the entire scalp (totalis) or body (universalis). CD8 NKG2D T cells dominate hair follicle pathogenesis, but the specific mechanisms driving hair loss are not fully understood.To provide a detailed insight into the systemic cytokine signature associated with AA, and to assess the association between cytokines and depression.We conducted multiplex analysis of plasma cytokines from patients with AA, patients with psoriatic arthritis (PsA) and healthy controls. We used the Hospital Anxiety and Depression Scale (HADS) to assess the occurrence of depression and anxiety in our cohort.Our analysis identified a systemic inflammatory signature associated with AA, characterized by elevated levels of interleukin (IL)-17A, IL-17F, IL-21 and IL-23 indicative of a type 17 immune response. Circulating levels of the type 2 cytokines IL-33, IL-31 and IL-17E (IL-25) were also significantly increased in AA. In comparison with PsA, AA was associated with higher levels of IL-17F, IL-17E and IL-23. We hypothesized that circulating inflammatory cytokines may contribute to wider comorbidities associated with AA. Our assessment of psychiatric comorbidity in AA using HADS scores showed that 18% and 51% of people with AA experienced symptoms of depression and anxiety, respectively. Using linear regression modelling, we identified that levels of IL-22 and IL-17E are positively and significantly associated with depression.Our data highlight changes in both type 17 and type 2 cytokines among people with AA, suggesting that complex systemic cytokine profiles may contribute both to the pathogenesis of AA and to the associated depression. What's already known about this topic? NKG2D CD8 T cells cause hair loss in alopecia areata (AA) but the immunological mechanisms underlying the disease are not fully understood. AA is associated with changes in levels of interleukin (IL)-6, tumour necrosis factor-α, IL-1β and type 17 cytokines. Psychiatric comorbidity is common among people with AA. What does this study add? People with AA have increased plasma levels of the type 2 cytokines IL-33, IL-31 and IL-17E (IL-25), in addition to the type 17 cytokines IL-17A, IL-21, IL-23 and IL-17F. Levels of IL-17E and IL-22 positively predict depression score. What is the translational message? AA is associated with increased levels of multiple inflammatory cytokines, implicating both type 17- and type 2 immune pathways. Our data indicate that therapeutic strategies for treating AA may need to address the underlying type 17- and type 2 immune dysregulation, rather than focusing narrowly on the CD8 T-cell response. An immunological mechanism might contribute directly to the depression observed in people with AA.? 2019 British Association of Dermatologists.

MOON H N

LEW B L

, et al. Role of T helper 17 cells and T regulatory cells in alopecia areata: comparison of lesion and serum cytokine between controls and patients[J]. J Eur Acad Dermatol Venereol, 2018, 32(6):1028-1033.

Alopecia areata (AA) is an organ-specific autoimmune disease with T-cell-mediated attack of hair follicle autoantigens. As T helper 17 (Th17) cells and T regulatory (Treg) cells are crucially involved in the pathogenesis, the role of Th17 and Treg cytokines has not been studied yet.To determine whether AA is associated with alterations in lesional and serum Th17 and Treg cytokines and studied whether they were associated with clinical type.Scalp skin samples from 45 patients and eight normal controls were obtained for PCR specific for IFN-γ, TNF-α, TGF-β, IL-1, IL-2, IL-4, IL-10, IL-12A, IL-13, IL-17, IL-22 and IL-23. Serum cytokines were measured from 55 patients and 15 normal controls using ELISA.Lesional IL-17 and IL-22 were significantly increased in patient group. Moreover, positive correlations were shown between lesional IL-17, IL-22 and disease severity. Serum IL-1, IL-17, TNF-α and TGF-β were significantly increased, and positive correlation was shown between serum IL-17 and disease severity.These results showed significantly high Th17 cytokines in both lesion and serum in AA patients, which may highlight a functional role of these cytokines in the pathogenesis of AA.? 2017 European Academy of Dermatology and Venereology.

KEREN A

GINZBURG A

, et al. iNKT cells ameliorate human autoimmunity: lessons from alopecia areata[J]. Autoimmun, 2018, 91:61-72.

MCELWEE K

GILHAR A

, et al. Hair follicle immune privilege and its collapse in alopecia areata[J]. Exp Dermatol, 2020, 29(8):703-725.

