奥拉替尼十年了：经验总结和未来方向

王帆

Oclacitinib 10 years later: lessons learned and directions for the future

奥拉替尼十年了:经验总结和未来方向

作者：Rosanna Marsella； Wayne Rosenkrantz

 

翻译：王帆

 

ABSTRACT

摘要

Oclacitinib was approved in the United States 10 years ago for the management of atopic dermatitis (AD) and allergic skin disease in dogs. Many studies and case reports have been published in the past 10 years on the efficacy and safety of this medication, both at labeled doses to treat allergic dogs and off label to treat other diseases and given to other species. Concerns and confusion have occurred for both clinicians and owners regarding the longterm safety of this drug. The purpose of this review is to present the current knowledge on the efficacy, speed of action, effects on the immune system, and clinical safety of oclacitinib, based on evidence and published literature. We also aim to summarize the lessons learned in the past 10 years and to propose directions for the future.

10年前在美国，奥拉替尼被批准用于治疗犬特应性皮炎(AD)和过敏性皮肤病。在过去的10年里，许多研究和病例报告都发表了这种药物的有效性和安全性，无论是在标签剂量下治疗过敏症患犬，还是在标签外治疗其他疾病和治疗其他物种。临床医师和宠主均对该药物的长期安全性感到担忧和困惑。本综述的目的是基于现有证据和已发表的文献，介绍奥拉替尼的疗效、作用速度、对免疫系统的影响和临床安全性。我们还旨在总结过去10年的经验教训，并提出未来的方向。

 

Introduction

介绍

Oclacitinib was approved in the United States in 2013 for the control of pruritus associated with allergic dermatitis and control of atopic dermatitis (AD) in dogs at least 12 months of age. Oclacitinib represented the first Janus kinase (JAK) inhibitor approved for use in dogs and is still the only one approved in veterinary medicine. JAK inhibitors are approved in human medicine to treat myelofibrosis, rheumatoid arthritis, and psoriatic arthritis in humans, as well as AD. A list of approved JAK inhibitors and examples of diseases for which they are used is provided (Table 1). Interestingly, a JAK inhibitor, baricitinib, approved for rheumatoid arthritis has received emergency use authorization for severe COVID-19 in children to decrease inflammation. Oclacitinib has become an important tool for veterinarians to manage allergies and provide relief to affected patients by targeting signaling of cytokines important for allergies. Although oclacitinib is not labeled for other species or to treat diseases other than allergies, veterinarians have used it empirically to treat other conditions.

奥拉替尼于2013年在美国获得批准，用于控制大于12月龄犬的过敏性皮炎和特应性皮炎(AD)相关的瘙痒症状。奥拉替尼是首个获批用于犬的Janus激酶(JAK)抑制剂，也是唯一一种获批用于兽医的JAK抑制剂。JAK抑制剂在人类医学中被批准用于治疗人类的骨髓纤维化、类风湿关节炎、银屑病关节炎以及AD。本文提供了已批准的JAK抑制剂列表及其用于疾病的实例(表1)。有趣的是，已批准用于类风湿性关节炎的JAK抑制剂巴瑞替尼(baricitinib)已获得紧急使用授权，用于儿童重症COVID-19，以减轻炎症。奥拉替尼已成为兽医治疗过敏症和通过靶向对过敏有重要作用的细胞因子信号传导，从而缓解患者症状的重要工具。尽管奥拉替尼未标明用于其他物种，也未用于治疗过敏症以外的疾病，但兽医已根据经验将其用于治疗其他疾病。

 

For the purpose of this review, published literature was searched from May 2013 until December 2022. The keyword oclacitinib was used and 86 published articles were found. In addition to published research articles and case reports and proceedings from meetings were added.

本综述检索了2013年5月至2022年12月的已发表文献。使用关键词oclacitinib，检索到86篇已发表文章。除了已发表的研究文章和病例报告外，还增加了会议记录。

 

Mechanism of Action and Pharmacokinetics in Dogs

在犬的作用机理和药代动力学

Oclacitinib is a selective JAK1 inhibitor targeting the signaling of cytokines involved in pruritus and inflammation like IL-2, IL-4, IL-6, IL-13, and IL-31. In isolated enzyme test systems, oclacitinib inhibited JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2) by 50% at concentrations (IC50) of 10, 18, 99, and 84 nm, respectively. Oclacitinib was most potent against the JAK1 enzyme, showing a 1.8-fold selectivity for JAK1 versus JAK2 and 9.9-fold selectivity toward JAK1 versus JAK3. In cell-based in vitro studies, oclacitinib did not have major effects on granulocyte-macrophage colony-stimulating factor (GM-CSF), erythropoietin (EPO), IL-12, or IL-23 at the tested concentrations.1 In canine AD, cytokines produced by activated T-helper type (Th) 1, Th2, Th17, and Th22 cells as well as innate immune cells and keratinocytes after allergen exposure (Figure 1) are important.

