CCL20 and IL22 Messenger RNA Expression After Adalimumab vs Methotrexate Treatment of Psoriasis: A Randomized Clinical Trial.
CCL20 and IL22 Messenger RNA Expression After Adalimumab vs Methotrexate Treatment of Psoriasis: A Randomized Clinical Trial.
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DOI：
10.1001/jamadermatol.2015.0452
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发表时间：
2015-08
期刊：
影响因子：
10.9
通讯作者：
Gottlieb AB
中科院分区：
文献类型：
--
作者：
Goldminz AM;Suárez-Fariñas M;Wang AC;Dumont N;Krueger JG;Gottlieb AB
甲氨蝶呤是治疗银屑病的一线全身性药物，尽管其起效较慢，总体上不如肿瘤坏死因子阻滞剂有效。区分银屑病对阿达木单抗和甲氨蝶呤钠的反应。在2009年8月18日至2011年10月11日期间入组的30例来自Tufts Medical Center门诊皮肤病中心的患者中进行的单中心、随机、评估者设盲、2组临床试验。18 - 85岁慢性斑块型银屑病患者，最低医师总体评估评分为3分（评分越高表明疾病越严重），银屑病斑块至少2 cm，以1：1的比例随机接受皮下阿达木单抗或口服甲氨蝶呤治疗。由设盲评估员对基线和第1、2、4和16周获得的皮肤活检标本进行组织学分级，以评估治疗反应。分析时间为2013年4月16日至2015年1月5日。阿达木单抗皮下给药（负荷剂量后每2周一次40 mg）或低剂量口服甲氨蝶呤钠（7.5-25 mg/周），疗程16周。基因组、免疫组织化学和信使RNA（mRNA）谱的变化。与甲氨蝶呤无应答者相比，甲氨蝶呤应答者经历了辅助性T细胞相关（TH 1，TH 17和TH 22）mRNA表达的显著下调。阿达木单抗治疗患者之间的比较受限于无应答者的数量（n = 1）。在阿达木单抗和甲氨蝶呤应答者之间，我们发现在任何研究时间点的基因表达或在第16周的T细胞相关mRNA表达均无显著差异。阿达木单抗应答者表现出趋化因子的早期下调（C-C基序）配体20（CCL 20）mRNA（第2周的平均值[SE]为-1.83 [0.52]，P < .001;第16周为-3.55 [0.54]，P < .001）与甲氨蝶呤应答者的晚期下调相比（第2周，0.02 [0.51]，P = .96;第16周，-2.96 [0.51]，P < .001）。在阿达木单抗应答者中，观察到白细胞介素22（IL 22）mRNA的类似差异，显示早期下调（第2周，-3.17 [1.00]，P < .001;第16周，-3.58 [1.00]，P < .001）与甲氨蝶呤应答者的晚期下调相比（第2周，-0.44 [0.68]，P = .64;第16周，-5.14 [0.68]，P < .001）。研究过程中关键mRNA和免疫组化标记物表达的方差分析结果仅在比较阿达木单抗和甲氨蝶呤应答者的CCL 20（P = .03）和IL 22（P = .006）mRNA方面具有显著性。甲氨蝶呤是一种免疫调节剂，对银屑病中辅助性T细胞信号传导有影响。阿达木单抗和甲氨蝶呤应答者在研究完成时相似的基因组和免疫组织化学应答特征以及mRNA下调水平表明疾病驱动而非治疗驱动的通路调节。阿达木单抗和甲氨蝶呤的反应通过CCL 20和IL 22 mRNA表达的正常化模式进行区分，并可以解释每种治疗的临床反应的不同发作和程度。clinicaltrials.gov标识符：NCT 00932113
Methotrexate is a first-line systemic agent for treating of psoriasis, although its onset of effects is slower and overall it is less effective than tumor necrosis factor blockers. To differentiate the response of psoriatic disease to adalimumab and methotrexate sodium. Single-center, randomized, assessor-blind, 2-arm clinical trial of 30 patients from the outpatient dermatology center of Tufts Medical Center, enrolled from August 18, 2009, to October 11, 2011. Patients aged 18 to 85 years with chronic plaque-type psoriasis, a minimum Physician Global Assessment score of 3 (higher scores indicate more severe disease), and a psoriatic plaque of at least 2 cm were randomized in a 1:1 fashion to receive subcutaneous adalimumab or oral methotrexate. Skin biopsy specimens obtained at baseline and weeks 1, 2, 4, and 16 were given a histologic grade by blinded assessors to evaluate treatment response. Analyses were conducted from April 16, 2013, to January 5, 2015. A 16-week course of subcutaneous adalimumab (40 mg every 2 weeks after a loading dose) or low-dosage oral methotrexate sodium (7.5–25 mg/wk). Changes in genomic, immunohistochemical, and messenger RNA (mRNA) profiles. Methotrexate responders experienced significant downregulation of helper T-cell– related (TH1, TH17, and TH22) mRNA expression compared with methotrexate nonresponders. Comparisons among adalimumab-treated patients were limited by the number of nonresponders (n = 1). Between adalimumab and methotrexate responders, we found no significant differences in gene expression at any study point or in the expression of T-cell–related mRNA at week 16. Adalimumab responders demonstrated early downregulation of chemokine (C-C motif) ligand 20 (CCL20) mRNA (mean [SE] at week 2, −1.83 [0.52], P < .001; week 16, −3.55 [0.54], P < .001) compared with late downregulation for methotrexate responders (week 2, 0.02 [0.51], P = .96; week 16, −2.96 [0.51], P < .001). Similar differences were observed with interleukin 22 (IL22) mRNA showing early downregulation for adalimumab responders (week 2, −3.17 [1.00], P < .001; week 16, −3.58 [1.00], P < .001) compared with late downregulation for methotrexate responders (week 2, −0.44 [0.68], P = .64; week 16, −5.14 [0.68], P < .001). Analysis of variance findings for key mRNA and immunohistochemical marker expression over the study course were significant only for CCL20 (P = .03) and IL22 (P = .006) mRNA comparing adalimumab and methotrexate responders. Methotrexate is an immunomodulator with effects on helper T-cell signaling in psoriasis. Similar genomic and immunohistochemical response signatures and levels of mRNA downregulation at study completion among adalimumab and methotrexate responders suggest a disease-driven instead of therapeutic-driven pathway regulation. Adalimumab and methotrexate responses are differentiated by patterns of normalization of CCL20 and IL22 mRNA expression and may explain the varied onset and degree of clinical responses by each treatment. clinicaltrials.gov Identifier: NCT00932113
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影响因子：
6.5
作者：
Kennedy-Crispin, Milene;Billick, Erika;Mitsui, Hiroshi;Gulati, Nicholas;Fujita, Hideki;Gilleaudeau, Patricia;Sullivan-Whalen, Mary;Johnson-Huang, Leanne M.;Suarez-Farinas, Mayte;Krueger, James G.
通讯作者：
Krueger, James G.
影响因子：
6.5
作者：
Mabuchi, Tomotaka;Singh, Tej Pratap;Takekoshi, Tomonori;Jia, Guang-fu;Wu, Xuesong;Kao, Mandy C.;Weiss, Ido;Farber, Joshua M.;Hwang, Sam T.
通讯作者：
Hwang, Sam T.
影响因子：
2
作者：
Wittkowski, KM;Lee, E;Krueger, JG
通讯作者：
Krueger, JG
影响因子：
4.4
作者：
Cheuk, Stanley;Wiken, Maria;Eidsmo, Liv
通讯作者：
Eidsmo, Liv
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y