Efficacy and safety of pimecrolimus cream in the long-term management of atopic dermatitis in children.
Efficacy and safety of pimecrolimus cream in the long-term management of atopic dermatitis in children.
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DOI：
10.1542/peds.110.1.e2
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发表时间：
2002-07
期刊：
影响因子：
8
通讯作者：
U. Wahn;J. Bos;M. Goodfield;R. Caputo;K. Papp;A. Manjra;A. Dobozy;C. Paul;S. Molloy;T. Hultsch;M. Graeber;R. Cherill;Y. de Prost
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作者：
U. Wahn;J. Bos;M. Goodfield;R. Caputo;K. Papp;A. Manjra;A. Dobozy;C. Paul;S. Molloy;T. Hultsch;M. Graeber;R. Cherill;Y. de Prost
目的 吡美莫司乳膏 (SDZ ASM 981) 是一种炎症细胞因子的非类固醇抑制剂，对特应性皮炎 (AD) 有效。我们评估了吡美莫司早期治疗 AD 体征/症状是否可以通过预防疾病发作来影响长期结果。方法 将吡美莫司早期干预与传统 AD 治疗策略（即润肤剂和外用皮质类固醇）进行比较。在这项为期 1 年的对照双盲研究中，713 名 AD 患者（2-17 岁）按 2:1 的比例随机接受基于吡美莫司的治疗方案或传统治疗方案。两组均使用针对干性皮肤的润肤剂。早期 AD 体征/症状使用吡美莫司乳膏进行治疗，或者在常规治疗组中使用媒介物进行治疗，以防止进展为耀斑。如果发生耀斑，则必须使用中等效力的外用皮质类固醇。主要疗效终点是 6 个月时的耀斑分级。对安全性进行临床监测，并在研究完成时进行皮肤召回抗原测试。结果 患者的基线特征：两组的平均年龄约为 8 岁，大多数患者在基线时患有中度疾病。患者随访和研究药物暴露：吡美莫司组的平均随访时间（+/-标准误差）为303.7（+/-5.30）天，对照组为235.2（+/-9.40）天。对照组的停药率显着高于吡美莫司组（12 个月时为 51.5% vs 31.6%），并且对照组中患有严重或非常严重疾病的患者比例较高。对照组停药率较高的主要原因是治疗效果不理想（30.4% vs 12.4%）。这导致吡美莫司组的平均研究药物治疗天数显着高于对照组：211.9（研究天数的 69.8%）与 156.0（研究天数的 66.3%）。在完成 12 个月研究的患者中，吡美莫司组和载体组中分别有 14.2% 和 7.0% 的患者持续使用研究药物。疗效 根据对 AD 发作分级的主要疗效分析（Van Elteren 检验），吡美莫司组患者的 AD 发作明显少于对照组患者。与对照组相比，吡美莫司组完成 6 或 12 个月未出现耀斑的患者比例大约是对照组的两倍（6 个月时为 61.0% vs 34.2%；12 个月时为 50.8% vs 28.3%）。无论基线疾病严重程度如何，吡美莫司组中观察到的耀斑较少，因此即使是重症患者也能从治疗中受益。对首次发作时间的分析表明，吡美莫司治疗与显着更长的无发作期相关（对数秩检验）。协变量分析表明，尽管所有基线疾病严重程度亚组的患者均受益于治疗，但根据研究人员的总体评估，对基线湿疹面积和严重程度指数评分的首次发作时间以及患者在基线时是否患有“严重”或“非常严重”疾病具有统计学显着影响。年龄没有显着影响。与对照组相比，吡美莫司组需要局部皮质类固醇治疗的患者较少（6 个月时为 35.0% vs 62.9%；12 个月时为 42.6% vs 68.4%），并且吡美莫司组患者接受局部皮质类固醇治疗的天数较少（分别为 57.4% vs 31.6% [吡美莫司 vs 对照组] 0 天）在研究的 12 个月中，1-14 天为 17.1% vs 27.5%，>14 天为 25.5% vs 41.0%）。尽管吡美莫司治疗的患者比对照组患者接受研究的时间更长，但吡美莫司的这种类固醇节约作用是明显的。吡美莫司组花在二线皮质类固醇上的平均研究天数比例为 4.08%，对照组为 9.10%。随着时间的推移对湿疹面积和严重程度指数的分析显示，中位分数显着较低，因此表明与对照组相比，吡美莫司组的疾病控制更好。从研究人员的总体评估分析中获得了类似的结果（未显示）。在研究期间，治疗组使用抗组胺药的患者数量非常平衡（吡美莫司与对照组分别为 57.2% 和 62.9%）。安全性 治疗组之间的不良事件总体发生率没有明显差异。最常见的不良事件是常见的儿童感染和疾病，包括鼻咽炎、头痛和咳嗽。吡美莫司组中疑似药物相关不良事件的发生率没有显着差异（24.7% vs 18.7%——吡美莫司 vs 对照组），并且严重不良事件的发生率较低（8.3% vs 5.2%——吡美莫司 vs 对照组）。不良事件发生率的生命表分析显示，除咳嗽外，治疗组之间没有显着差异。两个治疗组的局部耐受性均良好。最常见的应用部位反应是烧灼感（10.5% vs 9.3%——吡美莫司 vs 对照）。治疗组之间应用部位反应的持续时间或严重程度没有重大差异，其中大多数是轻度至中度和短暂的，发生在治疗的第一周内。两组均报告有皮肤感染。首次发生细菌性皮肤感染的时间的生命表分析以及调整后的细菌性皮肤感染的发生率均没有组间差异。虽然治疗组之间个体病毒性皮肤感染的发生率没有显着差异，但分组病毒性皮肤感染的发生率（吡美莫司组为 12.4% vs 6.3%——吡美莫司 vs 对照组）显示吡美莫司组的发生率稍高。实验室值和生命体征显示组间无显着差异。在继续研究 12 个月的患者中，治疗组之间对回忆抗原的反应没有显着差异。结论 使用吡美莫司治疗早期 AD 体征/症状可有效预防一半以上患者病情恶化，减少或消除对局部皮质类固醇的需求。 6 个月时，在重要的疾病严重程度亚组以及各种预定义的疗效终点方面，一致地看到了益处。此外，这些益处持续了 12 个月，证明长期使用吡美莫司治疗可以更好地控制 AD。与传统治疗组相比，吡美莫司治疗具有良好的耐受性，并且与临床相关的不良事件无关。本文报告的结果为 AD 的有效长期治疗提供了前景，同时减少了对局部皮质类固醇的需求。
