0.0584%氢化可的松醋丙酯外用喷雾剂联合奥拉替尼全身性治疗特应性皮炎患犬的有效性...

王帆

Efficacy and safety of 0.0584% hydrocortisone aceponate topical spray and systemic oclacitinib combination therapy in dogs with atopic dermatitis: a randomized, double-blinded, placebo-controlled trial

0.0584%氢化可的松醋丙酯外用喷雾剂联合奥拉替尼全身性治疗特应性皮炎患犬的有效性和安全性评估:一项随机、双盲、安慰剂对照试验

作者：Junko Takahashi*, Satoko Kanda†, Ichiro Imanishi‡, Tadashi Hisano§, Teruyasu Fukamachi§, Norihito Taguchi¶, Shoko Momiyama**, Satoshi Nishiyama††, Tomoki Motegi‡‡ and Keita Iyori†

翻译：王帆

Background – Oclacitinib is an effective systemic therapy for dogs with atopic dermatitis (AD). Few studies have evaluated concurrent topical treatment with oclacitinib in dogs.

Objectives – To evaluate the efficacy and safety of combination therapy of oclacitinib and 0.0584% hydrocortisone aceponate (HCA) spray in dogs with AD.

Animals – Eighteen dogs with AD.

Methods and materials – This study was a randomized, double-blinded, placebo-controlled trial. All dogs were treated with oclacitinib (0.4–0.6 mg/kg twice daily for 14 days, then once daily for 14 days) and randomized to receive either HCA spray or placebo spray, applied once daily for seven days then every other day through to Day (D)28. Clinical assessments included the Canine Atopic Dermatitis Extent and Severity Index, 4th iteration (CADESI-4) and the pruritus Visual Analog Scale (PVAS) every seven days, and blood and urine tests every 14 days.

Results – The mean CADESI-4 and PVAS scores were significantly reduced on D7 and D14 compared to D0 in both groups (P < 0.05). From D14 to D21, CADESI-4 and PVAS scores were significantly increased in the placebo group (P < 0.005), and not in the HCA-treated group. The mean reduction from baseline of the HCA-treated group was significantly higher than that of the placebo group for the PVAS and CADESI-4 on D21 (59.9% versus 27.6%, P = 0.0216) and D28 (56.0% versus 30.5%, P = 0.0109), respectively. One dog in the HCA-treated group was withdrawn as a consequence of developing diarrhoea.

Conclusion – Topical application of 0.0584% HCA spray may be useful for preventing exacerbation of pruritus and clinical lesions when tapering oclacitinib therapy in dogs with AD.

摘要

背景 – 对于特应性皮炎(cAD)患犬, 奥拉替尼是一种有效的全身性治疗药物。很少有研究评估犬同时接受奥拉替尼和外部治疗的效果。

目的 – 评估奥拉替尼和0.0584%氢化可的松丙酸酯(HCA)喷雾剂联合治疗, cAD犬的有效性和安全性。

动物 – 18只cAD患犬。

方法和材料 – 本研究是一项随机、双盲、安慰剂对照试验。所有犬均接受奥拉替尼治疗(0.4–0.6 mg/kg, 每日两次, 持续14天, 然后每日一次, 持续14天) , 并随机接受HCA喷雾剂或安慰剂喷雾剂, 每日一次, 持续7 天, 然后隔日一次,直至第28天(D)。临床评估包括第4版犬特应性皮炎严重程度指数 (CADESI-04)和瘙痒视觉模拟量表(pVAS), 每7天一次, 以及血液和尿液检查, 每14天一次。

结果 – 与D0相比, 两组中D7和D14的平均CADESI-04和pVAS评分显著降低(P < 0.05)。从D14至D21, 安慰剂组的CADESI-04和pVAS评分显著增加(P < 0.005), 而HCA治疗组无显著增加。D21(59.9%与27.6%,P = 0.0216) 和D28(56.0%与30.5%,P = 0.0109) 时, HCA治疗组的pVAS和CADESI-04相对于基线的平均下降程度显著高于安慰剂组。HCA治疗组中的1只犬因发生腹泻而退出研究。

结论 – 在cAD患犬逐渐减少奥拉替尼治疗时, 外部应用0.0584%HCA喷雾剂可能有助于预防瘙痒和临床病变加重。

Introduction

介绍

Canine atopic dermatitis (cAD) has been defined as a chronic, inflammatory and pruritic allergic skin disease that involves environmental allergens in dogs. Although the pathogenesis is not fully understood, it has been described as multifactorial, resulting from interactions between factors such as genetic elements, skin barrier function and immunological aberrations. Because lifelong treatment is needed for cAD, the International Committee on Allergic Diseases of Animals (ICADA) proposed treatment guidelines in 2010, and updated them in 2015. The guidelines assessed the quality of evidence for various treatment options. Oral or topical corticosteroid and oclacitinib were recommended as therapeutic options with good evidence of high efficacy for acute flares of cAD; oral or topical glucocorticoid, oclacitinib, ciclosporin and topical tacrolimus were recommended for chronic cAD. Veterinarians should be aware of the need to customize treatment according to the severity in each case.