Anagen stage hair follicles (HFs) exhibit "immune privilege (IP)" from the level of the bulge downwards to the bulb. Both passive and active IP mechanisms protect HFs from physiologically undesired immune responses and limit immune surveillance. IP is relative, not absolute, and is primarily based on absent, or greatly reduced, intra-follicular antigen presentation via MHC class I and II molecules, along with prominent expression of "no danger" signals like CD200 and the creation of an immunoinhibitory signalling milieu generated by the secretory activities of HFs. Perifollicular mast cells, Tregs and other immunocytes may also contribute to HF IP maintenance in healthy human skin. Collapse of anagen hair bulb IP is an essential prerequisite for the development of alopecia areata (AA). In AA, lesional HFs are rapidly infiltrated by NKG2D + T cells and natural killer (NK) cells, while perifollicular mast cells acquire a profoundly pro-inflammatory phenotype and interact with autoreactive CD8+ T cells. Using animal models, significant functional evidence has accumulated that demonstrates the dominance of the immune system in AA pathogenesis. Purified CD8+T-cell and NK cell populations alone, which secrete fγ, suffice to induce the AA phenotype, while CD4+T-cells aggravate it, and Tregs and iNKT cells may provide relative protection against AA development. While IP collapse may be induced by exogenous agents, inherent IP deficiencies might confer increased susceptibility to AA for some individuals. Thus, a key goal for effective AA management is the re-establishment of a functional HF IP, which will also provide superior protection from disease relapse.? 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

DRAKE L A

SENNA M M

, et al. Alopecia areata: a review of disease pathogenesis[J]. Br J Dermatol, 2018, 179(5):1033-1048.

Alopecia areata is a disorder that results in nonscarring hair loss. The psychological impact can be significant, leading to feelings of depression and social isolation. Objectives In this article, we seek to review the pathophysiological mechanisms proposed in recent years in a narrative fashion.We searched MEDLINE and Scopus for articles related to alopecia areata, with a particular emphasis on its pathogenesis.The main theory of alopecia areata pathogenesis is that it is an autoimmune phenomenon resulting from a disruption in hair follicle immune privilege. What causes this breakdown is an issue of debate. Some believe that a stressed hair follicle environment triggers antigen presentation, while others blame a dysregulation in the central immune system entangling the follicles. Evidence for the latter theory is provided by animal studies, as well investigations around the AIRE gene. Different immune-cell lines including plasmacytoid dendritic cells, natural killer cells and T cells, along with key molecules such as interferon-γ, interleukin-15, MICA and NKG2D, have been identified as contributing to the autoimmune process.Alopecia areata remains incurable, although it has been studied for years. Available treatment options at best are beneficial for milder cases, and the rate of relapse is high. Understanding the exact mechanisms of hair loss in alopecia areata is therefore of utmost importance to help identify potential therapeutic targets.? 2018 British Association of Dermatologists.

KILANI R T

LI Y

, et al. Fibroblast cell-based therapy prevents induction of alopecia areata in an experimental model[J]. Cell Transplant, 2018, 27(6):994-1004.

Alopecia areata (AA) is an autoimmune hair loss disease with infiltration of proinflammatory cells into hair follicles. Current therapeutic regimens are unsatisfactory mainly because of the potential for side effects and/or limited efficacy. Here we report that cultured, transduced fibroblasts, which express the immunomodulatory molecule indoleamine 2,3-dioxygenase (IDO), can be applied to prevent hair loss in an experimental AA model. A single intraperitoneal (IP) injection of IDO-expressing primary dermal fibroblasts was given to C3H/HeJ mice at the time of AA induction. While 60-70% of mice that received either control fibroblasts or vehicle injections developed extensive AA, none of the IDO-expressing fibroblast-treated mice showed new hair loss up to 20 weeks post injection. IDO cell therapy significantly reduced infiltration of CD4 and CD8 T cells into hair follicles and resulted in decreased expression of TNF-α, IFN-γ and IL-17 in the skin. Skin draining lymph nodes of IDO fibroblast-treated mice were significantly smaller, with more CD4 CD25 FoxP3 regulatory T cells and fewer Th17 cells than those of control fibroblast and vehicle-injected mice. These findings indicate that IP injected IDO-expressing dermal fibroblasts can control inflammation and thereby prevent AA hair loss.

SCHRUM A G

ETZIONI A

, et al. Alopecia areata: animal models illuminate autoimmune pathogenesis and novel immunotherapeutic strategies[J]. Autoimmun Rev, 2016, 15(7):726-735.

