一项随机对照初步测试在奥拉替尼诱导治疗犬特应性皮炎期间使用四 ...

王帆

A randomised controlled trial testing the reboundpreventing benefit of four days of prednisolone during the induction of oclacitinib therapy in dogs with atopic dermatitis

一项随机对照初步测试在奥拉替尼诱导治疗犬特应性皮炎期间使用四天泼尼松龙预防反弹的好处

作者：Thierry Olivry| Viktorija Lokianskiene| Alejandro Blanco| Pablo Del Mestre| Kerstin Bergvall | Luc Beco

 

翻译：王帆

 

Abstract

ackground: A rebound of pruritus occasionally occurs after oclacitinib dose reduction in dogs with atopic dermatitis (AD).

Objectives: To determine whether an initial 4-day course of prednisolone decreases the probability of a pruritus rebound after reducing the frequency of oclacitinib administration.

Animals: Forty dogs with mild-to-moderate AD lesions and moderate-tosevere pruritus.

Materials and Methods: Dogs were randomised to receive oclacitinib at 0.4–0.6 mg/kg twice daily for 14days then once daily, alone or with prednisolone at 0.5 mg/kg, orally, twice daily for the first 4days. Clinicians graded the Canine Atopic Dermatitis Extent and Severity Index (CADESI)4 and 2D-investigator global assessment (IGA) before and after 28days; owners assessed the pruritis Visual Analog Scale (PVAS)10 and Owner Global Assessment of Treatment Efficacy (OGATE) on Day (D)0, D4, D14, D21 and D28. We considered a rebound any increase greater than one PVAS10 grade at D21 compared to D14.

Results: On D21, there were significantly fewer rebounds in the dogs receiving prednisolone (three of 20, 15%) compared to those given oclacitinib alone (nine of 20, 45%; Fisher's test, p = 0.041). Compared to oclacitinib mono-therapy, the concurrent administration of prednisolone for the first 4days led to significantly lower PVAS10 on D4 and D28, CADESI4 and 2D-IGA on D28, and OGATE on D21 and D28 (Wilcoxon–Mann–Whitney U-tests). Adverse effects of therapy were minor, intermittent and self-resolving.

Conclusions and Clinical Relevance: The initial addition of 4days of prednisolone significantly decreased the probability of a rebound of pruritus 1week after oclacitinib dose reduction. This short concomitant glucocorticoid administration led to a higher skin lesion improvement and improved perception of treatment efficacy with minimal adverse effects.

摘要

背景: 特应性皮炎(AD)患犬在降低奥拉替尼剂量后，偶见瘙痒反弹。

目的: 确定初期使用4天泼尼松龙是否可降低奥拉替尼减少给药频率后瘙痒反弹的概率。

动物: 40只患有轻度至中度 AD病变和中度至重度瘙痒的犬。

材料和方法: 犬随机分配使用奥拉替尼0.4–0.6 mg/kg每日两次给药14天，随后每日一次给药，单药治疗组或者前4天联合口服泼尼松龙0.5 mg/kg每日两次给药组。临床医生在28天前后使用犬特应性皮炎程度和严重指数(CADESI)4和2D研究者整体评估 (IGA)进行分级；宠主在第(D)0、D4、D14、D21和 D28天使用瘙痒视觉模拟量表(PVAS)10和宠主版疗效整体评估(OGATE)进行评估。我们认为与 D14相比，D21时PVAS10等级增加大于1即为反弹。

结果: 在D21，接受泼尼松龙组的犬反弹率(3/20，15%)显著少于接受奥拉替尼单药组的犬 (9/20，45%)(Fisher检验，p = 0.041)。与奥拉替尼单药治疗相比，在前4天同时给予泼尼松龙，使D4和D28时PVAS10、D28时CADESI4和2D-IGA以及D21和D28时OGATE 显著降低(Wilcoxon–Mann–Whitney U检验)。治疗的副作用为轻微、间歇发生和可自愈。

结论和临床相关性:最初4天使用泼尼松龙显著降低了奥拉替尼减量后1周瘙痒反弹的概率。这种短期糖皮质激素联合给药使得皮肤病变改善程度更高，以及疗效感知更好且副作用极小。

 

INTRODUCTION

介绍

Oclacitinib (Apoquel, Zoetis) is a first-in-class, firstgeneration, nonselective-yet-Janus kinase (JAK)1-predominant, JAK inhibitor (JAKinib) approved for the treatment of canine allergic and atopic dermatitis (AD).Oclacitinib exhibits a remarkably rapid and potent antipruritic and antilesional effect in dogs with AD.