犬特应性皮炎(cAD)被定义为犬的一种慢性、炎性和瘙痒性过敏性皮肤病，与环境过敏原有关。虽然发病机理尚不完全清楚，但已将其描述为由遗传因素、皮肤屏障功能和免疫异常等多因素相互作用的结果。由于cAD需要终生治疗，国际动物过敏性疾病委员会(ICADA)于2010年提出了治疗指南，并于2015年更新。该指南评估了各种治疗方案的证据质量。口服或外用皮质类固醇和奥拉替尼被推荐为治疗cAD急性发作的选择，有很好的证据证明它们的高有效性;慢性cAD推荐口服或外用糖皮质激素、奥拉替尼、环孢素和外用他克莫司。兽医应该意识到需要根据病情的严重程度定制治疗方案。

Oclacitinib (Apoquel, Zoetis Japan; Tokyo, Japan) is a nonselective Janus kinase (JAK) inhibitor approved for systemic treatment for cAD with a clinical efficacy comparable to systemic prednisolone and ciclosporin. The most frequent mild adverse events are gastrointestinal signs such as diarrhoea and vomiting. The effectiveness of oclacitinib monotherapy has been established in several well-organized clinical trials.

奥拉替尼是一种非选择性的Janus激酶(JAK)抑制剂，已获批准用于cAD的全身性治疗，其临床疗效可与全身使用泼尼松龙和环孢素相媲美。最常见的轻度副反应是腹泻和呕吐等胃肠道症状。单独使用奥拉替尼治疗的有效性已在多个严谨的临床试验中得到证实。

A 0.0584% hydrocortisone aceponate (HCA) spray (Cortavance, Virbac Japan; Osaka, Japan) is a potent topical corticosteroid with a low rate of percutaneous absorption that has been proven equally effective to ciclosporin in treating cAD. Its use has been shown to significantly reduce skin lesions within 14 days, without severe adverse events, and its efficacy in proactive long-term maintenance therapy of cAD with two consecutive days each week also has been validated.

0.0584%氢化可的松醋丙酯(HCA)喷雾剂是一种有效的外用皮质类固醇，经皮吸收率低，已被证明与环孢素治疗cAD的效果相同。它的使用已被证明在14天内能明显减轻皮肤病变，没有严重的副反应，并且每周连续两天的使用，作为主动长期维持治疗cAD的有效性也得到了验证。

Successful management of cAD often requires a combination of several modalities, including systemic and topical agents.The objective of this study was to evaluate the efficacy and safety of combination treatment with systemic oclacitinib and topical HCA spray to control pruritus and skin lesions in dogs with atopic dermatitis.

cAD的成功管理通常需要多模式结合，包括全身和外用药物。本研究的目的是评估全身使用奥拉替尼联合外用HCA喷雾剂控制特应性皮炎患犬的瘙痒和皮肤病变的有效性和安全性。

Methods and materials

材料和方法

Study design

研究设计

This study was conducted as a randomized, double-blinded, placebocontrolled clinical trial at five veterinary clinics in Japan. Five clinicians enrolled a total of 18 client-owned dogs with atopic dermatitis in a 28 day study. The study was conducted as per good clinical practice guidelines and written informed consent was obtained from the owner of each participating dog.

这项研究是在日本5家兽医诊所进行的随机、双盲、安慰剂对照临床试验。在一项为期28天的研究中，5名临床医生共招募了18只家养特应性皮炎患犬。研究严格根据《临床实践指南》进行，并获得了每只参与研究的犬的主人的书面知情同意书。

Inclusion and exclusion criteria

纳入和排除标准

All dogs enrolled were >12 months of age, with overall good health, and were evaluated by physical examination and clinical pathological testing (complete blood count, serum chemistry and urinalysis). All dogs had histories of chronic, nonseasonal pruritus and clinical signs suggestive of cAD, and fulfilled published criteria. Dogs with other pruritic dermatoses such as flea bite allergy dermatitis, bacterial or fungal dermatitis and/or otitis, and ectoparasite infestation were excluded. Dogs with cutaneous adverse food reactions were excluded after completing an eight week (minimum) elimination diet trial. All dogs were flea-free at day (D)0 and appropriate flea control/ prevention was used throughout the study. Dogs with a history of severe internal disease or tumour, pregnant or lactating dogs, and <1-year-old dogs also were excluded.