OBJECTIVE Pimecrolimus cream (SDZ ASM 981), a nonsteroid inhibitor of inflammatory cytokines, is effective in atopic dermatitis (AD). We assessed whether early treatment of AD signs/symptoms with pimecrolimus could influence long-term outcome by preventing disease flares. METHODS Early intervention with pimecrolimus was compared with a conventional AD treatment strategy (ie, emollients and topical corticosteroids). In this 1-year, controlled, double-blind study, 713 AD patients (2-17 years) were randomized 2:1 to a pimecrolimus-based or conventional regimen. Both groups used emollients for dry skin. Early AD signs/symptoms were treated with pimecrolimus cream or, in the conventional treatment group, vehicle to prevent progression to flares. If flares occurred, moderately potent topical corticosteroids were mandated. The primary efficacy endpoint was ranked flares at 6 months. Safety was monitored clinically, and a skin recall-antigen test was performed at study completion. RESULTS BASELINE CHARACTERISTICS OF THE PATIENTS: The mean age for both groups was approximately 8 years, and the majority of patients had moderate disease at baseline. PATIENT FOLLOW-UP AND EXPOSURE TO STUDY MEDICATION: The mean duration of follow-up (+/-standard error) was 303.7 (+/-5.30) days in the pimecrolimus group and 235.2 (+/-9.40) days in the control group. The discontinuation rate was significantly higher in the control group than in the pimecrolimus group (51.5% vs 31.6% at 12 months), and proportionately more patients with severe or very severe disease discontinued in the control group. The main reason for the higher discontinuation rate in the control group was unsatisfactory therapeutic effect (30.4% vs 12.4%). This resulted in a substantially higher mean number of study medication treatment days in the pimecrolimus group compared with the control group: 211.9 (69.8% of study days) versus 156.0 (66.3% of study days). Of those patients who completed 12 months on study, 14.2% and 7.0% of patients in the pimecrolimus and vehicle groups, respectively, used study medication continuously. EFFICACY Patients in the pimecrolimus group experienced significantly fewer AD flares than those in the control group, according to the primary efficacy analysis on ranked flares of AD (Van Elteren test). The proportion of patients who completed 6 or 12 months with no flares was approximately twice as high in the pimecrolimus group compared with control (61.0% vs 34.2% at 6 months; 50.8% vs 28.3% at 12 months). Fewer flares were observed in the pimecrolimus group regardless of baseline disease severity, so even severe patients derived benefit from the treatment. The analysis of time to first flare showed that treatment with pimecrolimus was associated with a significantly longer flare-free period (log- rank test). Covariate analysis indicated a statistically significant effect on time to first flare of baseline Eczema Area and Severity Index score, and whether patients had "severe" or "very severe" disease at baseline according to the Investigators' Global Assessment, although patients in all baseline disease severity subgroups benefited from treatment. Age had no significant effect. Fewer patients in the pimecrolimus group required topical corticosteroid therapy compared with control (35.0% vs 62.9% at 6 months; 42.6% vs 68.4% at 12 months), and patients in the pimecrolimus group spent fewer days on topical corticosteroid therapy (57.4% vs 31.6% [pimecrolimus vs control, respectively] spent 0 days on topical corticosteroid therapy, 17.1% vs 27.5% 1-14 days, and 25.5% vs 41.0% >14 days over the 12 months of the study). This steroid-sparing effect of