奥拉替尼(爱波克)是一类第一代非选择性Janus激酶(JAK)1-优势，JAK抑制剂(JAKinib)被批准用于治疗犬过敏性和特应性皮炎(AD)。奥拉替尼在AD犬中表现出显著的快速和有效的止痒和抗病变作用。

 

In three randomised-controlled trials (RCTs) enrolling dogs with AD or allergic dermatitis, the reduction of frequency of administration of oclacitinib after 2weeks (i.e. from twice daily to once daily) was associated with an unexpected—yet transient—increase in manifestation of pruritus. Such a ‘rebound phenomenon’, which appeared as a mean rise in Day (D)21 or D28 pruritus scores compared to those on D14, was unique to this clinical sign, as it was not observed with skin lesion assessments. A plausible hypothesis for this rebound is the recently published observation of an increase in the transcription of pruritogenic cytokines in allergic skin lesions—as compared with untreated mice—after the abrupt discontinuation of oclacitinib therapy. Such a theory is logical, as this JAKinib, at first, only blocks the intracellular signalling of JAKdependent cytokine receptors without inhibiting the production and release of pro-allergic cytokines by resident and inflammatory cells. Then, as a consequence of the short half-life of oclacitinib in dogs (about 4 h), any elevated skin levels of pruritogenic cytokines [e.g. interleukin (IL)-31] could result in the activation of sensory neurons and itch once the oclacitinib's administration is reduced to once a day. However, with the continuous administration of oclacitinib, the secretion of pro-allergic cytokines is expected to wane following the eventual deactivation of inflammatory and resident cells. The cytokine changes occurring in the skin in the first month of oclacitinib administration to dogs with AD have not been reported to confirm or refute the above theory as of yet.

在三个随机对照试验(RCT)中，登记患有AD或过敏性皮炎的犬，两周后降低给药频率(即从每天两次减少到每天一次)与瘙痒表现的意外但短暂的增加有关。这种“反弹现象”，出现在第21天或第28天瘙痒评分比第14天平均上升，是这种临床症状所特有的，因为在皮肤病变评估中没有观察到。对这种反弹的一个合理假设是，最近发表的一项观察发现，在突然停止奥拉替尼治疗后，过敏性皮肤病变中与未治疗的小鼠相比，致痒细胞因子的转录增加。这样的理论是合乎逻辑的，因为这种JAKinib最初只阻断JAKinib依赖性细胞因子受体的细胞内信号，而不抑制驻留细胞和炎症细胞产生和释放促过敏细胞因子。然后，由于奥拉替尼在犬体内的半衰期很短(约4小时)，一旦奥拉替尼的给药量减少到每天一次，皮肤上任何促痒细胞因子(如白介素(IL)-31)水平的升高都可能导致感觉神经元的激活和瘙痒。然而，随着奥拉替尼的持续使用，促过敏细胞因子的分泌在炎症细胞和驻留细胞最终失活后预计会减弱。AD犬给药第一个月皮肤细胞因子的变化尚未见报道，以证实或反驳上述理论。

 

Because one of the numerous anti-allergic effects of glucocorticoids is the inhibition of transcription of cytokine-encoding genes, the addition of steroids during the induction phase of oclacitinib therapy should prevent any increase in cytokine secretion, and thus, might reduce the probability of a rebound in pruritus.

因为糖皮质激素的众多抗过敏作用之一是抑制细胞因子编码基因的转录，在奥拉替尼治疗的诱导期添加类固醇应该可以防止细胞因子分泌的增加，从而可能减少瘙痒反弹的可能性。

 

The objective of this RCT was to test the hypothesis that a 4-day course of prednisolone at the onset of oclacitinib therapy reduces the proportion of atopic dogs exhibiting a rebound in pruritus, 1week after decreasing the frequency of administration of the drug. We also expected this early adjunctive glucocorticoid therapy, albeit short, to lead to a greater improvement in clinical signs and better perception of the benefit of oclacitinib therapy after 1month.

本随机对照试验的目的是检验这样一个假设，即在奥拉替尼治疗开始时服用4天的泼尼松龙可以减少特应性皮炎犬在减少给药频率1周后出现瘙痒反弹的比例。我们也希望这种早期辅助糖皮质激素治疗，虽然时间较短，但能在1个月后使临床症状有更大的改善，并对奥拉替尼治疗的疗效有更好的感知。

 

This trial is reported following the guidelines of the 2010 CONSORT statement (http://www.consort-statement.org; page last accessed 7 February 2022), with slight modifications in the order of sections to facilitate reading. The reporting of outcome measures includes those from the core outcome set proposed in the 2018 Core Outcome Set for Canine AD (COSCAD'18).

该试验是根据2010 CONSORT声明(http://www.consort-statement.org;最后访问的页面为2022年2月7日)，为方便阅读，对章节顺序进行了轻微修改。结果指标的报告包括2018年犬AD核心结果集(COSCAD'18)中提出的核心结果集。

 

MATERIALS AND METHODS

材料与方法

Ethics

伦理

The two interventions prescribed herein (oclacitinib or prednisolone) were at dosages recommended in the 2015 Practice Guidelines for the Treatment of Canine AD. Consequently, the protocol was considered to follow the best clinical practice standards. Nevertheless, we obtained consent from the owners to enrol their dogs in the study with the possible prescription of an off-label concurrent administration of the two drugs for 4days in one of the treatment groups.