所有入组犬均大于12月龄，健康状况良好，并进行体格检查和临床病理检查(全血细胞计数、血清化学和尿液分析)。所有的犬都有慢性、非季节性瘙痒病史和提示cAD的临床症状，并符合发表标准。排除其他瘙痒性皮肤病患犬，如跳蚤叮咬过敏性皮炎、细菌性或真菌性皮炎和/或耳炎，以及外寄生虫感染。在完成(至少)8周的食物排除试验后，排除皮肤食物副反应患犬。所有犬在第0天(D0)驱跳蚤，并在整个研究过程中采用适当的控制/预防跳蚤的方法。有严重内科疾病或肿瘤病史患犬、怀孕或哺乳期犬以及小于一岁的犬也被排除在外。

Prohibited medications and therapies

避免用药和治疗

The set withdrawal times for prohibited medications were as follows: antimicrobial or antifungal agents, seven days; systemic or topical glucocorticoids, 28 days; injectable methylprednisolone acetate, 56 days; oral ciclosporin, 28 days; antihistamines, 14 days; essential fatty acid supplements (EFAs), 56 days; interferon-gamma, three months; and allergen-specific immunotherapy, six months. Shampooing could be continued if it had been used for longer than one month before the study. The frequency of application and the shampoo ingredients could not be changed.

禁用药物的停药时间如下:抗生素或抗真菌药，7天;全身或外用糖皮质激素，28天;注射用醋酸甲泼尼松龙，56天;口服环孢素，28天;抗组胺药,14天;必需脂肪酸补充剂(EFAs)， 56天;γ-干扰素,3个月;过敏原特异性免疫治疗，6个月。如果在研究前已使用香波一个月以上，则可以继续使用香波。使用频率和香波成分不能改变。

Allocation and masking

分配和盲法

Dogs were randomized to one of two treatment groups: A or B (i.e. oclacitinib + HCA spray or oclacitinib + placebo spray) in a 1:1 ratio based on a randomization list. The investigator prescribed oclacitinib tablets and an identical bottle labelled as either group A or group B that was sent to the study facility by a centralized dispensary. The investigators evaluating clinical scores and laboratory test results, as well as the owners, were blinded to treatment allocation.

根据随机列表，犬被随机分为两组:A组或B组(即奥拉替尼 + HCA喷雾剂或奥拉替尼 +安慰剂喷雾剂)，比例为1:1。研究者规定奥拉替尼片和标记为A组或B组的相同瓶子，由统一的药房送到研究机构。评估临床评分和实验室检测结果的研究人员以及所有人都不知道治疗分配情况。

Drug administration

用药管理

All dogs were given oclacitinib orally at a dose of 0.4–0.6 mg/kg, twice daily for 14 days, and then once daily up to D28 (Figure 1a). The 0.0584% HCA spray or placebo spray containing propylene glycol methyl ether were applied concurrently with oral oclacitinib once daily for seven days and then every other day until the end of the study (Figure 1a). The spray application was limited to the neck, chest, abdomen, feet and digits, excluding the head and mucocutaneous areas. Owners were instructed to use two pumps (0.26 mL) per 100 cm2 surface area, keeping 10 cm away from the dogs skin according to the manufacturers instructions. Topical HCA or placebo spray bottles were collected on D28 to confirm administration.

所有犬奥拉替尼口服剂量为0.4-0.6 mg/kg，每日2次，连续14天，然后每日1次，直到D28(图1a)。0.0584% HCA喷雾剂或含有丙二醇甲醚的安慰剂喷雾剂与口服奥拉替尼同时应用，每日1次，连续7天，然后每隔一天使用一次，直到研究结束(图1a)。喷雾适用范围限于颈部、胸部、腹部、爪部及趾部，不用于头部及皮肤黏膜区域。根据制造商的说明，要求主人每100cm2的皮肤表面按压两下(0.26 mL/下)，与犬皮肤间隔10cm距离。在第28天收集HCA或安慰剂外用喷雾瓶以确认是否给药。

Study schedules and efficacy assessments

研究表和效果评估

Physical examination, owner-assessed pruritus using a Visual Analog Score (PVAS), and investigator-assessed severity of dermatitis using the Canine Atopic Dermatitis Extent and Severity Index, 4th iteration (CADESI-4)were recorded as baseline data for each enrolled dog at D0. The owner was scheduled to consult the same investigator for physical examination, assessment of adverse effects, PVAS and CADESI-4 on D7, D14, D21 and D28 (Figure 1b).

