本帖最后由 王帆 于 2022-2-12 20:46 编辑
Prolonged twice-daily administration of oclacitinib for the control of canine atopic dermatitis: a retrospective study of 53 client-owned atopic dogs 长期每日两次给予奥拉替尼控制犬特应性皮炎：一项对53只家养特应性皮炎患犬的回顾性研究
作者：Daria Denti、Marco Caldin、Laura Ventura和Michela de Lucia
翻译：郑江涛 校对：王帆
Background – Oclacitinib administered at the licensed dose twice daily for two weeks and then once daily as required is recommended for the treatment of atopic dogs. In some cases, the once-daily regimen is insufficient to control the clinical signs. Objectives – To provide preliminary safety and efficacy data on the prolonged twice-daily administration of oclacitinib in atopic dogs. Animals – Fifty-three client-owned atopic dogs Methods and materials – The medical records of dogs with atopic dermatitis treated with oclacitinib twice daily for more than two weeks were reviewed retrospectively. Animal details, treatment dose and duration, concurrent diseases, adjunctive medications and possible adverse events were recorded. Treatment efficacy was assessed retrospectively and, when available, the selected blood parameters before and during the treatment were compared. Statistical analyses of the collected data were performed. Results – The median treatment duration was 113 days. Excellent-to-good efficacy was observed in 38 dogs(72%), including 24 of 33 dogs that failed to respond to the once-daily regimen. Eight dogs showed a poor response despite the addition of systemic glucocorticoids. Pyoderma, gastrointestinal signs and otitis externa were the most frequent adverse events recorded whilst on treatment. Blood tests performed in 35 dogs showed slightly decreased leucocyte, neutrophil, eosinophil and monocyte counts that remained within the reference ranges in most cases. Three dogs developed hypercholesterolemia. Conclusions and clinical relevance – Prolonged twice-daily administration of oclacitinib generally was welltolerated and was effective in most of the treated dogs. Regular clinical evaluation and blood tests are advisable for this treatment regimen. 摘要 背景-奥拉替尼以许可剂量给药，每日两次，持续两周，然后根据需要每日一次，推荐用于治疗犬特应性皮炎。在某些病例中，每日一次的方案不足以控制临床症状。 目的-提供特应性皮炎的患犬长期每日两次服用奥拉替尼的初步安全性和有效性数据。 动物- 53只家养特应性皮炎的患犬 方法和材料-回顾性分析特应性皮炎患犬只接受奥拉替尼每日两次治疗超过两周的医疗记录。记录动物详细信息、治疗剂量和持续时间、并发疾病、辅助药物和可能的不良反应。对治疗效果进行回顾性评估，并对治疗前和治疗期间所选的血液参数进行比较。对收集的数据进行统计分析。 结果-中位治疗时间为113天。在38只犬（72%）中观察到了从优秀到良好的疗效，包括33只犬中的24只，它们对每日一次的方案没有效果。尽管添加了全身性糖皮质激素，8只犬仍表现疗效差。脓皮病、胃肠道症状和外耳炎是治疗期间最常见的不良反应。对35只犬进行的血液测试显示，白细胞、中性粒细胞、嗜酸性粒细胞和单核细胞计数略有减少，但在大多数病例中仍在参考范围内。三只犬有出现高胆固醇血症。 结论和临床相关性-长期每日两次服用奥拉替尼通常耐受性良好，并且在大多数接受治疗的犬中有效。这种治疗方案建议定期进行临床评估和血液检查。
Introduction 介绍 Oclacitinib is a small-molecule drug that modulates inflammatory and pruritogenic cytokines through the inhibition of the Janus kinase/ signal transducer and activator of transcription (JAK/STAT) signalling pathway.It is approved for the treatment of pruritus associated with allergic dermatitis and the clinical management of atopic dermatitis (AD) in dogs.Administration of the drug at a dose of 0.4–0.6 mg/kg twice daily for the first two weeks and then once daily for maintenance is recommended.The effectiveness and safety of this dosing regimen has been demonstrated.Adverse effects are uncommon and consist mainly of gastrointestinal signs and skin infections.At the labelled dose, minimal changes in haematological and serum chemical parameters have been described, including a minimal decrease in white blood cell count, and increases in serum cholesterol and alkaline phosphatase (ALP) activity levels.An increase in pruritus and clinical lesions has been described in some atopic dogs when tapering oclacitinib therapy from twice to once daily, which requires adjunctive treatments.Based on the authors’ experience, those cases also might benefit from prolonged twice daily dosing of oclacitinib. Unfortunately, in a premarketing study, this latter regimen showed an insufficient margin of safety and is not currently recommended. However, adverse effects were not observed when oclacitinib was administered twice daily at the registered dose for an extended period, ranging from one to 12 months, to treat a small number of cases of immunemediated diseases.Thus, the objective of this retrospective study was to describe the efficacy, adverse events and variations in selected laboratory parameters in a series of client-owned atopic dogs treated with oclacitinib twice daily for more than two weeks. 