本文规定的两种干预措施(奥拉替尼或泼尼松龙)的剂量在2015年犬AD治疗实践指南中推荐。因此，该方案被认为遵循最佳临床实践标准。尽管如此，我们获得了犬主人的同意，让他们的犬参加研究，其中一个治疗组的处方可能是标签外两种药物联合给药4天。

 

Trial design

试验设计

This trial was a 4-week long, open, parallel, 1:1 randomised trial comparing the efficacy of oclacitinib monotherapy to prednisolone and oclacitinib given together for the first 4days.
该试验是一项为期4周、开放、平行、1:1的随机试验，比较了奥拉替尼单药治疗与前四天泼尼松龙和奥拉替尼联合给药的疗效。

 

Animals

动物

We aimed to enrol at least 40 dogs of any breed, sex and neuter status, aged 12months or older, with a minimum weight of 3.0 kg.

我们的目标是登记至少40只犬，任何品种，性别和性别状态，年龄12月龄或以上，最低体重3.0公斤。

For selection, the following six criteria had to be met:

1.a diagnosis of AD made according to current standards (i.e. a clinical diagnosis with the exclusion of resembling dermatoses), and,

2.if a diagnosis of food-induced AD had been made following a standard restriction-provocation dietary trial, the atopic signs had to remain uncontrolled after feeding a diet not containing causative ingredients, and,

3.there was no evidence of active bacterial or yeast skin infections, and,

4.the dogs did not receive any oral glucocorticoid or oclacitinib, or allergy-interfering medications in the preceding 2weeks before selection, and

5.the atopic skin lesions were of at least mild severity [i.e. a Canine Atopic Dermatitis Extent and Severity Index, 4th iteration (CADESI4) score>10], and,

6.the pruritus manifestations were of at least a moderate grade (i.e. a 10-grade pruritus Visual Analog Scale [PVAS10] score>3.5) in the preceding 24h.
在甄选时，须符合以下六项标准:
1.根据现行标准作出的AD诊断(即排除相似皮肤病的临床诊断)，且
2.如果在一项标准的食物排查激发试验后诊断为食物诱导AD，在喂食不含致病成分的饮食后，特应性皮炎症状未经控制持续存在，且，

3.没有证据表明有活跃的细菌或酵母菌皮肤感染，且
4.在入选前2周内，患犬未使用口服糖皮质激素或奥拉替尼或干扰过敏的药物
5.特应性皮炎皮肤病变的严重程度至少为较度[即犬特应性皮炎程度和严重程度指数，第四版(CADESI4)评分>10]，且
6.在入选前24小时内瘙痒表现至少为中等级别(即瘙痒视觉模拟评分10级[PVAS10]评分>3.5)。

 

Interventions

处置 

Dogs were given one of two interventions. In the oclacitinib monotherapy (OM) group, they were treated with oclacitinib at the approved dosage of 0.4–0.6 mg/kg, twice daily for 14 days, then once daily for 14 days. In the prednisolone-oclacitinib group (PO), the dogs received oclacitinib as those in the OM group, and we also added prednisolone at the targeted dosage of 0.5±0.2 mg/kg twice daily for the first 4 days. Such a short duration of prednisolone was selected arbitrarily to decrease the risk of adverse events.

犬被给予两种处置中的一种。奥拉替尼单药治疗(OM)组，按批准剂量0.4-0.6 mg/kg给予奥拉替尼治疗，每日2次，连续14天，随后每日1次，连续14天。在泼尼松龙-奥拉替尼组(PO)中，奥拉替尼使用方法与OM组相同，同时联用泼尼松龙目标剂量0.5±0.2 mg/kg，每日2次，连续4天。随意选择如此短时间的使用泼尼松龙，目的是降低副作用风险。

 

During this trial, we permitted the use of topical antiseptics, topical ear antimicrobials without glucocorticoids, topical ear cleansers and allergen-specific immunotherapy, and only if the latter had been administered for more than one consecutive year without full control of atopic signs.

在本试验中，我们允许使用外用防腐剂、外用不含糖皮质激素的抗菌耳药、外用洗耳液和过敏原特异性免疫疗法，且仅在后者连续使用一年以上且未完全控制过敏性症状的情况下。

 

By contrast, we prohibited the concurrent use of anti-allergic drugs whose effects could alter the interpretation of the benefit of tested interventions. Forbidden drugs were as follows: topical, otic and oral glucocorticoids; topical and oral calcineurin inhibitors; injectable lokivetmab; topical and oral antihistamines; and any other medications known to have any anti-inflammatory or antipruritic effect. Finally, the dog's diet and oral supplements could not be changed for the 8weeks preceding and during this trial.

相比之下，我们禁止同时使用抗过敏药物，因为这些药物的效果可能会改变对试验干预措施的好处的解释。禁止使用的药物有:外用、耳药和口服糖皮质激素;外用和口服钙调神经磷酸酶抑制剂;注射洛基维特单抗;外用和口服抗组胺药;以及其他已知有抗炎或止痒作用的药物。最后，在试验前8周和试验期间，犬的饮食和口服补充剂不能改变。

 

Outcomes

结果

In this study, veterinarian investigators were asked to rate the skin lesions using two validated instruments. The CADESI4 was graded on D0, before starting treatment, and 4weeks later (D28). As two of the lesions of the CADESI4 (lichenification and alopecia) are insensitive to change during short-duration trials, we also extracted the erythema grade of the CADESI4 to report the CADESI4-E, as described previously. Likewise, clinicians also graded, on D0 and D28, their perception of the overall severity of AD skin lesions using the newly validated 2D-Investigator Global Assessment (IGA) scale.