体格检查，由主人使用视觉模拟评分(PVAS)评估瘙痒，以及由研究者使用犬特应性皮炎严重程度指数评估皮炎的严重程度，D0时使用第四版(CADESI-4)记录每只入组犬的基础数据。要求主人预约同一研究者在D7、D14、D21和D28时进行体格检查、副反应、PVAS和CADESI-4(图1b)的评估。

Safety assessments

安全性评估

Abnormal health events were recorded weekly through an interview with the owner, and physical and dermatological examination. Haematological and serum chemical findings, urinalysis and adrenocorticotropic hormone (ACTH) stimulation testing were carried out on D0, D14 and D28 (Figure 1b).

每周通过对主人回访、体格检查和皮肤检查记录健康异常情况。D0、D14和D28分别进行血液学和血清生化检查、尿液分析和促肾上腺皮质激素(ACTH)刺激试验(图1b)。

Data analysis

数据分析

The Shapiro–Wilk W-test was used to estimate the normality of the CADESI-4 and PVAS data. The CADESI-4 and PVAS of the two groups before and after treatment were analysed with the paired Students t-test, and intergroup differences were analysed by Students t-test with STATVIEW software (v5.0, Hulinks; Tokyo, Japan). The post-hoc statistical power of CADESI-4 and PVAS was analysed with G*POWER software (v3.1.9.7 Heinrich-Heine-Universitat Dusseldorf; Germany). A P-value of <0.05 was considered statistically significant.

Results

结果

Study population and completion

研究数量和完成率

A total of 18 dogs were enrolled (Table 1). Most were of pure-bred heritage; the most frequently represented breeds were shiba inu (n = 5) and toy poodle (n = 3). The HCA-treated group comprised nine dogs (six breeds and crosses): shiba inu (n = 2), toy poodle (n = 1), shih tzu (n = 1), miniature dachshund (n = 1), Pekingese (n = 1), English bulldog (n = 1) and two mixed-breed dogs. The placebo group comprised nine dogs (seven breeds): shiba inu (n = 3), toy poodle (n = 1), shih tzu (n = 1), miniature dachshund (n = 1), Maltese terrier (n = 1) and French bulldog (n = 1). Thirteen males and five females were included: seven males (six castrated) and two females (all spayed) in the HCA-treated group, and six males (five castrated) and three females (two spayed) in the placebo group. The dogs were between two and 12 years of age (means 6.4 years in the HCA-treated group, 8.2 years in the placebo group). Appropriate use of the topical HCA or placebo treatments was confirmed by the residual amount in the spray bottles. One dog in the HCA-treated group discontinued the study on D21 as a consequence of developing diarrhoea.

共纳入18只犬(表1)。大多数为纯种犬;最常见的代表品种是日本柴犬(n = 5)和玩具贵宾犬(n = 3)。HCA治疗组九只犬(六个品种犬和杂交犬):日本柴犬(n = 2)、玩具贵宾犬(n = 1)、西施犬(n = 1)、迷你腊肠犬(n = 1)、京巴犬(n = 1)、英国牛头犬(n = 1)和两个杂交犬。安慰剂组九只犬(七个品种):日本柴犬(n = 3)、玩具贵宾犬(n = 1)、西施犬(n = 1)、迷你腊肠犬(n = 1)、马尔济斯犬(n = 1)和法国斗牛犬(n = 1)。十三只雄性和五只雌性包括:HCA治疗组七只雄性(6只已去势)和两只雌性(都已绝育)和安慰剂组6只雄性(5只已去势)和三只雌性(两只已绝育)。这些犬的年龄在2到12岁之间(HCA治疗组的平均年龄为6.4岁，安慰剂组的平均年龄为8.2岁)。按说明使用外用HCA或安慰剂治疗并确认喷雾剂瓶内的剩余剂量。HCA治疗组中的一只犬由于出现腹泻而在D21终止研究。

Assessment of efficacy

有效性评估

Owner-assessed PVAS score

主人的PVAS评分

The mean PVAS scores at each time point (D0, D7, D14, D21 and D28) are shown in Figure 2. There were no significant intergroup differences in mean PVAS at any time point, and within each group, the mean PVAS was significantly decreased at each point of evaluation compared to D0 (P < 0.05). However, the PVAS score on D21 and D28, when oral oclacitinib was tapered from twice daily to once daily, were significantly increased compared to D14 in the placebo group (P = 0.004 on D21, P = 0.010 on D28), and not in the HCA-treated group (P = 0.760 on D21, P = 0.170 on D28). The mean proportional reductions in PVAS from baseline to D7, D14, D21 and D28 were 41.6%, 62.3%, 59.9% and 54.1% in the HCAtreated group, and 53.0%, 54.8%, 27.6% and 30.8% in the placebo group, respectively. On D21, the mean reduction of PVAS from baseline was significantly greater in the HCA-treated group than the placebo group (P = 0.022).