奥拉替尼是选择性JAK1抑制剂，靶向参与瘙痒和炎症的细胞因子(如IL-2、IL-4、IL-6、IL-13和IL-31)的信号传导。在分离的酶测试系统中，奥拉替尼在浓度(IC50)分别为10、18、99和84 nm时将JAK1、JAK2、JAK3和酪氨酸激酶2 (TYK2)抑制50%。奥拉替尼对JAK1酶的作用最强，对JAK1的选择性是对JAK2的1.8倍，对JAK1的选择性是对JAK3的9.9倍。在基于细胞的体外研究中，奥拉替尼在测试浓度下对粒细胞-巨噬细胞集落刺激因子(GM-CSF)、红细胞生成素(EPO)、IL-12或IL-23无显著影响1在犬AD中，活化的辅助性t细胞(Th) 1、Th2、Th17和Th22细胞以及固有免疫细胞和角质形成细胞在过敏原暴露后产生的细胞因子(图1)很重要。

 

Pharmacokinetics of oclacitinib maleate showed rapid absorption in dogs and high absolute oral bioavailability ranging from 79% to 89%, which is not affected by food administration.2 The time to maximum concentration (tmax) is less than 1 hour, and the half-life ranges from 4.0 to 5.9 hours. These are properties that support a twice-daily or once-daily dosing regimen in dogs. Twice a day dosing (up to 2 weeks) provides plasma exposures that inhibit JAK1-dependent cytokines relevant in the disease process throughout the dosing interval.

马来酸奥拉替尼的药代动力学表现为犬体内吸收快，绝对口服生物利用度高，在79% ~ 89%之间，不受食物给药的影响达到最大浓度的时间(tmax)小于1小时，半衰期为4.0 ~ 5.9小时。这些特性支持犬每天两次或一天一次的给药方案。每天两次给药(长达2周)提供血浆暴露，在整个给药间隔内抑制与疾病过程相关的JAK1依赖性细胞因子。

 

A twice-daily regimen significantly improves pruritus and dermatitis and can be transitioned to a once-daily dosing for long-term management of clinical signs.Once-daily dosing generates plasma concentrations that are above the amount required to inhibit JAK1-dependent cytokines by 50% (IC50), effectively inhibiting proinflammatory JAK1-dependent cytokines (e.g. IL-2, IL-4, IL-6, IL-13, and IL-31) while not inhibiting non-JAK1– dependent cytokines such as GM-CSF and EPO (Figure 2, published in Clinician’s Forum in 2022). This selectivity provides a margin of safety between the inhibition of proinflammatory cytokines involved in the disease process versus those involved in normal functions such as hematopoiesis. The immunomodulatory effects of oclacitinib that allow for select functions of the immune system to be inhibited without broad suppression are likely due to both the selectivity of oclacitinib for JAK1-dependent cytokines and the chosen dosing regimen. Specifically, the once-daily dosing allows for temporary inhibition of JAK1-dependent cytokines and select functions of T cells for only part of the day.

每日2次给药方案可显著改善瘙痒和皮炎，并可转为每日1次给药，以便对临床症状进行长期管理。每日一次给药产生的血浆浓度超过将JAK1依赖性细胞因子抑制50%所需的浓度(IC50)，从而有效抑制促炎JAK1依赖性细胞因子(如IL-2、IL-4、IL-6、IL-13和IL-31)，而不抑制非JAK1依赖性细胞因子(如GM-CSF和EPO)(图2,2022年在临床医师论坛上发表)。这种选择性在抑制参与疾病过程的促炎细胞因子与抑制参与正常功能(如造血)的促炎细胞因子之间提供了一个安全界值。奥拉替尼的免疫调节作用使免疫系统的某些功能受到抑制，而不产生广泛抑制，这可能是由于奥拉替尼对JAK1依赖性细胞因子的选择性和所选给药方案。具体而言，每日一次给药允许暂时抑制JAK1依赖性细胞因子，并仅在一天的部分时间内选择T细胞的功能。

 