奥拉替尼是一种小分子药物，通过抑制Janus激酶/信号转导子和转录激活子（JAK/STAT）信号通路调节炎症和和致痒细胞因子。已批准用于治疗与过敏性皮炎相关的瘙痒症和犬特应性皮炎（AD）的临床治疗管理。建议给药剂量为，前两周0.4–0.6 mg/kg，每日两次，随后每日一次维持给药。该给药方案的有效性和安全性已得到证实。不良反应不常见，主要包括胃肠道症状和皮肤感染。在标签剂量下，血液学和血清化学参数的最小变化已被描述，包括白细胞数极轻微下降，以及血清胆固醇和碱性磷酸酶（ALP）活性水平的增加。当奥拉替尼治疗从每日两次逐渐减少到每日一次时，一些特应性皮炎患犬瘙痒和临床病变增加，这需要辅助治疗。根据作者的经验，这些病例也可能对每日两次的奥拉替尼剂量有效。不幸的是，在一项上市前研究中，后一种方案的安全性不足，目前不推荐使用。然而，当奥拉替尼以注册剂量长期每日两次给药时，未观察到不良反应。从1个月到12个月不等，用于治疗少数免疫介导的疾病。因此，本回顾性研究的目的是描述一系列使用奥拉替尼每日两次治疗超过两周的家养特应性皮炎患犬的疗效、不良反应和所选实验室参数的变化。
Methods and materials 方法和材料 Case selection 病例选择 This was a nonexperimental retrospective study in which data were retrieved from the medical records of the included dogs. Therefore, institutional animal care and use committee approval were not required. Informed consent was obtained from the animal owners before using the data for the study. No personally identifiable data were used.Cases were retrieved through a comprehensive digital search of the Dermatology Service electronic database of a single referral centre using the search terms “dog”,“atopic dermatitis” and “oclacitinib treatment”. Dogs with a diagnosis of nonseasonal atopic dermatitis (cAD) and treated with oclacitinib (Apoquel, Zoetis Italia; Rome,Italy) at a dose of 0.4–0.6 mg/kg twice daily for more than two weeks were selected for the study. As this study is based on the retrospective analysis of medical records,dogs included in this study could have been treated with many different drugs in addition to oclacitinib.The diagnosis of cAD was based on published guidelines.16 Dogs with food allergy were excluded on the basis of a response to dietary elimination and challenge.Furthermore, all dogs received monthly flea prevention.Cases were seen by a board-certified dermatologist (MDL) and a European College of Veterinary Dermatology resident (DD) between April 2014 and September 2020. 这是一项非实验性的回顾性研究，数据是从纳入的犬的医疗记录中检索出来的。因此，不需要动物保护机构和委员会的批准。在将数据用于研究之前，获得了动物主人的同意。没有使用个人身份数据。通过使用搜索词“犬”、“特应性皮炎”和“奥拉替尼治疗”对单个转诊中心的皮肤科服务电子数据库进行综合数字搜索来检索病例。诊断为非季节性特应性皮炎（CAD）并接受奥拉替尼治疗的犬，剂量为0.4–0.6 mg/kg，每日两次，持续两周以上。由于本研究是基于病历的回顾性分析，除了奥拉替尼之外，本研究中的犬还可以使用许多不同的药物进行治疗。CAD的诊断基于已发表的指南。根据对食物排除和激发试验，排除了16只食物过敏的犬，此外，所有的犬都接受了每月一次的跳蚤预防。在2014年4月至2020年9月期间，一名委员会认证的皮肤科医生（MDL）和一名欧洲兽医学院皮肤科住院医师（DD）对病例进行了检查。
Clinical data collection 临床数据收集 The medical records were reviewed retrospectively to obtain pertinent data, including animal details, administered dose and duration of the twice-daily administration,and adjunctive medications. As a consequence of interand intra-patient variability in the use of antiseptic and emollient shampoos or solutions, and ear cleansers,these treatments were not reported in this study. The presence and follow-up of skin and ear infections, concurrent skin diseases diagnosed at the beginning of the treatment, as well as concomitant pre-existing conditions,were recorded. 对医疗记录进行回顾性审查，以获得相关数据，包括动物详细信息、给药剂量和每日两次给药的持续时间以及辅助药物。由于使用抗菌和保湿香波或溶液，以及洗耳液的患病动物间和患病动物内的差异，本研究中未报告这些治疗。记录就诊时和复诊时有无皮肤和耳部感染、治疗开始时诊断的并发皮肤病以及共存的基础病。
Any abnormal clinical sign that developed during the treatment was considered as a possible adverse event. 治疗期间出现的任何异常临床症状均被视为可能的不良反应。
The overall response to treatment was assessed retrospectively and subjectively based on the information available in the records at the end of the recorded treatment period. Briefly, responses were deemed “excellent” in the absence of pruritus and skin lesions, “good” in the presence of localised pruritus and skin lesions and “poor”when no improvement or recurrence of skin infections were reported. 在记录的治疗期结束时，根据记录中可用的信息，对治疗的总体效果进行回顾性和主观评估。简言之，无瘙痒和皮肤病变的病例，疗效为“极好”，存在局部瘙痒和皮肤病变的病例，疗效为“良好”，无效或皮肤感染复发的病例，疗效为“不佳”。