One of the most common human autoimmune diseases, alopecia areata (AA), is characterized by sudden, often persisting and psychologically devastating hair loss. Animal models have helped greatly to elucidate critical cellular and molecular immune pathways in AA. The two most prominent ones are inbred C3H/HeJ mice which develop an AA-like hair phenotype spontaneously or after experimental induction, and healthy human scalp skin xenotransplanted onto SCID mice, in which a phenocopy of human AA is induced by injecting IL-2-stimulated PBMCs enriched for CD56+/NKG2D+ cells intradermally. The current review critically examines the pros and cons of the available AA animal models and how they have shaped our understanding of AA pathobiology, and the development of new therapeutic strategies. AA is thought to arise when the hair follicle's (HF) natural immune privilege (IP) collapses, inducing ectopic MHC class I expression in the HF epithelium and autoantigen presentation to autoreactive CD8+ T cells. In common with other autoimmune diseases, upregulation of IFN-γ and IL-15 is critically implicated in AA pathogenesis, as are NKG2D and its ligands, MICA, and ULBP3. The C3H/HeJ mouse model was used to identify key immune cell and molecular principles in murine AA, and proof-of-principle that Janus kinase (JAK) inhibitors are suitable agents for AA management in vivo, since both IFN-γ and IL-15 signal via the JAK pathway. Instead, the humanized mouse model of AA has been used to demonstrate the previously hypothesized key role of CD8+ T cells and NKG2D+ cells in AA pathogenesis and to discover human-specific pharmacologic targets like the potassium channel Kv1.3, and to show that the PDE4 inhibitor, apremilast, inhibits AA development in human skin. As such, AA provides a model disease, in which to contemplate general challenges, opportunities, and limitations one faces when selecting appropriate animal models in preclinical research for human autoimmune diseases. Copyright ? 2016 Elsevier B.V. All rights reserved.

GHERARDINI J

PAPPELBAUM K

, et al. Resident human dermal γδT-cells operate as stress-sentinels: lessons from the hair follicle[J]. J Autoimmun, 2021, 124:102711.doi:10.1016/j.jaut.2021.102711.

ZIRAK B

RODRIGUEZ R S

, et al. Regulatory T Cells in skin facilitate epithelial stem cell differentiation[J]. Cell, 2017, 169(6):1119-1129.

The maintenance of tissue homeostasis is critically dependent on the function of tissue-resident immune cells and the differentiation capacity of tissue-resident stem cells (SCs). How immune cells influence the function of SCs is largely unknown. Regulatory T cells (Tregs) in skin preferentially localize to hair follicles (HFs), which house a major subset of skin SCs (HFSCs). Here, we mechanistically dissect the role of Tregs in HF and HFSC biology. Lineage-specific cell depletion revealed that Tregs promote HF regeneration by augmenting HFSC proliferation and differentiation. Transcriptional and phenotypic profiling of T and HFSCs revealed that skin-resident Tregs preferentially express high levels of the Notch ligand family member, Jagged 1 (Jag1). Expression of Jag1 on Tregs facilitated HFSC function and efficient HF regeneration. Taken together, our work demonstrates that Tregs in skin play a major role in HF biology by promoting the function of HFSCs.Copyright ? 2017 Elsevier Inc. All rights reserved.

HARRIS J E

RICHMOND J M

. Resident memory T cells in autoimmune skin diseases[J]. Front Immunol, 2021, 12:652191.doi:3389/fimmu.2021.652191.

GORDON C L

CHRISTO S N

, et al. Local heroes or villains: tissue-resident memory T cells in human health and disease[J]. Cell Mol Immunol, 2020, 17(2):113-122.

Tissue-resident memory T (T) cells are increasingly associated with the outcomes of health and disease. T cells can mediate local immune protection against infections and cancer, which has led to interest in T cells as targets for vaccination and immunotherapies. However, these cells have also been implicated in mediating detrimental pro-inflammatory responses in autoimmune skin diseases such as psoriasis, alopecia areata, and vitiligo. Here, we summarize the biology of T cells established in animal models and in translational human studies. We review the beneficial effects of T cells in mediating protective responses against infection and cancer and the adverse role of T cells in driving pathology in autoimmunity. A further understanding of the breadth and mechanisms of T cell activity is essential for the safe design of strategies that manipulate T cells, such that protective responses can be enhanced without unwanted tissue damage, and pathogenic T cells can be eliminated without losing local immunity.

DAI J

SINGH S

. Plasmacytoid dendritic cells and type I IFN: 50 years of convergent history[J]. Cytokine Growth Factor Rev, 2008, 19(1):3-19.

