斑块状银屑病司库奇尤单抗应答不良转换为依奇珠单抗的疗效及安全性观察.pdf

11:372023-03-26网络首发时间AbsDermatovenereolJun.2023,Vol.37,No.6Chin2023年6 月中国皮肤性病学杂老第37 卷第6 期斑块状银屑病司库奇尤单抗应答不良转换为依奇珠单抗的疗效及安全性观察叶珍珍，王文慧，郭金竹摘要 目的探讨司库奇尤单抗治疗中重度斑块状银屑病出现应答不良的患者，转换为依奇珠单抗治疗的疗效和安全性。方法纳入司库奇尤单抗治疗的中重度斑块状银屑病患者，达到PASI50但从未达到PASI90，以及曾达到PASI90后失去PASI75的患者，转换为依奇珠单抗治疗,观察其12 周及长期疗效及安全性。结果共纳入7 例患者，男5例，女2 例，年龄中位数39.7（34.0,57.3）岁，平均病程(26.79.1)年，平均BMI30.64.8。PA SI 评分从基线时（9.8 4.3）分下降至12周时（1.41.2）分，平均治疗时间（46.911.2）周，末次随访PASI评分（2.52.3）分。3例（42.8 6%）患者出现局限性湿疹,1例（14.2 9%）出现注射部位反应，1例（14.2 9%）出现口腔念珠菌病。结论司库奇尤单抗应答不良的中重度斑块状银屑病患者转换为依奇珠单抗，仍然能获得较好的治疗效果，且其安全性可。关键词银屑病；生物制剂转换;IL-17A；治疗中图分类号R 758.63文献标志码B文章编号 11001-7089(2023)06-0673-06DO110.13735/j.cjdv.1001-7089.202211025Efficacy and Safety of Switching to Ixekizumab in Secukinumab Non-Responders withPlaque PsoriasisYE Zhenzhen,WANG Wenhui,GUO Jinzhu(Department of Dermatology,Peking University Third Hospital,Beijing 100191,China)Corresponding authorGUO Jinzhu,E-mail:guojinzhu_826 tractObjectiveTo observe the efficacy and safety of switching to ixekizumab insecukinumab non-responders with moderate-to-severe plaque psoriasis.MethodsPatients with moderate-to-severe plaque psoriasis treated with secukinumab,who hadachieved PASI50 but never achieved PASI90,and who had achieved PASI90 at firstand then lost PASI75,were switched to ixekizumab.Its efficacy of 12 weeks and longterm and its safety was observed.Results A total of 7 patients were included,including 5 males and 2 females,with a median age of 39.7(34.0,57.3)years,anaverage disease duration of(26.7 9.1)years,and an average BMI of 30.6 4.8.The PASI score decreased from 9.8 4.3 at baseline to 1.4 1.2 at 12weeks.The average treatment time was(46.9 11.2)weeks,and the PASI scorewas 2.5 2.3 at the last follow-up.Localized eczema occurred in 3(42.86%)patients,injection site reaction in 1（14.2 9%),a n d o r a l c a n d i d i a s i s i n 1基金项目北京健康促进会医学科学研究基金项目（Z2022023058008）作者单位北京大学第三医院皮肤科，北京10 0 191【通信作者郭金竹,E-mail:guojinzhu_【网络首发地址https:/ 0 2 3年6 月第37 卷第6 期Chin J Derm Venereol,Jun.2023,Vol.37,No.6(14.29%).Conclusion For secukinumab non-responders with moderate-to-severeplaque psoriasis,switching to ixekizumab could achieve good therapeutic effect withacceptable safety.KeywordsPsoriasis;Biologics switching;IL-17A;Treatment银屑病是一种慢性、复发性、炎症性、系统性疾病,我国2 0 0 8 年流行病学调查患病率为0.47%1典型临床表现为鳞屑性红斑或斑块，局限或广泛分布,治疗困难，常罹患终身。