Whenever available, selected blood parameters, including red blood cell,leucocyte, neutrophil, lymphocyte,eosinophil and monocyte counts, as well as serum cholesterol and ALP activity levels before and during the treatment were recorded and compared. For each parameter, when more than one measurement was performed,the last one was considered for statistical evaluation. 在治疗前和治疗期间，记录并比较选定的血液参数，包括红细胞、白细胞、中性粒细胞、淋巴细胞、嗜酸性粒细胞和单核细胞计数，以及血清胆固醇和ALP活性水平。对于每个参数，当进行一次以上的测量时，最后一次测量被考虑用于统计评估。
Statistical methods 统计方法 Data are summarised using percentages, means and standard deviations. Differences in quantitative variables regarding the response to treatment were assessed using an ANOVA or Kruskal–Wallis tests,according to the results of a Shapiro–Wilk test of normality. Variations of the selected blood parameters were assessed using a Student’s t-test or Wilcoxon tests for paired data, according to the results of Shapiro–Wilk test of normality. Logistic regression was used to study the effect of the treatment dose and length on the occurrence of adverse effects. The correlations between the treatment dose and length with the variation in the selected blood parameters were assessed using Pearson correlation coefficients. Statistical significance was set at P < 0.05. Data were analysed using the statistical software R. 使用百分比、平均值和标准差对数据进行总结。使用ANOVA或Kruskal-Wallis检验评估关于治疗反应的定量变量的差异。根据夏皮罗-威尔克正态性检验的结果。使用Student s t-检验或Wilcoxon评估所选血液参数的变化根据Shapiro-Wilk正态性检验的结果，对配对数据进行检验。采用Logistic回归分析研究治疗剂量和治疗时间对不良反应发生的影响。使用Pearson相关系数评估治疗剂量和长度与所选血液参数变化之间的关系。统计学显著性设定为P<0.05。使用统计软件R对数据进行分析。
Results 结果 Study population and treatments 研究对象和治疗方案 Fifty-three dogs met the inclusion criteria. West Highland white terriers (n = 9) and Labrador retrievers (n = 9) were over-represented. The median age was 69 months (range 10–159 months) and the median weight was 13.5 kg (range 3.7–49 kg). In 33 of the 53 cases, the once-daily regimen failed to control the disease, as reported in the medical records. 53只犬符合纳入标准。西高地白㹴（n=9）和拉布拉多猎犬（n=9）的比例过高。年龄中位值为69个月（范围10-159个月），体重中位值为13.5公斤（范围3.7-49公斤）。据医疗记录报告，在53个病例中的33个病例中，每日一次的治疗方案未能控制病情。
The median dose of oclacitinib was 0.5 mg/kg twice daily (mean 0.49±0.06 mg/kg) and the median treatment duration was 113 days (range 21–1277 days). 奥拉替尼的中位剂量为0.5 mg/kg，每日两次（平均0.49± 0.06 mg/kg），中位治疗时间为113天（范围21-1277天）。
At the start of the twice-daily administration of oclacitinib, pyoderma (n = 15), Malassezia dermatitis (n = 2),interdigital nodules (n = 4), demodicosis due to Demodex canis (n = 1), and otitis externa (OE)/otitis media(OM) (n = 10) were observed. After topical and/or systemic treatments, these conditions resolved in all cases, except for the interdigital nodules, for which only mild improvement was observed (see Table S1 in Supporting information). Nineteen cases showed concomitant pre-existing diseases. Some of these conditions were chronic and managed accordingly, while others resolved during oclacitinib administration after appropriate treatment (Table S2). None of the preexisting diseases worsened during the twice-daily administration of oclacitinib. 在每日两次服用奥拉替尼开始时，脓皮病（n=15）、马拉色菌皮炎（n=2）、趾间结节（n=4）、犬蠕形螨导致的蠕形螨病（n=1）和外耳炎（OE）/中耳炎（OM）（n=10）。在外部和/或全身治疗后，这些疾病在所有病例中都得到了解决，趾间结节除外，其仅有轻微改善（见表S1支持信息）。19例伴有基础病。其中一些疾病是慢性病，并进行了相应的管理，而另一些则在适当的治疗后在服用奥拉替尼期间得到解决（表S2）。在每天两次服用奥拉替尼期间，先前存在的疾病均未恶化。
Table 1. Possible adverse events during the prolonged twice-daily administration of oclacitinib in 53 atopic dogs. 表1。53只特应性皮炎患犬每日两次长期服用奥拉替尼，可能的不良反应
Adverse event 不良反应 | Oclacitinib-treated dogs [n=53; n (%)] 奥拉替尼治疗的犬[n=53；n（%） | | | Otitis externa/otitis media 外耳炎/中耳炎 | | | | Malassezia dermatitis 马拉色菌皮炎 | | | | | | | | | | | | Demodicosis (Demodex injai) 蠕形螨病（隐在蠕形螨） | | Urinary tract infection 泌尿道感染 | | | | | | | | | | | | | | | | | | Oedema due to protein-losing enteropathy 蛋白丢失性肠病 | | | | | | | | | | | | | | Cavernous hemangioma 海绵状血管瘤 | | Keratin inclusion cyst 角质囊肿 | |