D0、D7、D14、D21、D28的平均PVAS评分如图2所示。各时间点的平均PVAS组间无显著差异，在各组内，各评估点的平均PVAS均较D0显著降低(P <0.05)。然而,口服奥拉替尼从每天两次减到每天一次时,安慰剂组在D21和D28的PVAS分数，与D14相比均有显著提高(D21的P = 0.004, D28的P = 0.010),而HCA治疗组没有增加(D21的P = 0.760, D28的P = 0.170)。PVAS从基线到D7、D14、D21和D28的平均比例下降分别为41.6%、62.3%、59.9%和54.1%，安慰剂组分别为53.0%、54.8%、27.6%和30.8%。在D21，与基线相比，HCA治疗组的PVAS平均降低显著大于安慰剂组(P = 0.022)。

Investigator-assessed CADESI-4 score

研究员的CADESI-4评分

The mean CADESI-4 scores for each group are shown in Figure 3. The mean CADESI-4 scores in the placebo group were significantly higher than the HCA-treated group on D21 (P = 0.020) and D28 (P = 0.020). In both groups, the mean CADESI-4 score at each time point had significantly decreased compared to D0 (P < 0.005). However, in the placebo group only, the D21 CADESI-4 score was significantly (P = 0.004) higher than on D14.

各组的CADESI-4平均评分如图3所示。安慰剂组的CADESI-4平均评分显著高于HCA治疗组(P = 0.020)和D28 (P = 0.020)。两组患犬在各时间点的CADESI-4平均评分均较D0显著降低(P<0.005)。然而，仅在安慰剂组，D21 CADESI-4评分显著高于D14评分(P = 0.004)。

The mean proportional reductions in CADESI-4 scores from baseline to D7, D14, D21 and D28 were 37.4%, 51.5%, 52.0% and 56.0% in the HCA-treated group, and 35.3%, 49.5%, 34.1% and 30.5% in the placebo group, respectively. On D28, the mean reduction in CADESI-4 from baseline was significantly higher in the HCA-treated group than in the placebo group (P = 0.011).

与基线相比，与D7、D14、D21和D28相比，HCA治疗组CADESI-4平均评分的分别下降37.4%、51.5%、52.0%和56.0%，安慰剂组分别下降35.3%、49.5%、34.1%和30.5%。在D28，与基线相比，HCA治疗组的CADESI-4的平均降低显著高于安慰剂组(P = 0.011)。

Safety assessment

安全性评估

A summary of adverse health events and clinical pathological results is shown in Table 2. A 3-year-old English bulldog in the HCA-treated group dropped out on D21 as a consequence of developing diarrhoea, which resolved spontaneously a few days after discontinuation of oclacitinib, and did not occur again when HCA spray was restarted after the trial. Bacterial cystitis was observed in a 9-year-old toy poodle in the placebo group on D14; however, it had resolved without treatment by D28. Dermatological examination revealed no cutaneous adverse events such as skin atrophy or cutaneous infection from ectoparasites, bacteria or fungi. Elevated alkaline phosphatase (ALP) was detected in three of nine dogs in the placebo group. The ACTH stimulation tests revealed no abnormalities before or after treatment in either group (Table 3).

副反应情况和临床病理结果总结见表2。HCA治疗组的一只3岁的英国斗牛犬因腹泻而在D21退出，在停用奥拉替尼几天后腹泻自行缓解，试验后重新使用HCA喷雾剂后不再发生腹泻。安慰剂组1只9岁的玩具贵宾犬在第14天观察到细菌性膀胱炎;然而，在D28未治疗的情况下，就缓解了。皮肤科检查未发现皮肤副反应，如皮肤萎缩或皮肤外寄生虫、细菌或真菌感染。在安慰剂组的9只犬中，有3只检测到碱性磷酸酶(ALP)升高。ACTH刺激试验显示，两组患犬治疗前后均无异常(表3)。

Statistical power analysis

统计分析

The power analysis with G*POWER software revealed that the statistical power of CADESI-4 and PVAS was 0.65 and 0.11, respectively, by post hoc test.