Effects of Oclacitinib on the Immune System

奥拉替尼对免疫系统的影响

Several in vitro studies evaluated the effects of oclacitinib on various immune cell populations. To understand the clinical relevance of these studies it is important to note that maximum blood concentrations of oclacitinib after administration at labeled doses are around 1 μM, which equates to 337 ng/ml of oclacitinib). One study showed that oclacitinib inhibited IL-2-dependent proliferation of blood cells in a dose-dependent manner (IC50 = 63 to 189 nM), and a second study demonstrated oclacitinib did not inhibit concanavalin A–stimulated T-cell proliferation of canine lymphocytes. A third study showed that oclacitinib (0.1 to 1µM) caused a dramatic decrease in CD4+ and CD8+ T-cells in both T-regulatory and T-effector subsets. Using murine immune cells, the same investigators found a strong cytoreductive and proapoptotic effect with oclacitinib (0.1 to 1 µM) and reported a loss of both CD4+ and CD8+ T cells after exposure to oclacitinib. Oclacitinib did not affect the proliferation of CD4+ T cells or the number of interferon-γ (IFN-γ)- and IL-17-producing CD4+ and CD8+ T cells, suggesting oclacitinib has selective immunomodulatory effects focused on Th2 cells and not on Th1-mediated immunity.

几项体外研究评估了奥拉替尼对各种免疫细胞群的影响。为了理解这些研究的临床意义，一定要注意，以标签剂量给药后，奥拉替尼的最大血药浓度约为1 μM，相当于奥拉替尼337 ng/ml)。一项研究表明，奥拉替尼以剂量依赖性方式抑制血细胞的Il -2依赖性增殖(IC50 = 63 ~ 189 nM)，第二项研究表明奥拉替尼不能抑制刀豆蛋白A刺激的犬淋巴细胞的T细胞增殖。第三项研究表明，奥拉替尼(0.1 ~ 1µM)引起T调节和T效应亚群中CD4+和CD8+ T细胞的显著减少。同一研究人员使用小鼠免疫细胞发现奥拉替尼具有很强的细胞减少和促凋亡作用(0.1 ~ 1µM)，并报告奥拉替尼暴露后CD4+和CD8+ T细胞均减少。奥拉替尼不影响CD4+ T细胞的增殖，也不影响产生干扰素-γ (IFN-γ)和IL-17的CD4+和CD8+ T细胞的数量，提示奥拉替尼具有聚焦于Th2细胞的选择性免疫调节作用，而非Th1介导的免疫。

 

Oclacitinib in vitro suppresses cytokine production of IL-2, IL-15, proinflammatory cytokines (IFN-γ and IL-18), and the regulatory cytokine IL-10. However, these effects are seen only when high concentrations of oclacitinib were used (10 μM), which are over 10 times the concentration achieved using the labeled dose. Concentrations consistent with the labeled dose (1 μM) have no effect on cytokine production (IL-2, IL-10, IL-15, IL-18, IFN-γ, and tumor necrosis factor-α). However, in a study7 using peripheral mononuclear cells (PBMCs) isolated from allergic dogs and stimulated with house dust mite allergen, oclacitinib could inhibit the secretion of IL-31 (IC50 = 40 nM) from PBMCs.

奥拉替尼在体外可抑制IL-2、IL-15、促炎细胞因子(IFN-γ和IL-18)和调节细胞因子IL-10的产生。然而，这些效应仅在使用高浓度奥拉替尼(10 μM)时才能观察到，而高浓度奥拉替尼是使用标记剂量时达到的浓度的10倍以上。与标记剂量一致的浓度(1 μM)对细胞因子(IL-2、IL-10、IL-15、IL-18、IFN-γ、肿瘤坏死因子-α)的产生无影响。然而，在一项研究中，奥拉替尼可以抑制尘螨过敏原刺激的犬的外周血单个核细胞(PBMCs)分泌IL-31 (IC50 = 40 nM)。

 

A recently published study focused on T-regulatory cell numbers and serum IL-10 and transforming growth factor-β1 (TGF-β1) levels in atopic dogs treated with either cyclosporine or oclacitinib for 9 or more months and showed that, while cyclosporine significantly lowered the percentage of T regulatory lymphocytes compared to healthy dogs, no differences existed between oclacitinib and the healthy dog group. No significant differences were detected in IL-10 and TGF-β1 serum concentrations between healthy dogs and atopic dogs that were treated with oclacitinib or cyclosporine.