During the treatment period, systemic antibiotics were required in 15 dogs (28%) to treat pyoderma (n = 13), urinary tract infection (n = 1), OM (n = 1), oronasal fistula(n = 1) and anal sac abscess (n = 1), and systemic antifungal agents were used in six dogs with Malassezia dermatitis (11.3%). 在治疗期间，15只犬（28%）需要全身使用抗生素治疗脓皮病（n=13）、泌尿道感染（n=1）、OM（n=1）、口鼻瘘（N=1）和肛囊脓肿（N=2），6只患马拉色菌皮炎的犬（11.3%）需要全身使用抗真菌药物。
Short (less than one week) (n = 2) or prolonged (one to three weeks) (n = 8) courses of systemic glucocorticoids were prescribed once to 10 dogs (18.9%) to control flareups of cAD. Topical glucocorticoids were administered in 22 cases (41.5%), which included prophylactic application to the ear canals in 13 dogs. 10只犬（18.9%）接受了一次短期（少于一周）（n=2）或长期（一至三周）（n=8）的全身糖皮质激素治疗。控制CAD的突然发病。22例（41.5%）外用糖皮质激素，其中13只犬预防性应用于耳道。
The clinical data of treated dogs, oclacitinib dose and length of administration, the possible adverse events, and concurrent medications are reported in Table S3. 表S3中报告了接受治疗的犬的临床数据、奥拉替尼的剂量和给药时间、可能的不良反应和合并用药。
Response to treatment 治疗效果 Excellent, good and poor responses were observed in 16(30%), 22 (42%) and 15 cases (28%), respectively.Twenty-four of the 33 (73%) dogs that failed to respond to the once-daily regimen showed excellent or good responses to the prolonged twice-daily administration(Table S3). No statistically significant correlations between the response to treatment and the administered dose, length of treatment, body weight and age of the treated dogs were observed. 分别有16例（30%）、22例（42%）和15例（28%）疗效为极好、良好和不佳。33只（73%）对每日一次给药方案无效的犬中有24只（73%）对长期每日两次给药方案有极好或良好疗效。（表S3）。疗效与给药剂量、治疗持续时间、治疗犬的体重和年龄之间无统计学显著相关性。
Possible adverse events 可能的不良反应 One self-limiting episode of the following gastrointestinal signs was observed in nine dogs: anorexia (n = 1), nausea(n = 1), vomiting (n = 4), soft stool (n = 4) and diarrhoea(n = 3). No correlation was identified between gastrointestinal signs and treatment dose and duration. During the treatment period, pyoderma (n = 14), OE/OM(n = 10), interdigital nodules (n = 9), Malassezia dermatitis (n = 6), oronasal fistula (n = 1), urinary tract infection(n = 1) and anal sac abscess (n = 1) were reported. A proportion of the pyoderma (n = 6), OE (n = 3) and Malassezia dermatitis (n = 1) cases were relapses. Some dogs developed more than one condition. 在9只犬中观察到以下胃肠道症状的一次自限性发作：厌食（n=1）、恶心（n=1）、呕吐（n=4）、软便（N=4）和腹泻（n+3）。未发现胃肠道症状与治疗剂量和持续时间之间存在相关性。在治疗期间，脓皮病14例、OE/OM10例、趾间结节9例、马拉色菌皮炎6例、口鼻瘘1例、泌尿道感染1例、肛囊脓肿1例。部分脓皮病（n=6）、OE（n=3）和马拉色菌皮炎（n=1）病例复发。有些犬患上了不止一种疾病。
The occurrence of pyoderma (P = 0.02), urinary tract infection, anal sac abscess and oronasal fistula (P = 0.01)was significantly correlated with treatment duration. 脓皮病（P=0.02）、泌尿道感染、肛囊脓肿和口鼻瘘（P=0.01）的发生与治疗时间显著相关。
Demodex injai was detected in the perioral area of a West Highland white terrier (Case 27) in conjunction with erythema, scales and partial alopecia. Parasitological cure was obtained after a two month weekly administration of a 10% imidacloprid and 2.5% moxidectin spot-on (Advocate, Bayer HealthCare; Leverkusen, Germany).During the following three years, D. injai was detected occasionally in the perioral area of the same dog even after oclacitinib discontinuation. 在一只西高地白㹴（病例27）的口周区域检测到隐在蠕形螨，并伴有红斑、皮屑和部分脱毛。用10%吡虫啉和2.5%莫西克丁滴剂，每周一次，给药两个月后，达到寄生虫学治愈。在随后的三年中，即使在停用奥拉替尼后，同一只犬的口周区域也偶尔检测到隐在蠕形螨。