Discussion

讨论

This study evaluated a combination therapy of topical HCA spray and systemic oclacitinib in dogs with chronic cAD. To reduce pruritus and skin lesions, the ICADA therapeutic guidelines for cAD recommend HCA spray for localized and systemic lesions, and oclacitinib for widespread lesions.All dogs in this study had multiple or widespread chronic skin lesions. As daily topical corticosteroid therapy can be difficult for pet owners, especially in widespread skin lesions, medication compliance has a great influence on treatment outcome. In this study, either a topical HCA or placebo spray was applied to limited areas including the neck, chest, abdomen, feet and digits. Using the topical spray for specific areas might benefit compliance, as we confirmed the appropriate residual amount of lotion in the spray bottles in all cases in both groups.

本研究评估了外用HCA喷雾剂联合全身使用奥拉替尼治疗犬慢性cAD的有效性。为了减轻瘙痒和皮肤病变，ICADA的cAD治疗指南推荐HCA喷雾剂用于局部和全身性病变，奥拉替尼用于全身性病变。研究中所有的犬都有多发性或全身性慢性皮肤病变。由于每日外用皮质类固醇治疗对宠物主人来说很困难，特别是在全身皮肤病变中，用药依从性对治疗结果有很大的影响。在这项研究中，在颈部、胸部、腹部、爪部和趾部等特定区域，外用HCA或安慰剂喷雾。对特定区域使用外用喷雾剂可能有利于依从性，因为我们在两组的所有病例中都确定了喷雾剂瓶中的剩余量。

A significant decrease in CADESI-4 and PVAS scores was observed on D7 and D14 compared to baseline in both groups. Previous reports have revealed that oclacitinib has rapid efficacy for pruritus associated with cAD, beginning within 4 h of administration of the first dose (0.4–0.6 mg/kg, twice daily). The speed of onset of oclacitinib is as fast as oral prednisolone (0.5–1 mg/kg, once daily for six days, then every other day), and faster than oral ciclosporin (3.2–6.6 mg/kg, once daily), especially within 14 days of administration in dogs with cAD. The topical 0.0584% HCA spray also has been shown to have rapid clinical efficacy for pruritus and dermatitis within 14 days in dogs with cAD in a randomized, doubleblinded, placebo-controlled trial. In our study, there were no significant intergroup differences in the score and mean reduction percentage from baseline in either PVAS or CADESI-4 on D14. Previous reports have shown that the mean reduction rate of the pruritus or dermatitis scores (CADESI-2 or dermatitis Visual Analog Scale score) with oclacitinib monotherapy (14 days) was 63.2% to 67.5% or 48.4% to 71.0%, respectively, in dogs with allergic and atopic dermatitis. Monotherapy with topical HCA spray previously has been shown to reduce the pruritus and CADESI-3 scores by 26.9% and 50.5%, respectively, after 14 days application in cAD cases. Considering these observations, we could not confirm an obvious additive effect of oral oclacitinib and topical HCA spray within 14 days in dogs with cAD.

与基线相比，两组患犬在D7和D14时CADESI-4和PVAS评分均显著降低。之前的报道显示，在首次给药4小时内开始，奥拉替尼对cAD相关瘙痒有快速疗效(0.4 - 0.6 mg/kg，每日两次)。奥拉替尼的起效速度与口服泼尼松龙(0.5-1 mg/kg，每日1次，连续6天，然后隔日1次)相同，快于口服环孢素(3.2-6.6 mg/kg，每日1次)，尤其是在给药14天内。在一项随机、双盲、安慰剂对照试验中，0.0584% HCA喷雾剂对cAD患犬在14天内的瘙痒和皮炎也有快速的临床疗效。在我们的研究中，D14的PVAS或CADESI-4评分和平均下降百分比均无显著组间差异。既往报道单独使用奥拉替尼治疗犬过敏性皮炎和特应性皮炎后14天，瘙痒性皮炎评分(CADESI-2评分或皮炎视觉模拟评分)平均降低率分别为63.2% ~ 67.5%和48.4% ~ 71.0%。在cAD病例中，单独外用HCA喷雾剂治疗，14天后瘙痒和CADESI-3评分分别降低了26.9%和50.5%。考虑到这些观察结果，我们不能确定口服奥拉替尼和外用HCA喷雾剂14天内对cAD犬有明显的累积作用。

In the current study, PVAS and CADESI-4 scores were significantly increased from D14 to D21 in the placebo group, when oral oclacitinib was tapered from twice to once daily. This was not observed in the HCA-treated group. A similar phenomenon was reported in previous studies evaluating oclacitinib monotherapy in cAD. A blinded, randomized, placebo-controlled trial of the efficacy of oclacitinib showed a reduction from baseline in owner-assessed pruritus score from D14 (oclacitinib with 0.4–0.6 mg/kg, twice daily, 66.7%) to D28 (oclacitinib with 0.4–0.6 mg/kg, once daily, 47.4%) in dogs with cAD. Another blinded, randomized clinical trial comparing the efficacy of oclacitinib and ciclosporin for cAD showed that the mean reduction rate from baseline between D14 (oclacitinib with 0.4–0.6 mg/kg, twice daily) and D28 (oclacitinib with 0.4–0.6 mg/kg, once daily) was 63.2% to 50.9% in PVAS and 58.7% to 58.3% in CADESI-2, respectively.7 This suggests that both pruritus and dermatitis could rebound when reducing the frequency of oclacitinib administration.