XING L

CERISE J

, et al. CXCR3 blockade inhibits T cell migration into the skin and prevents pevelopment of alopecia areata[J]. J Immunol, 2016, 197(4):1089-1099.

Alopecia areata (AA) is an autoimmune disease of the hair follicle that results in hair loss of varying severity. Recently, we showed that IFN-γ–producing NKG2D+CD8+ T cells actively infiltrate the hair follicle and are responsible for its destruction in C3H/HeJ AA mice. Our transcriptional profiling of human and mouse alopecic skin showed that the IFN pathway is the dominant signaling pathway involved in AA. We showed that IFN-inducible chemokines (CXCL9/10/11) are markedly upregulated in the skin of AA lesions, and further, that the IFN-inducible chemokine receptor, CXCR3, is upregulated on alopecic effector T cells. To demonstrate whether CXCL9/10/11 chemokines were required for development of AA, we treated mice with blocking Abs to CXCR3, which prevented the development of AA in the graft model, inhibiting the accumulation of NKG2D+CD8+ T cells in the skin and cutaneous lymph nodes. These data demonstrate proof of concept that interfering with the Tc1 response in AA via blockade of IFN-inducible chemokines can prevent the onset of AA. CXCR3 blockade could be approached clinically in human AA with either biologic or small-molecule inhibition, the latter being particularly intriguing as a topical therapeutic.

JIN Y Q

WU W

. SOCS3 treatment prevents the development of alopecia areata by inhibiting CD8+ T cell-mediated autoimmune destruction[J]. Oncotarget, 2017, 8(20):33432-33443.

YüCESOY S N

CO?KUN E

, et al. Evaluation of the level of serum interleukins (IL-2, IL-4, IL-15 andIL-17) and its relationship with disease severity in patients with alopecia areata[J]. An Bras Dermatol, 2021, 96(5):551-557.

LE DUFF F

BUTORI C

, et al. Effects of low-dose recombinant interleukin 2 to promote T-regulatory cells in alopecia areata[J]. JAMA Dermatol, 2014, 150(7):748-751.

An impaired inhibitory function of circulating CD4+CD25+ regulatory T (Treg) cells was reported to play a key role in alopecia areata (AA). We report the first use to our knowledge of low-dose interleukin 2 for treating severe AA by promoting the recruitment of Treg cells.We conducted a prospective open pilot study in 5 patients with severe AA resistant to previous systemic treatments. Subcutaneous interleukin 2 (1.5 million IU/d) was administered during 5 days, followed by three 5-day courses of 3 million IU/d at weeks 3, 6, and 9. The primary outcome was the evolution of the Severity of Alopecia Tool (SALT) score, evaluated by 2 independent investigators on standardized photographs. Lesional skin biopsy specimens and peripheral blood lymphocyte phenotype were analyzed. The median SALT score went from 82 (range, 63-100) at baseline to 69 (range, 28-100) at 6 months. Immunochemical analysis revealed the appearance or a notable increase in Treg cell count in 4 of 5 patients at the end of the treatment compared with baseline. No serious adverse event was reported.The partial regrowth achieved in 4 of 5 patients and the recruitment of Treg cells in lesional skin support the interest of promoting Treg cells for treating AA. Further investigations are now required to confirm and to optimize the design in order to enhance the Treg cell response.clinicaltrials.gov Identifier: NCT01840046.

BOUAZIZ J D

FONTAS E

, et al. Low-Dose IL-2 for treating moderate to severe alopecia areata: a 52-week multicenter prospective placebo-controlled study assessing its impact on T regulatory cell and NK cell populations[J]. J Invest Dermatol, 2021, 141(4):933-936.

陳靜, 張守民. 斑禿合并特應(yīng)性皮炎免疫學(xué)特性及治療研究進(jìn)展[J]. 中國麻風(fēng)皮膚病雜志, 2022, 38(5):343-346.

RENERT-YUVAL Y

BARES J

, et al. Phase 2a randomized clinical trial of dupilumab (anti-IL-4Rα) for alopecia areata patients[J]. Allergy, 2022, 77(3):897-906.

NAPOLITANO M

FERRILLO M

, et al. Dupilumab and alopecia: a janus effect[J]. Dermatol Ther, 2019, 32(5):e13023.

SIU K

ALEXIS A F

, et al. Etanercept does not effectively treat moderate to severe alopecia areata: an open-label study[J]. J Am Acad Dermatol, 2005, 52(6):1082-1084.