在这项研究中，兽医研究人员被要求使用两种验证过的工具对皮肤病变进行评级。CADESI4在D0、开始治疗前和4周后(D28)进行评级。由于CADESI4的两个病变(苔藓化和脱毛)在短时间试验中对变化不敏感，我们也提取了CADESI4的发红等级来报告CADESI4-E，如前所述。同样地，临床医生也使用新验证的2D -调查员整体评估(IGA)量表，在D0和D28对AD皮肤病变的整体严重程度进行评分。

 

We also asked one of the owners (the same person at each visit) to assess the dog's manifestation of pruritus during the 24h preceding D0, D4, D14, D21 and D28 using the validated PVAS10 scale.

我们还要求其中一名宠主(每次来访的同一人)在治疗前24h、D0、D4、D14、D21和D28，使用有效的PVAS10量表评估犬的瘙痒表现。

 

Likewise, on D4, D14, D21 and D28, we requested the same owner to rate their perception of the efficacy of treatment using the newly proposed Owner Global Assessment of Treatment Efficacy (OGATE).

同样，在D4、D14、D21和D28上，我们要求相同的宠主使用新提议的宠主疗效整体评估(OGATE)对他们对治疗效果的感知进行评级。

 

The primary outcome measure was the proportion of dogs in each group that had a rebound of pruritus on D21, such a rebound being defined as a PVAS10 on D21 that was at least one grade superior to that on D14, the last day of the twice-daily administration of oclacitinib.

主要结果指标是每组犬在第21天瘙痒反弹的比例，这种反弹定义为第21天的PVAS10至少比第14天(每日两次给药的最后一天)的PVAS10高一级。

 

For secondary outcome measures, we compared, between groups:

1. the absolute PVAS10 values on D4, D14, D21 and D28

2. the absolute CADESI4 and CADESI4-E scores on D28

3. the proportion of dogs with a 2D-IGA of clear-toalmost clear (0 or 1) with at least a two-grade improvement from baseline scores on D28.

对于次要结果指标，我们在组间进行了比较:
1.D4、D14、D21和D28的PVAS10绝对值
2.D28时CADESI4和CADESI4-E的绝对评分
3.2D-IGA为清晰至几乎清晰(0或1)的犬只比例，在D28评分时比基线评分至少提高了两个等级。

 

Finally, in addition to the outcome measures proposed above, we also reported those included in the COSCAD'18.

最后，除了上述提出的结果衡量标准外，我们还报告了COSCAD'18包含的结果衡量标准。

 

Safety evaluation

安全性评估

We recorded all adverse events during the study and separated those expected to be seen in dogs with AD (e.g. itch, erythema, skin or ear infections) and those that were unexpected.

我们记录了研究过程中所有的副作用，并将预期会出现在AD犬上的副作用(如瘙痒、发红、皮肤或耳部感染)和意料之外的副作用分开。

 

Sample size

样本数

In an unpublished open pilot study performed by one of the authors (LB), eight of 13 dogs with AD (62%) given oclacitinib per the approved regimen exhibited a pruritus increase 1week after the frequency of administration of oclacitinib was reduced from twice to once daily. Using these pilot data and an online calculator (http://power andsamplesize.com, page last accessed 7 February 2022), we determined that if we enrolled 16 dogs per group, this study would have an 80% power to detect a significant two-thirds reduction in the proportion of dogs having a rebound if given prednisolone with oclacitinib (one-sided analysis, p = 0.05). To allow for the expected participant attrition during the trial, we planned to enrol 20 dogs per group.

在一项未发表的公开试点研究中，由作者之一(LB)进行的，13只AD犬中有8只(62%)在按批准的方案给予奥拉替尼后，在给药频率从每天两次减少到一次后的1周内瘙痒增加。使用这些试验数据和一个在线计算器(http://power andsamplesize.com，最后访问时间为2022年2月7日)，我们确定，如果我们每组登记16只犬，本研究将有80%的能力检测到，在服用泼尼松龙和奥拉替尼时，出现反弹的犬的比例显著降低三分之二(片面分析，p = 0.05)。为了考虑试验期间预期的参与者减员，我们计划每组招募20只犬。

 

Randomisation and blinding

随机性和盲法

The dogs were randomised to be allocated in the OM or PO group using an online tool (www.random.org, page last accessed 14 February 2022) in a 1:1 ratio without blocks. While owners were made aware of our wish to compare two oclacitinib protocols, we did not specifically explain the expected effect of the addition of the prednisolone.