在本研究中，口服奥拉替尼从每日2次减到每日1次时，安慰剂组的PVAS和CADESI-4评分从D14到D21显著增加。在HCA治疗组中没有观察到这种情况。在以前评价单独使用奥拉替尼治疗cAD的研究中也报道了类似的现象。一项对奥拉替尼有效性的盲法、随机、安慰剂对照试验显示，在cAD患犬中，主人的瘙痒评分从D14 (奥拉替尼0.4-0.6 mg/kg，每日两次，66.7%)降低到D28 (奥拉替尼0.4-0.6 mg/kg，每日一次，47.4%)。另一个盲法、随机临床试验比较奥拉替尼和环孢素治疗cAD的效果表明,从基线到D14 (奥拉替尼 0.4 - 0.6mg/kg,每天两次)和D28 (奥拉替尼 0.4 - 0.6mg/kg,每天一次)PVAS平均降低率是63.2%到50.9%和CADESI-2平均降低率是58.7%到58.3% 。这表明，当减少给药频率时，瘙痒和皮炎都可能反弹。

Oclacitinib is a JAK inhibitor that primarily inhibits the JAK1-dependent signalling pathways of pro-inflammatory or pro-allergic cytokines such as interleukin (IL)-2, IL-4, IL-6 and IL-13 in dogs with cAD. It also inhibits IL-31, a pruritogenic cytokine that has been shown to play a key role in pruritus in cAD. Oral oclacitinib is rapidly and wellabsorbed with a Tmax of <1h and a t1/2 of 4.1 h in dogs. Oclacitinib plasma levels have been shown to be directly related to the reduction in pruritus in laboratory dogs in which pruritus was induced by IL-31 injection. Although the IL-31-induced pruritus level decreased rapidly 4 h after a single dose of oclacitinib (0.4 mg/kg), it increased 18–24 h after its administration. Depending on the severity of skin lesion or dose of oclacitinib in each case of cAD, once-daily oclacitinib was insufficient to control IL-31-induced pruritus for a full day. Pruritus rebound following treatment discontinuation has been reported for corticosteroids or calcineurin inhibitors in humans with atopic dermatitis. A recent study of chronic allergic contact dermatitis using BALB/c mice revealed that although oclacitinib significantly reduced pruritus during treatment, its abrupt withdrawal led to a rapid rebound with an increase in pruritogenic cytokines including IL-31 and fast peripheral sensitization.

奥拉替尼是一种JAK抑制剂，主要抑制cAD患犬中促炎或促过敏细胞因子(如白细胞介素(IL)-2、IL-4、IL-6和IL-13的JAK1依赖的信号通路。它还抑制IL-31，一种已被证明在cAD的瘙痒中发挥关键作用的致痒细胞因子。口服奥拉替尼吸收迅速，犬的Tmax为1h, t1/2为4.1h。在注射IL-31致瘙痒的实验犬中，血浆奥拉替尼水平已被证明与瘙痒的减轻直接相关。单剂量奥拉替尼 (0.4 mg/kg)给药4 h后，IL -31诱导的瘙痒水平迅速下降，但给药18-24 h后瘙痒水平上升。根据皮肤病变的严重程度或每个cAD病例的奥拉替尼剂量，每日一次的奥拉替尼不足以控制一整天IL -31诱导的瘙痒。使用糖皮质激素或钙调磷酸酶抑制剂治疗人特应性皮炎时，停止治疗后有瘙痒反弹的报道。最近一项使用BALB/c小鼠进行的慢性过敏性接触性皮炎研究显示，尽管在治疗过程中奥拉替尼显著降低了瘙痒，但其突然停用导致了快速反弹，并增加了包括IL-31在内的致痒细胞因子，以及神经末梢迅速致敏。

In the present study, the mean reduction of PVAS on D21 and that of CADESI-4 on D28 was significantly better in the HCA-treated group than the placebo group. Topical corticosteroids exhibit a strong anti-inflammatory and antipruritic effect that stems from their wide targeting of cells expressing glucocorticoid receptors. A previous study showed that the 0.0584% HCA spray was equally effective as oral ciclosporin in treating cAD for ≤84 days, and the clinical response of the HCA spray was quite rapid, with most of the improvements in clinical lesions and pruritus noted at D28. Topical HCA spray also has been recommended as maintenance therapy for preventing acute flare of cAD. Our study indicated that concurrent 0.0584% topical HCA spray therapy might be beneficial to prevent exacerbation or rebound of pruritus and skin lesions when decreasing the frequency of oral oclacitinib in cAD.