在我国，白细胞介素17A（IL-17 A）抑制剂司库奇尤单抗（secukinumab）及依奇珠单抗（ixekizumab）已分别于2 0 19年3月及2019年8 月获准用于中重度斑块状银屑病的治疗，并分别于2 0 2 1年3月及2 0 2 2 年1月进人国家医保目录。随着中重度斑块状银屑病患者应用生物制剂时间的延长，可能会出现应答不良的现象，为了达到更好的治疗效果，临床中可能会采取生物制剂转换的方法。目前我国生物制剂转换的数据较少，笔者对于司库奇尤单抗治疗的中重度斑块状银屑病应答不良的患者转换为依奇珠单抗的疗效和安全性进行了观察，结果报告如下。1对象与方法1.1研究对象收集自2 0 2 0 年12 月一2 0 2 2 年4月于北京大学第三医院诊断为中重度斑块状银屑病的7 例成年患者的病历资料。7 例患者均符合以下条件：应用司库奇尤单抗治疗达到PASI50但从未达到PASI90，以及曾达到PASI90后失去PASI75，并均转换为依奇珠单抗治疗。1.2方法总结患者的性别、年龄、银屑病病史、既往病史、既往治疗方案，司库奇尤单抗治疗前、司库奇尤单抗治疗12 周、转换为依奇珠单抗治疗时、依奇珠单抗治疗12 周以及末次随访时的PASI评分，不良事件等。依奇珠单抗的给药方法为皮下注射，第0 周注射16 0 mg，之后每2 周注射1次8 0 mg直至12 周,之后每4周注射1次8 0 mg。1.3乡统计学处理采用SPSS21.0软件建立数据库。如果变量呈正态分布则采用xs的形式表示；如果变量呈非正态分布，采用M(P25，P7 s）表示。2结结果2.1一般情况共纳人7 例中重度斑块状银屑病患者，男5例，女2 例，年龄中位数39.7（34.0，57.3)岁，平均病程（2 6.7 9.1）年。平均BMI为30.64.8,2例合并高血压,3例合并糖尿病,5例合并血脂异常,3例合并高尿酸血症,3例合并转氨酶升高，1例合并乙肝核心抗体阳性，1例合并银屑病关节炎，1例合并大疱性类天疱疮及慢性荨麻疹，并且因大疱性类天疱疮长期应用糖皮质激素治疗出现股骨头坏死，见表1。2.2既往银屑病治疗情况2 例患者因参与临床试验分别应用JAK抑制剂及依奇珠单抗，均达到PASI90,但由于试验结束停用药物导致银屑病复发。1例应用阿维A,1例应用甲氨蝶呤,3例应用阿达木单抗，均治疗失败，见表2。2.3应用司库奇尤单抗的治疗情况应用司库奇尤单抗治疗之前的平均PASI评分为（2 5.8 11.5）分，司库奇尤单抗平均治疗时间（44.7 10.0）周，7表17 例患者一般情况Tab.1General characteristics of the seven patientsAgeHistory of psoriasisPatientGenderBMIComorbidities(Year)(Year)1F4131.637Transaminase elevation2M3326.925DyslipidemiaHypertension,diabetes mellitus,dyslipidemia,hyperu-3M6723.729ricemia,bullous pemphigoid,chronic urticaria4M3737.117Dyslipidemia,hyperuricemia,transaminase elevation5M3232.717Dyslipidemia,transaminase elevation6M4134.922Diabetes mellitus,hyperuricemia,HbcAb positiveHypertension,diabetes mellitus,dyslipidemia,psoriatic7F6727.340arthritishttp:/.675.叶珍珍，王文慧，郭金竹.斑块状银屑病司库奇尤单抗应答不良转换为依奇珠单抗的疗效及安全性观察例患者中1例在治疗期间从未达到PASI90,6例曾达到PASI90后失去PASI75，故进行转换治疗，见表23。2.4转换为依奇珠单抗治疗12 周及维持治疗的疗效7 例患者转换时的平均PASI评分为（9.8 4.3）分，依奇珠单抗治疗12 周的平均PASI评分为(1.41.2)分。3例（42.8 6%）患者达到PASI90,6例（8 5.7 1%）患者达到PASI75，1例（14.2 9%）患者达到PASI50。6 例（8 5.7 1%）患者的PASI评分达到3分以下。依奇珠单抗末次随访平均治疗时间为（46.911.2）周，末次随访PASI评分为（2.52.3）分。2 例（2 8.57%）达到PASI100，1例(14.29%）达到PASI90,4例(57.14%）达到PASI50,见表3，图1 3。