使用在线工具(www.random.org，最后一次访问的页面是2022年2月14日)，犬被随机分配到OM组或PO组，比例为1:1，不含块。虽然所有人都知道我们希望比较两种奥拉替尼方案，但我们没有具体解释添加泼尼松龙的预期效果。

 

Statistical methods

统计学方法

PVAS10 values were analysed within each treatment group with nonparametric repeated-measures ANOVA (Friedman test) with Dunn's post-tests comparing each post-treatment value to its respective at baseline. Likewise, we compared before versus after CADESI4, CADESI4-E and 2D-IGA values using Wilcoxon matched-pairs signed-rank tests. We used Wilcoxon– Mann–Whitney U-tests for continuous variables and Fisher's exact test for categorical data for betweengroup comparisons. As we had two unidirectional hypotheses (post-treatmentOM scores), all statistical calculations were performed as one-tailed analyses with p<0.05, using statistical software (Prism 7, GraphPad Software).

对每个治疗组的PVAS10值进行非参数重复测量方差分析(Friedman检验)，Dunn后验将每个治疗后值与各自的基线值进行比较。同样，我们使用Wilcoxon匹配对符号秩检验比较CADESI4、CADESI4- e和2D-IGA值前后的差异。我们对连续变量使用Wilcoxon - Mann-Whitney u检验，对分类数据使用Fisher确切检验进行组间比较。由于我们有两个单向假设(治疗后tom评分)，所有统计计算均采用单尾分析(p<0.05)，使用统计软件(Prism 7, GraphPad software)。

 

RESULTS

结果

Participants

参与者

The trial took place between the 24th of January 2019 and the 9th of February 2022. Forty-two dogs were selected and randomised, of which two did not come back for reevaluation, and 40 completed the 4-week trial. At the time of data curation, one subject (Dog 7; OM group) was noted to have a PVAS10 score inferior to that required per protocol, yet we kept its values for intent-to-treat analyses.

试验于2019年1月24日至2022年2月9日期间进行。选取了42只犬进行随机分组，其中2只没有复诊再评估，40只完成了为期4周的试验。在数据整理时，一个受试犬(Dog 7;OM组)的PVAS10评分低于每个方案的要求，但我们在意向治疗分析中保留了它的值。

 

Baseline data

基础数据

Of these 40 dogs, 22 lived in Argentina, 11 in Lithuania, five in Sweden and two in Belgium. There were 14 cross-bred and 26 pure-bred dogs, including six French bulldogs, four West Highland white terriers, and four Labradors or golden retrievers. Signalment and baseline characteristics are summarised in Table 1, while details of all patients, per COSCAD'18 recommendations, are included in Table S1. Altogether, there were no significant differences between the OM and PO groups in sex balance, age or body weight at the time of enrolment.

在这40只犬中，22只生活在阿根廷，11只生活在立陶宛，5只生活在瑞典，2只生活在比利时。共有14只杂交犬和26只纯种犬，包括6只法国斗牛犬、4只西高地白㹴和4只拉布拉多或金毛猎犬。表1总结了症状和基线特征，而根据COSCAD'18建议，所有患犬的详细信息都包含在表S1中。总之，OM组和PO组在入组时的性别平衡、年龄和体重方面没有显著差异。

 

As shown in Table 1, the two groups of dogs had similar ranges of baseline skin lesion [CADESI4, CADESI4-E (its erythema component) and 2D-IGA] and pruritus scores (PVAS10).

如表1所示，两组犬的基线皮肤病变[CADESI4、CADESI4- E(发红)和2D-IGA]和瘙痒评分(PVAS10)范围相似。

 

Numbers analysed

数值分析

All 40 dogs received their originally assigned intervention, and all scores were used for intention-totreat analyses.

所有40只犬都接受了最初分配处置，所有分数都用于意向治疗分析。

 

Outcomes

结果

Manifestations of pruritus

瘙痒表现

Dogs from both OM and PO groups experienced a significant reduction in PVAS10 scores during this 4-week trial (Friedman's repeated-measure ANOVA, p<0.05; Figure 1a,b).

在为期4周的试验中，OM组和PO组的犬PVAS10评分均显著降低(Friedman重复测量方差分析，p<0.05;图1 a, b)。

 

In the OM group, nine of 20 dogs (45%) had experienced a rebound in pruritus (i.e. an increase of more than one PVAS10 grade) on D21 compared to D14, the point at which the administration of oclacitinib was reduced in frequency from twice to once daily. In atopic dogs concurrently given 4days of prednisolone, this proportion was significantly lower (three of 20, 15%; one-tailed Fisher's exact test, p = 0.041) at the same time point, than those receiving oclacitinib monotherapy. Consequently, the number-needed-to-treat (NNT), the rounded-up inverse of the difference in proportion between the two groups, was four. In other words, such a NNT means that one would have to treat four dogs with prednisolone to prevent one rebound compared to dogs treated with oclacitinib alone. When comparing pruritus scores between interventions at each reevaluation visit, the D4 and D28 values in the PO group were significantly lower than those in the OM group (Wilcoxon–Mann–Whitney Utest, p = 0.003 and 0.041, respectively; Figure 2), as can be seen with the more homogeneous decline in PVAS10 on D4 in dogs that had received prednisolone (Figure 1a,b); differences in scores between groups were not significant at the other two post-treatment time points.

