Goldminz Ari M, Suárez-Fariñas Mayte, Wang Andrew C, Dumont Nicole, Krueger James G, Gottlieb Alice B
Department of Dermatology, Tufts Medical Center, Boston, Massachusetts.
Laboratory of Investigative Dermatology, The Rockefeller University, New York, New York.
JAMA Dermatol. 2015 Aug;151(8):837-46. doi: 10.1001/jamadermatol.2015.0452.
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.
DESIGN, SETTING, AND PARTICIPANTS: 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 (T(H)1, T(H)17, and T(H)22) 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.
甲氨蝶呤是治疗银屑病的一线全身用药，尽管其起效较慢，总体疗效也低于肿瘤坏死因子阻滞剂。
区分银屑病对阿达木单抗和甲氨蝶呤钠的反应。
设计、地点和参与者：这是一项单中心、随机、评估者盲法、双臂临床试验，共纳入了30例患者，来自塔夫茨医疗中心门诊皮肤科，于2009年8月18日至2011年10月11日入组。年龄在18至85岁之间、患有慢性斑块型银屑病、医师整体评估最低评分为3分（分数越高表明疾病越严重）且银屑病斑块至少2厘米的患者，以1:1的比例随机接受皮下注射阿达木单抗或口服甲氨蝶呤。在基线以及第1、2、4和16周获取的皮肤活检标本由盲法评估者给出组织学分级，以评估治疗反应。分析于2013年4月16日至2015年1月5日进行。
皮下注射阿达木单抗16周疗程（负荷剂量后每2周40毫克）或低剂量口服甲氨蝶呤钠（7.5 - 25毫克/周）。
基因组、免疫组化和信使核糖核酸（mRNA）谱的变化。
与甲氨蝶呤无反应者相比，甲氨蝶呤反应者中辅助性T细胞相关（Th1、Th17和Th22）mRNA表达显著下调。阿达木单抗治疗患者之间的比较因无反应者数量有限（n = 1）而受限。在阿达木单抗和甲氨蝶呤反应者之间，我们发现在任何研究时间点的基因表达或第16周时T细胞相关mRNA的表达均无显著差异。与甲氨蝶呤反应者的后期下调相比，阿达木单抗反应者表现出趋化因子（C - C基序）配体20（CCL20）mRNA的早期下调（第2周时，平均值[标准误]为 - 1.83[0.52]，P <.001；第16周时， - 3.5[0.54]，P <.001）（甲氨蝶呤反应者第2周时为0.02[0.51]，P =.96；第16周时， - 2.96[0.51]，P <.001）。白细胞介素22（IL22）mRNA也观察到类似差异，阿达木单抗反应者表现出早期下调（第2周时， - 3.17[1.00]，P <.001；第16周时， - 3.58[1.00]，P <.001），而甲氨蝶呤反应者为后期下调（第2周时， - 0.44[0.68]，P =.64；第16周时， - 5.14[0.68]，P <.001）。在研究过程中，关键mRNA和免疫组化标志物表达的方差分析结果仅在比较阿达木单抗和甲氨蝶呤反应者时，CCL20（P =.03）和IL22（P =.006）mRNA有显著差异。
甲氨蝶呤是一种免疫调节剂，对银屑病中的辅助性T细胞信号传导有影响。阿达木单抗和甲氨蝶呤反应者在研究结束时类似的基因组和免疫组化反应特征以及mRNA下调水平表明是疾病驱动而非治疗驱动的途径调节。阿达木单抗和甲氨蝶呤的反应通过CCL20和IL22 mRNA表达的正常化模式得以区分，这可能解释了每种治疗临床反应的不同起效时间和程度。
美国国立医学图书馆临床试验注册中心标识符：NCT00932113。