表2 7 例患者既往治疗及司库奇尤单抗治疗情况Tab.2Previous and secukinumab treatment information of the seven patientsTreatment with secukinumabPatientsPrevious systemic treatmentPA.SIPASI at 12Efficacy at 12Durationbefore treatmentweeks of treatmentweeks of treatment(Week)1Treatment failure to acitretin16.81.3PASI9038JAK inhibitor reached PASI90 and relapsed214.50PASI10032afterdiscontinuation3Naive34.00PASI100504Naive44.012.2PASI50525Secondary failure to adalimumab15.53.6PA.SI7533Primary failure to methotrexate633.62.9PASI9053Secondary failure to adalimumabIxekizumab reached PASI90 and relapsed after7discontinuation22.00.8PASI9055Primary failure to adalimumab表37 例患者转换为依奇珠单抗治疗情况Tab.3Ixekizumab treatment information of the seven patientsDuration atPASI at 12Efficacy at 12PASI atEfficacy atPASIthe lastPatientCause of switchingweeksweeksthe lastthe lastbefore treatmentfollow-upof treatmentof treatmentfollow-upfollow-up(Week)115.6Lost PASI75 after achieved PASI903.7PASI75244.8PA.SI5028.9Lost PASI75 after achieved PASI1001.2PA.SI75460.4PASI9038.6Lost PASI75after achieved PASI1000.8PASI90510PASI10047.8Never achieved PASI90,PASI75 could be achieved2.4PA.SI50433.8PASI5059.2Lost PASI75 after achieved PASI900.3PA.SI90563.3PASI50615.2Lost PASI75 after achieved PASI901.3PASI90525.4PASI50Lost PASI75 after achieved PASI90,PASI75 should be73.50.4PASI75560PASI100maintained by once every 2 weeks,localized eczema2.5不良事件其中3例（例1、例2、例3,42.86%）患者出现局限性湿疹（包括1例光敏感，例1），1例（例2,14.2 9%）患者出现注射部位反应，1例（例7,14.2 9%）患者出现口腔念珠菌病。3讨论本研究纳人的患者均为对司库奇尤单抗治疗应答不良的中重度斑块状银屑病患者，转换为依奇珠单抗治疗，大部分患者获得良好效果,安全性与既往报告相似 2 3。司库奇尤单抗和依奇珠单抗都是靶向IL-17A的单克隆抗体,但二者的解离常数分别为100200pmol/L与1.8 pmol/L，说明依奇珠单抗作为高亲和力的人源化单克隆抗体，对于IL-17A的亲http:/?676中国皮肤性病学杂志2 0 2 3年6 月第37 卷第6 期Chin J Derm Venereol,Jun.2023,Vol.37,No.63a2h3h Back and lower limbs before treatment with secukinumab(PASI=33.6);Secondary failure to secukinumab in 53 weeks(PASI=15.2),back and lower limbs before switching to ixekizumab;Back and lower limbs after treatment with ixekizumab for12 weeks(PASI=1.3)图1司库奇尤单抗治疗前（例6）；图2司库奇尤单抗治疗应答不良，转换为依奇珠单抗治疗前（例6）；图3转换为依奇珠单抗治疗12 周后（例6）Fig.1Before treatment with secukinumab(Patient 6);Fig.2 Secondary failure to secukinumab,before switching to ixekizumab(Patient 6);Fig.3Twelve weeks after treatment with ixekizumab(Patient 6)和力大约是司库奇尤单抗的50 10 0 倍 4-5。无论是在三期临床试验数据的间接比较 6-7 ，还是真实世界队列研究的直接比较 8 ，依奇珠单抗都显示了更强的临床疗效,这与依奇珠单抗对于IL-17A的亲和力高是密切相关的。本研究的7 例患者,6 例患者BMI在2 5以上，4例患者在30 以上，超重和肥胖是这些对司库奇尤单抗治疗应答不良的共同特征。肥胖已经被认为是银屑病的共病 9。