Interleukin 23-Helper T Cell 17 Axis as a Treatment Target for Pityriasis Rubra Pilaris
Interleukin 23-Helper T Cell 17 Axis as a Treatment Target for Pityriasis Rubra Pilaris
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DOI：
10.1001/jamadermatol.2016.5384
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发表时间：
2017-04-01
期刊：
影响因子：
10.9
通讯作者：
Conrad, Curdin
中科院分区：
文献类型：
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作者：
Feldmeyer, Laurence;Mylonas, Alessio;Conrad, Curdin
重要性毛发红色糠疹（PRP）的治疗仅基于其与银屑病的相似性，而不是对其病理机制的任何了解。深入了解炎症的致病介质对于靶向和有效的治疗选择是必不可少的，这些治疗选择可以取代先前在难治性PRP中的偶然性治疗方法。（IL-23-T（H）17）通路与乌司奴单抗的联合治疗代表了PRP中一种有效的，并且基于其促炎细胞因子谱的靶向治疗选择。和参与者在本病例报告中，PRP患者在大学医院皮肤科接受乌司奴单抗门诊治疗，根据批准的银屑病给药方案。从该患者和另外2名难治性PRP患者中采集病变皮肤活检样本。测量促炎性先天性和T细胞衍生的细胞因子的信使RNA（mRNA）表达，并与银屑病患者和健康供体的皮肤样本进行比较。在乌司奴单抗治疗前以及治疗开始后4周和28周采集1例患者的皮损皮肤样本。干预皮下注射乌司奴单抗45 mg，在第0周和第4周，此后每季度一次。主要结果和测量主要结果是确定乌司奴单抗治疗期间促炎性先天性和T细胞衍生细胞因子表达的变化。第二个目标是评估临床和组织病理表型的促炎细胞因子的mRNA表达profile.Results在病变PRP皮肤样本从一个单一的病人，上调表达水平被发现为最促炎的先天性细胞因子，包括肿瘤坏死因子（TNF），IL-6，IL-12，IL-23，和IL-1 β。在适应性T细胞细胞因子中，在PRP中观察到TH 1细胞因子，特别是TH 17细胞因子IL-17 A、IL-17 F和IL-22的增加。接受乌司奴单抗治疗的PRP患者在2周后显示皮肤病变消退，1个月后几乎完全消退。临床和组织病理学改善的T（H）17细胞因子的表达水平，但不是干扰素-γ和TNF，这落后于improvementation.CONCLUSIONS和RELEVANCE在这种情况下，报告中的IL-23-T（H）17-轴在PRP的作用被确定，这表明一个共同的致病性炎症途径与银屑病，尽管明显的临床和组织病理学差异。此外，本报告提供了靶向IL-23-T（H）17通路作为难治性PRP治疗选择的依据。
IMPORTANCE Treatment of pityriasis rubra pilaris (PRP) is solely based on its resemblance to psoriasis rather than any knowledge of its pathomechanism. Insight into pathogenic mediators of inflammation is essential for targeted and valid treatment options that could replace previous serendipitous therapeutic approaches in refractory PRP.OBJECTIVE To determine whether blockade of the interleukin 23-helper T cell 17 (IL-23-T(H)17) pathway with ustekinumab represents an efficacious and, based on its proinflammatory cytokine profile, targeted treatment option in PRP.DESIGN, SETTING, AND PARTICIPANTS In this case report, a patient with PRP received outpatient treatment at a university hospital department of dermatology with ustekinumab according to the dosing regimen approved for psoriasis. Lesional skin biopsy samples were taken from this patient and 2 others with refractory PRP. Messenger RNA (mRNA) expression of proinflammatory innate and T-cell-derived cytokines were measured and compared with skin samples from patients with psoriasis and healthy donors. From 1 patient, lesional skin samples were taken before ustekinumab treatment and 4 and 28 weeks after treatment initiation. Follow-up was completed after 6 months.INTERVENTION Subcutaneous ustekinumab, 45mg, at weeks 0 and 4 and quarterly thereafter.MAIN OUTCOMES AND MEASURES The primary outcomewas to determine the changes in expression of proinflammatory innate and T-cell-derived cytokines during ustekinumab therapy. The secondary objective was to evaluate the clinical and histopathologic phenotype in relation to the mRNA expression profile of proinflammatory cytokines.RESULTS In lesional PRP skin samples from a single patient, upregulated expression levels were found for most proinflammatory innate cytokines, including tumor necrosis factor (TNF), IL-6, IL-12, IL-23, and IL-1 beta. Among adaptive T-cell cytokines, an increase of TH1 cytokines and, in particular, TH17 cytokines IL-17A, IL-17F, and IL-22 was seen in PRP. The patient with PRP who received ustekinumab showed regression of skin lesions after 2 weeks and almost complete resolution after 1 month. Clinical and histopathologic improvement paralleled the expression levels of T(H)17 cytokines but not of interferon-gamma and TNF, which lagged behind the amelioration.CONCLUSIONS AND RELEVANCE In this case report, a role of the IL-23-T(H)17-axis in PRP was identified, suggesting a shared pathogenic inflammatory pathway with psoriasis, despite evident clinical and histopathologic differences. In addition, this report provides a rationale for targeting the IL-23-T(H)17-pathway as a treatment option for refractory PRP.