在OM组中，20只犬中有9只(45%)在D21与D14相比出现瘙痒反弹(即PVAS10等级增加一个以上)，在D14时，奥拉替尼的给药频率从每天两次减少到一次。在同时给予泼尼松龙4天的特应性皮炎犬中，这一比例明显较低(3 / 20,15%;单尾Fisher确切检验，p = 0.041)优于接受奥拉替尼单药治疗的患犬。因此，需要治疗的数量(NNT)，即两组之间的比例差异的汇总倒数，为4。换句话说，这样的NNT意味着，与只接受奥拉替尼治疗的犬相比，一个人必须用泼尼松龙治疗4只犬才能防止一次反弹。在比较处置组每次复诊再评估的瘙痒评分时，PO组的D4和D28值显著低于OM组(Wilcoxon-Mann-Whitney Utest, p = 0.003和0.041;图2)，可以看出，接受泼尼松龙的犬在D4上PVAS10的下降更为均匀(图1a,b);在其他两个治疗后时间点，组间评分差异无统计学意义。

 

It is only on D4 that the proportion of dogs with normal-to-mild PVAS10 (PVAS10-N2M; COSCAD'18's outcome measure 2) was significantly—and almost twice—higher in the PO (17 of 20, 85%) than in the OM group (nine of 20, 45%; one-tailed Fisher's exact test, p = 0.009; Table 2).

只有在D4上，正常至轻度PVAS10 (PVAS10- n2m;COSCAD'18的预后指标2)在PO组(17 / 20,85%)明显高于OM组(9 / 20,45%;单尾Fisher确切检验，p = 0.009;表2)。

 

Skin lesions

皮肤病变

CADESI4 and CADESI4-E were significantly lower on D28 compared to those at baseline in both treatment groups (Wilcoxon matched-pair signed-rank tests, p<0.0001).

两治疗组在D28时CADESI4和CADESI4-E明显低于基线时(Wilcoxon配对符号秩检验，p<0.0001)。

 

While somewhat similar at baseline between groups (Table 1), CADESI4 and CADESI4-E were significantly lower in the PO than the OM group on D28 (Wilcoxon– Mann–Whitney U-test, p = 0.045 and 0.010, respectively; Figure 3a,b).

虽然两组间在基线时有些相似(表1)，但在D28时，PO的CADESI4和CADESI4- E明显低于OM组(Wilcoxon - Mann-Whitney u检验，p = 0.045和0.010;图3 a, b)。

 

At the end of the study, the proportion of dogs with CADESI4 values in the range of normal dogs (CADESI4-N; COSCAD'18 outcome measure 1) was nearly twice higher in the PO (nine of 20, 45%) than in the OM group (five of 20, 25%), yet the difference in proportion between the two groups was not significant (p = 0.160; Table 2).

在研究结束时，具有CADESI4的犬的比例在正常犬的范围内(CADESI4- n;COSCAD'18结果指标1)PO组(9 / 20,45%)是OM组(5 / 20,25%)的近两倍，但两组间的比例差异不显著(p = 0.160;表2)。

 

While the 2D-IGA extent-and-severity skin lesion scores were identical at baseline (Table 1), on D28 they were significantly lower (Wilcoxon–Mann–Whitney Utest, p = 0.001) in the PO [median (range): 2 (0–3)] than in the OM group [3 (0–3)]. However, at D28 the proportion of dogs with a 2D-IGA of clear-to-almost-clear (i.e. 0 or 1) and at least a two-grade improvement from baseline scores was twice higher (six of 20, 30%) in the PO than in the OM group (three of 20, 15%); this difference was not significant (p= 0.225), however.

虽然2D-IGA皮肤病变程度和严重程度评分在基线时是相同的(表1)，但在第28天，PO组[中位数(范围):2(0-3)]明显低于OM组[3 (0-3)](Wilcoxon-Mann-Whitney Utest, p = 0.001)。然而，在D28时，2D-IGA为干净到几乎干净(即0或1)且比基线评分至少提高两级的PO组犬的比例(6 / 20,30%)比OM组(3 / 20,15%)高两倍;然而，这种差异并不显著(p= 0.225)。

 

Owners' global assessment of treatment efficacy

宠主对疗效整体评估

On D21 and D28, but not earlier, the OGATE scores were higher in the PO than the OM group (Wilcoxon–Mann– Whitney U-test, p = 0.002 and 0.006, respectively). A good-to-excellent treatment response (OGATE-G2E; COSCAD'18 outcome measure 3) was rated by owners of a significantly higher proportion of dogs in the PO than the OM group on both D21 and D28 (p = 0.016 and 0.011, respectively; Table 2).

D21和D28时，PO组OGATE评分高于OM组(Wilcoxon-Mann - Whitney U-test, p = 0.002和0.006)，但不早于此。良好至极好的疗效(OGATE-G2E;在D21和D28两项测试中，PO组的犬犬比例显著高于OM组(p分别= 0.016和0.011;表2)。

 

Finally, as recommended in the COSCAD'18, we added, as an online supplementary material (Table S2), the number and percentage of dogs with CADESI4, CADESI4-E and PVAS10 values in the different categories of disease severity at each time point. Also included therein are the numbers and percentages of dogs with different OGATE scores over time.