A keratin inclusion cyst [Day (D)38 of treatment],cutaneous histiocytoma (D45 of treatment) and sebaceous adenomas (D81 and D180 of treatment) were diagnosed in one dog each (cases 53, 12, 1, 14), while one dog (Case 48) developed a lipoma and a cavernous haemangioma (D48 of treatment). The histiocytoma regressed spontaneously within one month while the haemangioma was surgically removed with no relapses observed in the following two and a half years. In another case (Case 37), a nodule was observed on the right inferior eyelid after 31 days of treatment. Cytological findings were inconclusive and follow-up of the lesion was not available. In one case, a mammary adenoma was surgically removed after 28 days of treatment (Case 23), with no recurrence noted in the following year. All cases showing possible adverse events were managed without changing the twice-daily administration of oclacitinib. All possible adverse events are summarised in Table 1. 角质囊肿[治疗第38天、皮肤组织细胞瘤（治疗第45天）和皮脂腺瘤（治疗第81天和第180天）各在一只犬（病例53、12、1、14）中被诊断，而一只犬（病例48）发展为脂肪瘤和海绵状血管瘤（治疗第48天）。组织细胞瘤在一个月内自行消退，而血管瘤被手术切除，在随后的两年半内没有复发。在另一病例（病例37）中，在治疗31天后，在右下眼睑观察到一个结节。细胞学检查结果不确定，无法对病变进行随访。在一个病例中，乳腺腺瘤在治疗28天后被手术切除（病例23），在接下来的一年中没有复发。所有出现可能不良反应的病例均在不改变每日两次奥拉替尼给药的情况下进行治疗。表1总结了所有可能的不良反应。
Possible severe adverse events 可能的严重不良反应 In Case 24, a thyroid carcinoma was diagnosed 15 months after the initiation of oclacitinib administration.The oclacitinib treatment was stopped and radiotherapy was performed. The dog was still alive four months after diagnosis. 在病例24中，在开始服用奥拉替尼15个月后诊断为甲状腺癌。停止奥拉替尼治疗并进行放疗。这只犬在确诊四个月后仍然活着。
Laboratory parameters 实验室参数 The results of the blood tests before and during treatment (median 81 days after starting the twice-daily regimen, range 21–570 days) were available in 35 cases(Table S4). Analysis of selected parameters revealed a significant (P < 0.001) reduction in the numbers of leucocytes, neutrophils, eosinophils and monocytes during treatment (Figure 1). These results did not change after excluding from the statistical analysis three dogs with significantly higher neutrophil (Case 27), eosinophil (Case 10）and monocyte (Case 33) counts compared to those in the rest of the study population before starting treatment.Some dogs showed eosinophil (n = 6), neutrophil (n = 3),monocyte (n = 2) and total leucocyte (n = 2) counts slightly below the reference ranges during treatment.Neutrophil and monocyte counts above the upper limits were reported in one case each. 35例患犬在治疗前和治疗期间（开始每日两次方案后的中位数为81天，范围为21-570天）的血液检测结果可用（表S4）。对所选参数的分析显示，治疗期间白细胞、中性粒细胞、嗜酸性粒细胞和单核细胞的数量显著减少（P<0.001）（图1）。在从统计分析中排除了与开始治疗前的其余研究患犬相比，中性粒细胞（病例27）、嗜酸性粒细胞（病例10）和单核细胞（病例33）计数显著较高的三只犬后，这些结果没有改变。在治疗期间，一些犬的嗜酸性粒细胞（n=6）、中性粒细胞（n=3）、单核细胞（n=2）和白细胞总数（n=2）计数略低于参考范围，中性粒细胞和单核细胞计数各有一例高于上限。
Serum cholesterol levels increased significantly during treatment (P = 0.004) and were slightly above the referencerange in five dogs, two of which were already hypercholesterolaemic before starting treatment. 血清胆固醇水平在治疗期间显著增加（P=0.004），并且在5只犬中略高于参考范围，其中两只在开始治疗前已经是高胆固醇血症。
Changes in the studied parameters were not signifi-cantly correlated with the treatment dose and duration,and did not lead the clinician to modify the treatment. 研究参数的变化与治疗剂量和持续时间无显著相关性，也不会导致临床医生修改治疗方案。
Figure 1. Boxplots of the relative differences of erythrocyte, leucocyte, neutrophil, lymphocyte, monocyte, and eosinophil counts and cholesterol and alkaline phosphatase (ALP) serum activity levels during treatment with oclacitinib administered twice daily for more than two weeks. The black lines within the boxes indicate the median of the relative difference, while the upper and lower boundaries of the boxes represent the 25th and 75th percentiles, respectively. Values above and below 0 (red star) indicate increased or decreased median value of the parameter. 图1。红细胞、白细胞、中性粒细胞、淋巴细胞、单核细胞和嗜酸性粒细胞计数以及胆固醇和碱性磷酸酶的相对差异的箱线图（ALP）血清活性水平在每天两次给予奥拉替尼超过两周的治疗期间。 方框内的黑线表示相对差异的中值，而方框的上边界和下边界分别表示第25个和第75个百分位数。高于和低于0（红星）的值表示参数中值的增加或减少。