由于肥胖会促进天然免疫的激活，从而使髓样树突状细胞成熟，导致获得性免疫活化，ThO细胞向Th17细胞方向分化 10 。此外,脂肪组织分泌的TNF-、IL-6 等炎症介质与银屑病密切相关,瘦素、抵抗素等脂肪因子会促进TNF-、CXCL8等炎症介质的产生，促进银屑病的发生和加重 。既往研究表明,单纯的减重治疗也可使银屑病的严重程度减轻 12 。在一项司库奇尤单抗的二期临床试验中，各个剂量组的90 kg以上患者的PASI75均低于90 kg以下患者 13。在另外两项三期临床试验中，应用司库奇尤单抗或依奇珠单抗治疗中重度斑块状银屑病，高体重组的PASI90及PASI100均低于正常体重组 14-15。这说明超重和肥胖的患者较正常体重患者的治疗更加困难。但依奇珠单抗的PASI175未受到体重的影响 15。在法国和美国的指南中，均推荐依奇珠单抗用于肥胖患者 16 17 。因此,对于超重和肥胖的中重度斑块状银屑病患者,如果出现司库奇尤单抗应答不良，可以尝试转换为依奇珠单抗进行治疗。在本研究的7 例患者中，12 周时有1例达到PASI50但未达PASI75，该患者为所有患者中BMI最大者,高达37.1,也是体重的绝对值最大者,高达115kg，同时，该患者的初始PASI评分也是最高者，高达44.0 分。从长期疗效来看，有4例达到PASI50但未达PASI75,BMI均在30 以上，进一步支持了肥胖作为银屑病的共病对于疾病的严重程度和治疗效果的影响，同时提示临床医师需要重视对于肥胖患者进行控制体重的生活方式指导和教育。http:/D677.叶珍珍，王文慧，郭金竹.斑块状银屑病司库奇尤单抗应答不良转换为依奇珠单抗的疗效及安全性观察生物制剂的治疗失败通常分为原发性治疗失败和继发性治疗失败。对于原发性治疗失败应转换为不同靶分子的生物制剂。本研究的7 例患者均为在治疗初期显示良好疗效，随后治疗过程中出现疗效衰减，无法维持治疗目标，医生和患者认为疗效不充分，属于继发性治疗失败。继发性治疗失败的原因包括产生抗药抗体、给药剂量不足、患者对生物制剂的敏感性降低、肥胖、感染、药物、依从性等 18 。本研究中,肥胖可能是其中重要原因之一。由于银屑病治疗目标的进化，国外的指南将PASI评分1 2 分或3分以下作为目标 16.19。我国的银屑病生物制剂治疗指南中,建议以皮损完全清除（PASI100）或PASI90、研究者总体评分0/1作为达到满意疗效的指标。基于以上治疗目标，本研究将治疗未达标的患者进行转换治疗,以进一步提高患者的生活质量。在一项6 9例司库奇尤单抗应答不良的研究中，转换为依奇珠单抗进行治疗12 周时的PASI75/90/100分别为8 1.16%，7 2.46%及40.58%，2 4周时的PASI75/90/100分别为8 0.0 0%，6 8.0 0%及38.00%20。另外两项31例及17 例的研究中,12周的PASI75 分别为7 0.97%及8 8.2 4%2 1.2 。在一项10 9例的研究中,2 4周的PASI75为46.30%2 3。一项2 5例的研究中,转换为依奇珠单抗后的治疗时间为（7.32.8）个月，PASI75/90/100分别为68.18%,40.90%及2 2.7 3%2 4。目前我国缺乏关于生物制剂转换治疗的临床数据。本研究与国外的研究有相似的结果,但存在局限性,本研究为单中心研究,样本量小，观察时间短，患者对于治疗的反应及所发生的不良事件存在异质性及偏倚，仍需要大样本量、多中心、长期的研究进一步证实，以提高对于中国中重度斑块状银屑病患者进行生物制剂转换治疗的临床经验。参考文献1丁晓岚,王婷琳，沈崴，等.中国六省市银屑病流行病学调查J.中国皮肤性病学杂志，2 0 10,2 4（7）：598-601.2 Griffiths CE,Reich K,Lebwohl M,et al.Comparison ofixekizumab with etanercept or placebo in moderate-to-severe psoriasis(UNCOVER-2 and UNCOVER-3):resultsfrom two phase 3 randomised trials J.Lancet,2015,386(9993):541-551.3 Papp KA,Leonardi CL,Blauvelt A,et al.Ixekizumab treat-ment for psoriasis:integrated efficacy analysis of threedouble-blinded,controlled 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Cohen E,Amitay-Laish I,et al.IL-17A inhibitor switching-fficacy of ixekizumab followingsecukinumab failure.A single-center experience J.ActaDerm Venereol,2019,99(9):769-773.收稿日期2022-11-02修回日期2023-02-12童诺异维A酸红霉素凝胶国药集团武汉中联四药药业有限公司封二全国科普行动日公益广告732为豆异维A酸软胶囊重庆华邦制药有限公司封三薇诺娜屏障特护霜昆明贝泰妮生物科技有限公司封四