pimecrolimus was evident despite pimecrolimus-treated patients being on study longer than patients in the control group. The average proportion of study days spent on second-line corticosteroids was 4.08% in the pimecrolimus group and 9.10% in the control group. Analysis of Eczema Area and Severity Index over time showed significantly lower median scores, thus indicating better disease control in the pimecrolimus group compared with the control group. Similar results were obtained from analysis of the Investigators' Global Assessment (not shown). The treatment groups were well balanced with respect to the number of patients using antihistamines during the study (57.2% vs 62.9%, pimecrolimus vs control, respectively). SAFETY There were no appreciable differences between treatment groups in the overall incidence of adverse events. The most frequent adverse events were common childhood infections and ailments, including nasopharyngitis, headache, and cough. The incidence of suspected drug-related adverse events was not significantly different in the pimecrolimus group (24.7% vs 18.7%--pimecrolimus vs control), and the incidence of serious adverse events was low (8.3% vs 5.2%--pimecrolimus vs control). Life-table analysis of incidence of adverse events revealed no significant differences between the treatment groups, except for cough. Local tolerability was good in both treatment groups. The most common application site reaction reported was sensation of burning (10.5% vs 9.3%--pimecrolimus vs control). There were no major differences between treatment groups in the duration or severity of application site reactions, most of which were mild-to-moderate and transient, occurring within the first week of treatment. Skin infections were reported in both groups. There were no between-group differences in the life-table analysis of time to first occurrence of bacterial skin infections nor in the adjusted incidence of bacterial skin infections. Although there were no significant differences between treatment groups in the incidence of individual viral skin infections, the incidence of grouped viral skin infections (12.4% vs 6.3%--pimecrolimus vs control) showed a slightly higher incidence in the pimecrolimus group. Laboratory values and vital signs showed no significant between-group differences. There were no significant differences between treatment groups in response to recall antigens in those patients who remained on study for 12 months. CONCLUSIONS Treatment of early AD signs/symptoms with pimecrolimus was effective in preventing progression to flares in more than half the patients, reducing or eliminating the need for topical corticosteroids. The benefits were consistently seen at 6 months across important disease severity subgroups and with respect to the various predefined efficacy endpoints. Furthermore, these benefits were sustained for 12 months, providing evidence that long-term treatment with pimecrolimus leads to better control of AD. Treatment with pimecrolimus was well tolerated and was not associated with clinically relevant adverse events compared with the conventional treatment group. The results reported here offer the prospect of effective long-term management of AD with reduced need for topical corticosteroids.