最后，根据COSCAD'18的建议，我们添加了每个时间点在不同疾病严重程度类别中具有CADESI4、CADESI4-E和PVAS10值的犬的数量和百分比，作为在线补充材料(表S2)。其中还包括随着时间推移获得不同OGATE分数的犬的数量和百分比。

 

Adverse events

副作用

Owners reported adverse events in one dog in the OM (vomiting) and five from the PO group [vomiting (two dog), diarrhoea (2), sleepiness (1) and polyuriapolydipsia (1)]. All adverse effects were minor, intermittent and spontaneously resolving; none necessitated symptomatic therapy or the interruption administration of oclacitinib or prednisolone. All adverse events are provided in Table S1.

据宠主报告，OM组的一只犬出现了副作用(呕吐)，PO组的5只犬出现了副作用[呕吐(2只)、腹泻(2只)、嗜睡(1只)和多尿多饮(1只)]。所有副作用都是轻微的、间歇性的、自发缓解的;无必要对症治疗或中断奥拉替尼或泼尼松龙给药。所有副作用见表S1。

 

DISCUSSION

讨论

Interpretation

解释说明

In this 4-week trial, the concomitant administration of 4days of prednisolone at the initiation of treatment with oclacitinib led to a significant reduction in the frequency of rebounds of pruritus by two-thirds. Furthermore, we observed that, compared to monotherapy with this JAKinib, the initial addition of glucocorticoids resulted in a greater reduction of owner-rated pruritus on D4 and D28, veterinarian-evaluated skin lesion scores on D28, and owner's global evaluation of treatment efficacy on D21 and D28.

在这个为期4周的试验中，在开始使用奥拉替尼治疗时，同时给予4天泼尼松龙，导致瘙痒反弹的频率显著降低了三分之二。此外，我们观察到，与JAKinib的单一治疗相比，最初添加糖皮质激素，使D4和D28的宠主瘙痒评估，D28兽医皮肤病变评分，和D21和D28的宠主疗效整体评估大幅下降。

 

For this trial, we had defined, as rebound, an increase of at least one PVAS10 grade, 1week (i.e. D21) after reducing the frequency of administration of oclacitinib from twice to once daily (i.e. D14), per the approved use of this drug. Such a rebound threshold had been extrapolated from the average increase in PVAS10 values after dose reduction in three RCTs reporting the efficacy of oclacitinib in allergic dogs.

在本试验中，我们定义了反弹，即根据该药物的批准使用，在将奥拉替尼的给药频率从每日两次减少到每日一次(即D14)后1周(即D21)，至少增加一个PVAS10等级。这样的反弹阈值是由三个RCT报告的奥拉替尼对过敏症患犬的疗效后剂量减少后PVAS10值的平均增加推断出来的。

 

Given the mechanism of action of both drug classes, it is not surprising that a short course of glucocorticoids can contribute to the improvement with JAKinib therapy for canine pruritus. On the one hand, JAKinibs can have a rapid effect on itch reduction due to their immediate inhibition of intracellular signalling following the binding of pruritogenic cytokines to their cognate receptors on sensory neurons. On the other, in humans, chronic atopic skin lesions result from the complex interplay of resident and infiltrating cells that intercommunicate via countless mediators, cytokines and others, few of them using JAKinib-targetable JAK-associated receptors.In this situation, however, glucocorticoids inhibit the production of most of the pro-inflammatory mediators present in AD skin, thus resulting in a broad and rapid cellular deactivation and anti-allergic clinical benefit.

考虑到这两类药物的作用机制，短疗程的糖皮质激素可以促进JAKinib治疗犬类瘙痒症的改善就不足为奇了。一方面，JAKinibs可以快速减少瘙痒，这是因为它们在瘙痒细胞因子与感觉神经元上的同源受体结合后立即抑制细胞内信号传导。另一方面，在人类中，慢性特应性皮肤病变是由驻留细胞和浸润细胞的复杂相互作用造成的，这些细胞通过无数的介质、细胞因子和其他物质相互交流，其中很少使用Jakinib靶向的Jak相关受体。然而，在这种情况下，糖皮质激素抑制了AD皮肤中大多数促炎介质的产生，从而导致广泛和快速的细胞失活和抗过敏的临床效益。

 

As mentioned above, the cessation of oclacitinib administration has been shown to increase the secretion of all measured cytokines [IL-31, TSLP and TNFalpha] in the skin of mice challenged with a T-helper 2 (Th2)-inducing contactant.In theory, in these mice, and probably in atopic dogs treated with oclacitinib, the temporary, concomitant administration of glucocorticoids at the time of JAKinib treatment induction should lead to an inhibition of cytokine gene transcription. As seen in our trial, the benefit of such an adjunctive therapy supports this hypothesis.