In this prospective, open-label pilot study, we evaluated the safety and efficacy of etanercept, a TNF-alpha inhibitor, in the treatment of moderate to severe alopecia areata, alopecia totalis, or alopecia universalis. Seventeen otherwise healthy adults with moderate to severe alopecia areata were enrolled. The primary outcome measure was the extent of hair regrowth during and after the end of treatment as evaluated by the Severity of Alopecia Tool (the SALT score). After between 8 and 24 weeks of continuous treatment with etanercept 50 mg given subcutaneously twice weekly, significant regrowth of hair was not shown in any of the subjects treated. Based on these results, etanercept appears to be ineffective in treating subjects with treatment-refractory, moderate to severe alopecia areata, alopecia totalis, or alopecia universalis.

BISSONNETTE R

. Safety and efficacy of adalimumab for the treatment of severe alopecia areata: case series of three patients[J]. J Cutan Med Surg, 2012, 16(4):257-260.

Current therapeutic options for extensive alopecia areata (AA) often lead to disappointing results.To study the efficacy and safety of adalimumab in patients with severe AA.This was a prospective, open-label, single-center, pilot study. Three subjects of the planned 10 were enrolled and received two weekly subcutaneous (SC) loading doses of adalimumab 80 mg followed by 40 mg SC every week for 6 months. Patients were evaluated for efficacy and safety on a monthly basis.Enrolment in this trial was stopped following publication of studies showing no improvement in patients with AA treated with tumor necrosis factor α antagonists. One patient had a favorable response to adalimumab, whereas the two other patients had no benefit from the therapy. Adalimumab was well tolerated by patients with AA.Adalimumab was well tolerated in patients with AA but did not induce clinically significant hair regrowth.

LIN A

TRABOULSI C

, et al. Treatment of crohn's disease and concomitant alopecia areata with tofacitinib[J]. ACG Case Rep J, 2021, 8(11):e00690.

SUZUKI T

SAKABE J I

, et al. Plasmacytoid dendritic cells as a possible key player to initiate alopecia areata in the C3H/HeJ mouse[J]. Allergol Int, 2020, 69(1):121-131.

Alopecia areata (AA) is a tissue-specific autoimmune disease, and interferon (IFN)-γ has been regarded as the key cytokine in the pathogenesis of AA. The clinical observation that AA can occur after viral infection or IFN-α administration implies that IFN-α-producing plasmacytoid dendritic cells (pDCs) may be involved in the AA pathogenesis.We generated AA in C3H/HeJ mice by intradermal injection of T cells derived from lymph nodes of AA-bearing syngeneic mice and stimulated IL-2, IL-7, and IL-15. Distribution of IFN-γ producing pDCs were immunohistochemically analyzed. Realtime PCR were also demonstrated to detect the expression of IFN-γ mRNA. Hair follicles were cultured with IFN-α in order to calculate the hair elongation. Imiquimod was employed to induce catagen stage. PDCs were injected into C3H/HeJ mice to initiate AA.In this mouse, IFN-α-producing pDCs densely infiltrated around HFs in not only AA lesional but also vicinity of AA lesion. Importantly, intradermal injection of pDCs induced AA lesions. Finally, IFN-α inhibited hair elongation of murine vibrissae and upregulated MHC class I and CXCL10 levels in vitro.These findings suggest that IFN-α-producing pDCs initiate AA by inducing apoptosis and increasing Th1/Tc1 chemokine production such as CXCL10, that accumulates Th1/Tc1 cells and result in autoimmune reactions against hair follicles.Copyright ? 2019 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.

NIA J K

HASHIM P W

, et al. Efficacy and safety of secukinumab treatment in adults with extensive alopecia areata[J]. Arch Dermatol Res, 2018, 310(8):607-614.

CAVANI A

CANZONA F

, et al. Mild therapeutic response of alopecia areata during treatment of psoriasis with secukinumab[J]. Eur J Dermatol, 2020, 30(5):602-603.

MAGNANO M

PATRIZI A

, et al. Generalized hypertrichosis due to secukinumab in a patient with moderate psoriasis: a case of serendipity or zemblanity?[J]. Dermatol Ther, 2019, 32(3):e12894.

UNGAR B

NODA S

, et al. Extensive alopecia areata is reversed by IL-12/IL-23p40 cytokine antagonism[J]. J Allergy Clin Immunol, 2016, 137(1):301-304.