Discussion 讨论 To the best of our knowledge, this is the first description of the efficacy and safety of a prolonged twice-daily administration of oclacitinib in a large series of clientowned atopic dogs. Based on the subjective evaluation,excellent-to-good disease control was obtained in 72% of the treated dogs, including 73% (24 of 33) of cases that failed to respond to the once-daily regimen. However,this success rate cannot be compared with the results of previous studies that evaluated the standard protocol as validated scales and clinical scores were not used here.Nevertheless, the fact that most of the dogs that did not improve with the standard protocol showed an excellentto-good response to the prolonged twice-daily regimen suggests that the latter might be more effective, at least in some cases. Several well-conducted studies have reported the reduced efficacy of oclacitinib administered for pruritus control in allergic dogs after D14 when the drug is tapered from twice to once daily.Cosgrove et al. reported a mean owner pruritus Visual Analog Scale (pVAS) score of 2.6 (“very mild itching”) in oclacitinibtreated dogs by D14, which increased to 4.1 (“mild itching”) at D28.Another study observed a 67.5% reduction in pruritus from baseline at D14, which decreased to 52.5% by D28. Moreover, a ≥50% reduction in pruritus was achieved in 74% of dogs at D14 compared to 51% of dogs at D28.A small randomised placebo-controlled study evaluating the combination of oclacitinib and 0.0584% hydrocortisone aceponate spray in atopic dogs,showed that in the placebo-controlled group, both pruritus (pVAS) and severity of dermatitis scores [Canine Atopic Dermatitis Extent and Severity Index, 4th iteration(CADESI-04)] increased significantly after changing the regimen from twice to once daily.The reduced ability of oclacitinib to control pruritus and lesions associated with cAD when administered once daily might be explained by the decreased 24 h oclacitinib maleate plasma concentration.Although in many cases, this slight reduction in efficacy does not affect the efficacy of treatment, other cases may experience a significant worsening of the clinical picture.While combination therapy with topical glucocorticoids has been proposed for these cases,resuming the twice-daily administration of oclacitinib may help regain control of the disease, especially when pruritus and lesions are diffuse. 据我们所知，这是首次对大量家养特应性皮炎患犬，评估长期每日两次给予奥拉替尼的疗效和安全性。根据主观评价，72%的治疗犬达到了从极好到良好的疗效，包括73%（33只中的24只）对每日一次方案无效的病例。然而，这一成功率不能与以前评估标准方案的研究结果进行比较，因为这里没有使用有效评分表和临床评分表。然而，大多数标准方案没有改善的犬对长期每日两次方案表现出极好的效果，这一事实表明，至少在某些病例中，后者可能更有效。几项进行得很好的研究报道，在第14天后，当药物从每天两次逐渐减少到一次时，用于控制过敏犬瘙痒的奥拉替尼的疗效降低。科斯格罗夫等人据报道，在第14天，奥拉替尼治疗的犬的平均主人瘙痒视觉评分表（PVAS）评分为2.6（“非常轻微的瘙痒”），增加到4.1（“轻度瘙痒”）。另一项研究观察到，在第14天，瘙痒从基线减少67.5%，到第28天减少到52.5%。此外，在第14天时，74%的犬的瘙痒减轻≥50%，而在第28天时，这一比例为51%。一项小型随机安慰剂对照研究评估了特应性皮炎患犬联合使用奥拉替尼和0.0584%氢化可的松醋丙酯喷雾剂，结果显示，在安慰剂对照组中，将方案从每天两次改为每天一次后，瘙痒（PVAS）和病变严重程度评分[犬特应性皮炎严重程度指数，第4次版（CADESI-04）均显著增加。每天给药一次时，奥拉替尼控制与CAD相关的瘙痒和病变的能力降低，这可能是由于马来酸奥拉替尼24小时血浆浓度降低所致。尽管在许多病例中，这种疗效的轻微降低并不影响治疗的效果，但其他病例可能经历临床表现的显著恶化。虽然已建议对这些病例进行外用糖皮质激素联合治疗，但恢复每日两次服用奥拉替尼可能有助于重新控制病情，尤其是当瘙痒和病变呈弥漫性时。
Before starting oclacitinib administration, four of the 15 cases with poor responses showed interdigital nodular pododermatitis that did not improve after treatment.Notably, interdigital nodules might have a multifactorial nature (e.g. recurrent trauma, orthopaedic diseases,infections), including and not limited to AD in the dog. 在开始服用奥拉替尼之前，15例不良反应的病例中有4例出现趾间结节足皮炎，治疗后没有改善。值得注意的是，趾间结节可能具有多因素性质（例如复发性创伤、骨科疾病、感染），包括但不限于AD患犬。
Despite the prolonged twice-daily administration of oclacitinib, 10 dogs (18.9%) required a short or prolonged course of systemic glucocorticoids to control flare-ups of AD. Interestingly, eight of these cases showed persistent pruritus or recurrences of skin infections and were considered poor responders. Safety data on the combination therapy of oclacitinib and systemic glucocorticoids are lacking. In an open-label long-term (≤630 days) compassionate study, systemic steroids were administered to 31 of 24 oclacitinib-treated atopic dogs to control flare-ups or to treat concomitant diseases. Six of the 31 dogs in this compassionate study showed abnormal health events,including vomiting, diarrhoea, haematochezia, haematemesis and diabetic ketoacidosis. The latest guidelines from the International Committee on Allergic Diseases of Animals (ICADA) do not recommend the prolonged concomitant administration of oclacitinib and other immunomodulatory drugs, as a result of the potential for dose-dependent drug induced immunosuppression predisposing to potentially severe opportunistic infections of the skin or other organs. 