本研究中，与安慰剂组相比，HCA治疗组D21和D28的PVAS的平均降低明显好于对照组。外用糖皮质激素表现出强烈的抗炎和止痒作用，这源于它们广泛针对表达糖皮质激素受体的细胞。既往研究显示0.0584% HCA喷雾剂治疗cAD≤84天的疗效与口服环孢素相当，且HCA喷雾剂的临床疗效相当快，在第28天，大部分临床病变和瘙痒症状得到改善。外用HCA喷雾剂也被推荐作为预防cAD急性发作的维持疗法。我们的研究表明，当降低cAD患犬口服奥拉替尼的频率时，同时0.0584%的HCA外用喷雾剂治疗可能有助于防止皮肤瘙痒和皮肤病变的加重或反弹。

The four week combination treatment of oral oclacitinib and topical HCA spray was well-tolerated. Although both oclacitinib and topical corticosteroids have a potential immunosuppressive effect in dogs, there was no evidence of secondary infections in the HCA-treated group. Other adverse effects of topical corticosteroid therapy include cutaneous atrophy and adrenal suppression. Neither dermatological examination nor the ACTH stimulation test revealed abnormalities before or after treatment. The 0.0584% topical diester glucocorticoid HCA avoids cutaneous and systemic adverse effects seen with traditional topical glucocorticoids by virtue of its metabolism into largely inactive moieties within the skin. A previous randomized, double-blinded, placebo-controlled trial showed that no changes in haematological and biochemical results and ACTH stimulation tests occurred in dogs with cAD treated with HCA spray once daily to every other day for ≤70 days.

口服奥拉替尼和外用HCA喷雾剂联合治疗四周耐受性良好。虽然奥拉替尼和外用皮质类固醇对犬有潜在的免疫抑制作用，但在HCA治疗组中没有继发性感染的证据。外用皮质类固醇治疗的其他副作用包括皮肤萎缩和肾上腺抑制。皮肤科检查和促肾上腺皮质激素刺激试验均未发现治疗前后异常。0.0584%的外用双酯糖皮质激素HCA避免了传统外用糖皮质激素的皮肤和全身副反应，因为它能代谢掉皮肤内大部分失活分子。之前的一项随机、双盲、安慰剂对照试验显示，在cAD患犬身上，每天至每隔一天使用HCA喷雾剂治疗，持续70天，血液学和生化结果以及促肾上腺皮质激素(ACTH)刺激试验没有发生变化。

Unfortunately, one dog in the HCA-treated group withdrew from the trial as a consequence of developing diarrhoea. Short-term, self-resolving diarrhoea was observed in two of 15 dogs in a previous clinical trial of topical HCA monotherapy. In previous clinical trials evaluating oclacitinib monotherapy, 1.6–6.1% cases had diarrhoea. The incidence of diarrhoea in this study (one of nine, 11.1%) was comparable to that of previous reports.

可惜的是，接受HCA治疗组的一只犬因腹泻而退出试验。在之前的一项外用HCA单药临床试验中，15只犬中有2只观察到短期的、能自行缓解的腹泻。在之前评估单独使用奥拉替尼治疗的临床试验中，1.6-6.1%的病例出现腹泻。本研究中腹泻的发病率(九分之一，11.1%)与以前的报告相似。

To the best of the authors’ knowledge, this study is the first controlled clinical trial to evaluate combination therapy of a topical corticosteroid and a systemic JAK inhibitor in dogs with cAD. It should be noted that the statistical power of PVAS was 0.11; this low power was likely to have been caused by the small sample size and thus the effect of each treatment cannot be deduced using the PVAS. Although the number of cases was small, the results suggest that a combination therapy of 0.0584% HCA spray and oral oclacitinib might be well-tolerated and more effective than oclacitinib monotherapy during the initial four weeks of treatment in cAD.

据作者所知，这项研究是第一个评估外用皮质类固醇和全身JAK抑制剂联合治疗cAD患犬的对照临床试验。值得注意的是，PVAS的统计幂为0.11;这种低率可能是由于样本量小造成的，因此不能通过PVAS推断每种治疗的效果。虽然病例数较少，但结果提示，在cAD治疗的最初4周，0.0584% HCA喷雾剂联合口服奥拉替尼的联合治疗可能比单独使用奥拉替尼耐受性更好，更有效。

liuying

BrentChris