如前所述，停止给药已被证明能增加小鼠皮肤中所有测量到的细胞因子[IL-31, TSLP和TNFα]的分泌，这些细胞因子是由T辅助因子2 (Th2)诱导接触剂刺激的。理论上，在这些小鼠中，可能在用奥拉替尼治疗的特应性皮炎犬中，在JAKinib治疗诱导时临时同时给药糖皮质激素应该会导致细胞因子基因转录的抑制。在我们的试验中，这种辅助治疗的好处支持了这一假设。

 

While our study was underway, another small RCT compared the efficacy of oclacitinib with or without the concurrent application of a topical glucocorticoid spray (hydrocortisone aceponate, Cortavance, Virbac). In that trial, the PVAS10 increased significantly on D21 only in the group treated with oclacitinib and the placebo spray, and not in the group also receiving the topical hydrocortisone aceponate. Moreover, the simultaneous application of the topical glucocorticoid also led, as in our trial, to a significant reduction in skin lesion scores during the second half of that study as compared with the placebo control.Altogether, the results of both trials, albeit involving a small number of dogs, support the benefit of concurrent short-term glucocorticoid therapy while initiating treatment with oclacitinib. We alluded to such a possible benefit in a recent editorial in this journal.

当我们的研究正在进行时，另一个小型的随机对照试验比较了奥拉替尼与外用糖皮质激素喷雾(氢化可的松醋丙酯、皮乐美)时的疗效。在该试验中，只有在口服奥拉替尼和安慰剂喷雾剂的组中，PVAS10在D21时显著增加，而在外用氢化可的松醋丙酯的组中没有。此外，在我们的试验中，与安慰剂对照组相比，外用糖皮质激素的同时应用也导致了在该研究的后半段皮肤病变评分的显著降低。总之，这两项试验的结果，尽管只涉及了少量的犬，但都支持在开始使用奥拉替尼治疗的同时进行短期糖皮质激素治疗的好处。我们在本刊最近的一篇社论中提到了这种可能的好处。

 

Adverse effects

副作用

In this trial, we documented intermittent adverse events, which were more commonly seen in the PO than in the OM group. Outside the obvious polyuriapolydipsia (seen in one dog only) that can be attributed to the prednisolone, it is difficult to directly link the development of gastro-intestinal signs to either of the two drugs administered. Indeed, as shown in the first placebo-controlled trial of oclacitinib monotherapy in dogs with AD, vomiting and diarrhoea were seen equally in both treatment groups. In any case, all of these adverse events were mild, intermittent and spontaneously resolving, thus highlighting the minimal harm caused by oclacitinib or the dual therapy.

在本试验中，我们记录了间歇性副作用，这在PO组比OM组更常见。除了明显的多尿多饮症状(只在一只犬上出现)可以归因于泼尼松龙之外问题，很难直接将胃肠道症状的发展与两种药物的任何一种联系起来。事实上，正如第一个奥拉替尼单药治疗AD犬的安慰剂对照试验所显示的，呕吐和腹泻在两个治疗组中是相同的。在任何病例中，所有这些副作用都是轻微的、间歇性的和自发缓解的，因此突出了奥拉替尼或双重疗法造成的最小伤害。

 

Limitations

局限性

In this trial, the short duration and small number of dogs were a limitation. However, the significant difference between groups in the primary outcome measure supported the validity of the original power calculation. Another limitation was the lack of blinding and masking of the intervention. However, the pet owner who graded the PVAS10 used for the primary outcome measure had not been made aware beforehand of the possible reductive effect of prednisolone on itch rebound.

在这项试验中，持续时间短和犬的数量少是一个限制。然而，组间在主要结果测量上的显著差异支持原始功率计算的有效性。另一个限制是缺乏给药盲法和遮挡。然而，给PVAS10评分用于主要结果测量的宠物主人事先没有意识到泼尼松龙对瘙痒反弹的可能减少作用。

 

Generalisability

普遍性

We believe that the results of this trial are generalisable to most dogs with AD, as we had a nearly equal representation of both genders, the ages at enrolment mirror those of dogs with AD needing treatment, their skin lesion scores reflected mild-to-severe lesions, and their PVAS10 moderate-to-severe itch.

我们相信，这项试验的结果可以推广到大多数AD患犬，因为我们有几乎相同的性别数量，登记的年龄反映了需要治疗的AD犬的年龄，它们的皮肤病变评分反映了轻到严重的病变，它们的PVAS10中度到严重的瘙痒。

 

Implications for practice and research

对实践和研究的启示

Altogether, the results of this trial suggest the likely superior benefit of adding a short course of glucocorticoids when starting oclacitinib therapy. This will result in a lower risk of itch rebound when reducing the frequency of administration of this JAKinib, an improvement in skin lesions, and a higher perception of treatment efficacy by the owner in the second half of the first month of treatment. We recommend the performance of additional trials to evaluate the benefit of sequential (glucocorticoids-then-oclacitinib) or possibly longer concomitant glucocorticoid regimens in dogs with moderate-to-severe skin lesions.

总之，这项试验的结果表明，在开始奥拉替尼治疗时，添加短疗程的糖皮质激素可能有更好的效果。这将导致在减少这种JAKinib的给药频率时，瘙痒反弹的风险降低，皮肤病变的改善，并且在治疗的第一个月的下半月，宠主的疗效感知更高。我们建议在中度至重度皮肤病变的犬中进行额外的试验，以评估顺序(先使用糖皮质激素，再使用奥拉替尼)或可能长期伴随的糖皮质激素方案的好处。

 

 

 

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