尽管长期每日两次服用奥拉替尼，10只犬（18.9%）仍需要短期或长期的全身糖皮质激素治疗来控制AD的发作。有趣的是，这些病例中有8例表现为持续性瘙痒或皮肤感染复发，并被认为疗效不佳。缺乏奥拉替尼和全身性糖皮质激素联合治疗的安全性数据。在一项标签外长期（≤630天）同情研究中，对24只接受奥拉替尼治疗的特应性皮炎患犬中的31只给予全身性类固醇，以控制发作或治疗伴随疾病。在这项同情研究中，31只犬中有6只表现出健康异常，包括呕吐、腹泻、便血、呕血和糖尿病酮症酸中毒。国际动物过敏性疾病委员会（ICADA）的最新指南不建议长期联合使用奥拉替尼和其他免疫调节药物。由于潜在的剂量依赖性药物诱导的免疫抑制，易导致皮肤或其他器官的潜在严重条件性感染。
In our study, the prolonged twice-daily administration of oclacitinib was generally well-tolerated. Mild and selflimiting gastrointestinal adverse effects were described in 17% of dogs, and no cases required treatment interruption. The frequencies of vomiting (7.5%) and diarrhoea(5.7%) were not higher than those reported previously for the licensed protocol (vomiting 2.3–14%; diarrhoea 1.6–6.1%).This finding is consistent with those of a double-blinded, placebo-controlled study including 179dogs administered with oclacitinib twice daily for≤30 days as a continuation of a seven day efficacy and safety study, in which diarrhoea (2.8%) and vomiting(3.3%) were observed. 在我们的研究中，长期每日两次服用奥拉替尼的耐受性良好。在17%的犬中描述了轻度和自限性的胃肠道不良反应，没有需要中断治疗的病例。呕吐（7.5%）和腹泻（5.7%）的发生率并不高于先前报告的许可方案（呕吐2）的发生率。3–14%;腹泻1.6-6.1%）。这一发现与一项双盲、安慰剂对照研究的结果一致，该研究包括179只犬每天两次服用奥拉替尼≤30天，作为一项为期7天的疗效和安全性研究的延续。其中腹泻（2.8%）和呕吐（3.3%）。
In our case series, pyoderma (26%) and OE (19%)occurred more frequently than reported previously in dogs treated with oclacitinib according to the standard protocol (≤12%).Although pyoderma and OE are very common in atopic dogs, there are some concerns regarding the possible immunosuppressive effect of the prolonged twice-daily administration of oclacitinib.Early safety studies showed a dose-dependent association between a long-term twice-daily administration of oclacitinib and viral skin papillomas, interdigital furunculosis, demodicosis and bacterial pneumonia in young adult beagle dogs, suggesting an immunosuppressive activity.However, an in vitro study reported that only a very high dose of oclacitinib, corresponding to an oral administration of 3–4 mg/kg twice daily, reduced T-cell activity and cytokine production.In our study, the dogs appeared to remain immunocompetent during treatment, based on their ability to overcome skin, ear and non-cutaneous infections after the administration of appropriate systemic or topical antimicrobials, without changing the oclacitinib treatment regimen. Moreover, we observed a frequency of non-cutaneous infections(5.7%) lower or similar to those reported previously for the recommended protocol (≤12%).Furthermore,extra-label use of oclacitinib twice-daily for 48 days in a 10-month-old French bulldog (Case 26) with concurrent pyoderma and septic osteomyelitis successfully controlled atopic dermatitis and did not hinder the resolution of both the pyoderma and osteomyelitis. However, the observed correlation between the duration of treatment and the development of pyoderma and noncutaneous infections suggests the need for careful monitoring when administering prolonged twice-daily oclacitinib treatment. 在我们的病例系列中，根据标准方案，脓皮病（26%）和OE（19%）在接受奥拉替尼治疗的犬中发生的频率比以前报道的更高（虽然脓皮病和OE在特应性皮炎患犬中非常常见，但仍有一些关于长期每日两次给予奥拉替尼可能产生免疫抑制作用的担忧。早期的安全性研究显示，在年轻成年比格犬中，长期每日两次给予奥拉替尼与病毒性皮肤乳头状瘤、趾间疖病、蠕形螨病和细菌性肺炎之间存在剂量依赖关系，提示其具有免疫抑制活性。然而，一项体外研究报道，只有非常高剂量的奥拉替尼（相当于每日两次口服3–4 mg/kg）才能降低T细胞活性和细胞因子的产生。在我们的研究中，犬似乎在治疗期间保持免疫活性，这是基于在给予适当的全身或外部抗微生物药物后，它们抗皮肤、耳部和非皮肤感染的能力。而不改变奥拉替尼治疗方案。此外，我们观察到非皮肤感染的频率（5.7%）低于或类似于先前推荐方案的报告（≤12%）。此外，在10个月大的法国斗牛犬中额外使用奥拉替尼每日两次，持续48天（病例26）并发脓皮病和败血性骨髓炎，成功地控制了特应性皮炎，并且没有阻碍脓皮病和骨髓炎的缓解。然而，观察到的治疗持续时间与脓皮病和非皮肤感染的发展之间的相关性表明，在长期每日两次的奥拉替尼治疗时，需要仔细监测。