KIM S R

CROTTS S

, et al. IL-12/IL-23 neutralization is ineffective for alopecia areata in mice and humans[J]. J Allergy Clin Immunol, 2019, 144(6):1731-1734.

BENETON N

REYGAGNE P

, et al. Alopecia areata developing during ustekinumab therapy: report of two cases[J]. Eur J Dermatol, 2013, 23(6):912-913.

FENG S

SUN B

, et al. Benefit and risk profile of tofacitinib for the treatment of alopecia areata: a systemic review and meta-analysis[J]. J Eur Acad Dermatol Venereol, 2020, 34(1):192-201.

Recent insights showed the possibility of using JAK inhibitors for the treatment of alopecia areata (AA). Most of the previous articles evaluated the overall efficacy of existing JAK inhibitors rather than evaluating one of them alone. Currently, the benefit and risk profile of tofacitinib for the treatment of AA is still not clear.To estimate the safety and efficacy of tofacitinib in patients with AA based on summarizing the clinical outcomes.The systematic review and meta-analysis was performed according to PRISMA guidelines. ROBINS-I (Risk of Bias in Non-randomized Studies-of Interventions) was used for quality assessment.We enrolled 14 studies including six clinical trials and eight observational studies with 275 patients. The result of meta-analysis showed that tofacitinib has reasonable effectiveness in patients with AA. The pooled good/complete hair regrowth rate of tofacitinib treating patient with AA was 54.0% (95% CI: 46.3%-61.5%), and the pooled rate of partial response in patients with AA taking tofacitinib was 26.1% (20.7-32.2%). Approximately a quarter of patients had experience of relapse, most of which was reported due to discontinuation of tofacitinib. In terms of toxicity, reported adverse effects included only mild symptoms. Upper respiratory infection, headache and acne were the most common adverse events.Tofacitinib seems to be a promising drug for the treatment of AA with only mild adverse effects. More thorough larger sized randomized clinical trials are required to further assess the safety and clinical efficacy of tofacitinib for the treatment of AA.? 2019 European Academy of Dermatology and Venereology.

KO J

FORMAN S

. et al. Efficacy and safety of the oral janus kinase inhibitor baricitinib in the treatment of adults with alopecia areata: phase 2 results from a randomized controlled study[J]. J Am Acad Dermatol, 2021, 85(4):847-853.

DENIRO K L

BRICHTA L

, et al. Topical janus kinase inhibitors for the treatment of pediatric alopecia areata[J]. J Am Acad Dermatol, 2017, 77(1):167-170

SEBARATNAM D F

. JAK inhibitors for alopecia areata: a systematic review and meta-analysis of the european academy of dermatology and venereology[J]. J Eur Acad Dermatol Venereol, 2019, 33(5):850-856.

There have been a number of case reports and small clinical trials reporting promising outcomes of Janus Kinase (JAK) inhibitors tofacitinib, ruxolitinib and baricitinib for alopecia areata (AA). The majority of the literature to date is based on small volume data, with a lack of definitive evidence or guidelines. To determine the expected response of AA to JAK inhibitor therapy and factors which influence response and recurrence rates. A systematic review and meta-analysis was performed according to PRISMA guidelines. From 30 studies and 289 cases, there were 72.4% responders, good responders 45.7% and partial responders 21.4%. Mean time to initial hair growth was 2.2 ± 6.7 months, and time to complete hair regrowth was 6.7 ± 2.2 months. All 37 recurrences occurred when treatment was ceased after 2.7 months. Oral route was significantly associated with response to treatment compared to topical therapy. No difference was found between paediatric and adult cases in proportion of responses. There is promising low-quality evidence regarding the effectiveness of JAK inhibitors in AA. Future large-sized randomized studies are required to confirm findings.? 2019 European Academy of Dermatology and Venereology.

李夢麗, 盧誠, 萬慧陽, 等. 小分子Janus激酶抑制劑的研究進(jìn)展[J]. 中國新藥雜志, 2021, 30(23):2178-2188.

GUTTMAN-YASSKY E

. A novel therapeutic paradigm for patients with extensive alopecia areata[J]. Expert Opin Biol Ther, 2016, 16(8):1005-1014.

SALLEE B N

WANG E H C

, et al. An open-label study evaluating the efficacy of abatacept in alopecia areata[J]. J Am Acad Dermatol, 2021, 84(3):841-844.

劉伊雯, 王磊, 周君浩, 等. 斑禿的藥物治療研究進(jìn)展[J]. 中國皮膚性病學(xué)雜志, 2022, 36(7):841-845.

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