None of our cases was diagnosed with demodicosis due to D. canis, despite its occasional reports in dogs administered the standard dose of oclacitinib.In our study, the West Highland white terrier (Case 41) diagnosed with demodicosis due to D. canis at the beginning of oclacitinib treatment was cured after isoxazoline administration and did not relapse during the twice-daily administration of oclacitinib despite isoxazoline withdrawal. During treatment, D. injai was detected in another West Highland white terrier (Case 27), showing localised erythema and scaling in the perioral skin. However, in this dog, D. injai occasionally was detected in the same area even after oclacitinib withdrawal, suggesting underlying factors other than oclacitinib, including a breed predisposition and AD. 我们的病例中没有被诊断为犬蠕形螨导致蠕形螨病的情况，尽管在给予标准剂量的奥拉替尼的犬中偶尔有报告。在我们的研究中，在奥拉替尼治疗开始时被诊断为犬蠕形螨导致蠕形螨病的西高地白㹴(病例41)，使用异恶唑啉后痊愈，并在奥拉替尼每日两次给药期间，使用异恶唑啉进行管理蠕形螨没有复发。在治疗期间，在另一只西高地白㹴（病例27）中检测到隐在蠕形螨，其口周皮肤出现局部红斑和皮屑。然而，在这只犬中，即使在停用奥拉替尼后，偶尔也会在同一区域检测到隐在蠕形螨，这表明除了奥拉替尼之外，还有其他潜在因素，包括品种倾向性和AD。
During treatment, there was no significant reduction in red blood cell count, and only three dogs developed mild neutropenia (Veterinary Cooperative Oncology Group classification) (8.6%).An in vitro study showed a much less potent effect of oclacitinib on erythropoietin and granulocyte-macrophage colony-stimulating factor (GMCSF) than that on pruritogenic and proinflammatory cytokines. 在治疗期间，红细胞计数没有明显减少，仅有3只犬出现轻度中性粒细胞减少症（兽医肿瘤协作组分类）。（8.6%）。一项体外研究显示，奥拉替尼对促红细胞生成素和粒细胞-巨噬细胞集落刺激因子（GM CSF）的影响远小于对致痒性和促炎性细胞因子的影响。
Consistent with previous studies,total serum cholesterol levels increased significantly during treatment and slightly exceeded the reference ranges in five dogs,two of which were hypercholesterolaemic before starting oclacitinib. Increased low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels were reported in humans with inflammatory chronic arthritis treated with JAK inhibitors. Inhibition of interleukin-6 signalling has been suggested as a mechanism responsible for hypercholesterolaemia in humans treated with JAK inhibitors. 与以前的研究一致，在5只犬中，总血清胆固醇水平在治疗期间显著增加，并略微超过参考范围。其中两名患犬在开始服用奥拉替尼之前患有高胆固醇血症。据报道，在接受JAK抑制剂治疗的炎症性慢性关节炎人医患者中，低密度脂蛋白（LDL）和高密度脂蛋白（HDL）胆固醇水平升高。在接受JAK抑制剂治疗的人中，白介素-6信号传导的抑制被认为是导致高胆固醇血症的一种机制。
During treatment, benign tumors were detected in seven cases. Thyroid carcinoma was diagnosed in an 11-year-old dog. Conclusions cannot be drawn as to causation because of the study design. Recently, the incidence of benign and malignant masses in allergic dogs treated with either the standard or higher than the recommended doses of oclacitinib has been investigated, with no statistically significant differences compared to a control population. 在治疗过程中，7例发现良性肿瘤。一只11岁的犬被诊断出患有甲状腺癌。由于研究设计的原因，无法得出因果关系的结论。最近，研究了使用标准剂量或高于推荐剂量的奥拉替尼治疗的过敏症患犬中良性和恶性肿物的发生率，与对照组相比，没有统计学上的显著差异。
As a result of the study limitations, including the small number of cases, retrospective collection of clinical data,lack of complete records on topical treatments, subjective evaluation of the treatment efficacy and absence of a control group, definite recommendations cannot be provided. However, these preliminary data suggest that for selected cases there are benefits of the prolonged twicedaily administration of oclacitinib beyond the recommended two weeks. Further blinded prospective studies with validated scales and a control population are needed to evaluate treatment efficacy. 由于研究的局限性，包括病例数少、回顾性收集临床数据、缺乏完整的外部治疗记录，对治疗效果的主观评价和缺乏对照组，无法提供明确的建议。然而，这些初步数据表明，对于选定的病例，长期每天两次服用奥拉替尼的时间超过推荐的两周是有益的。需要使用有效评分表和对照组进行进一步的盲法前瞻性研究，以评估治疗效果。
In conclusion, the prolonged twice-daily administration of oclacitinib was generally well-tolerated and effective in most cases in our study. Regular rechecks, including thorough clinical examinations and blood tests to monitor changes in white blood cell count and serum cholesterol levels are recommended. 总之，在我们的研究中，在大多数情况下，长期每日两次服用奥拉替尼的耐受性良好且有效。建议定期复查，包括全面的临床检查和血液测试，以监测白细胞计数和血清胆固醇水平的变化。
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发表于 2022-2-12 20:46:45
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