最近发表的一项研究关注于使用环孢素或奥拉替尼治疗9个月或9个月以上的特应性皮炎患犬的T调节性细胞数量和血清IL-10和转化生长因子-β1 (TGF-β1)水平，结果表明，与健康犬相比，环孢素显著降低了T调节性淋巴细胞的百分比，但奥拉替尼组和健康犬组之间没有差异。奥拉替尼或环孢素治疗后，健康犬和特应性体质犬血清中IL-10和TGF-β1浓度无显著差异。

 

Collectively, these studies show that oclacitinib has selective immunomodulatory effects on immune cells and can reduce the production of the Th2 cytokine IL-31. Immunosuppressive effects occur at much higher concentrations (10 μM) that are not achieved when oclacitinib is prescribed at the doses used to treat dogs with AD.

综上所述，这些研究表明奥拉替尼对免疫细胞具有选择性免疫调节作用，并可减少Th2细胞因子IL-31的产生。奥拉替尼的免疫抑制作用在更高的浓度(10 μM)下发生，而在治疗AD犬的剂量下，奥拉替尼无法达到这一效果。

 

Evidence of Clinical Efficacy for Canine Allergic Skin Disease and Comparison of Efficacy With Other Treatment Options

犬过敏性皮肤病的临床疗效证据及与其他治疗方案的疗效比较

Oclacitinib is listed as an effective treatment for canine AD in the current published guidelines, both to control acute flares and for chronic management.The safety and efficacy of oclacitinib were investigated first, and then the efficacy was compared to other approved treatments for canine AD (Table 2).

在目前发布的指南中，奥拉替尼被列为犬AD的有效治疗药物，用于控制急性发作和慢性管理。首先研究了奥拉替尼的安全性和有效性，然后与其他已批准的犬AD治疗方法进行了疗效比较(表2)。

 

A prospective, randomized, placebo-controlled study enrolled 299 privately owned atopic dogs to receive either placebo or oclacitinib for 112 days. On days 14 and 28, clinicians reported a decrease in the extent and severity of dermatitis scores (canine atopic dermatitis extent and severity index [CADESI]) of 48.4% in the oclacitinib group compared with a 1.7% reduction and a 3.6% increase in placebo-treated dogs. After day 28, most of the placebo dogs (> 86%) had moved to an open-label study to receive oclacitinib. Differences in client-assessed pruritus (pruritus visual analog scale [PVAS]) and clinician-assessed CADESI were significant at all time points (P < 0.0001). The authors concluded that treatment was effective and rapid.

一项前瞻性、随机、安慰剂对照研究纳入了299只家养特应性皮炎患犬，分别接受安慰剂或奥拉替尼治疗112天。在第14日和第28日，临床医师报告奥拉替尼组的皮炎严重程度评分(犬特应性皮炎严重程度指数[CADESI])降低了48.4%，而安慰剂组降低了1.7%，升高了3.6%。28天后，大多数安慰剂组的犬(＞86%)转为开放标签研究，接受奥拉替尼治疗。患病动物评估的瘙痒(瘙痒视觉模拟评分表[PVAS])和临床医师评估的CADESI在所有时间点均有显著差异(P＜0.0001)。作者的结论是，治疗是有效和快速的。

 

In a larger study,436 dogs diagnosed with allergic dermatitis with moderate to severe pruritus were randomized to either oclacitinib or placebo for 28 days. Oclacitinib (0.4 to 0.6 mg/kg twice daily) produced a rapid onset of efficacy within 24 hours. Owner-assessed PVAS scores were significantly better than placebo scores (P <0 .0001) on each assessment day. By day 7, 70.5% of oclacitinib-treated dogs compared to 23.2% of placebo achieved ≥ 50% reduction from baseline in pruritus, dermatitis, and PVAS scores. The conclusions were that oclacitinib was fast and effective.

在一项更大规模的研究中，436只被诊断患有中度至重度瘙痒的过敏性皮炎的犬被随机分配接受奥拉替尼或安慰剂治疗28天。奥拉替尼(0.4 ~ 0.6 mg/kg，每日2次)在24小时内迅速起效。宠主评估的PVAS评分显著优于安慰剂评分(P ＜0.0001)。截至第7日，奥拉替尼组70.5%的犬的瘙痒、皮炎和PVAS评分相对于基线降低≥50%，而安慰剂组为23.2%。结论是奥拉替尼快速有效。

 

Other medications used for the management of AD and pruritus in dogs include glucocorticoids, modified cyclosporine, lokivetmab, antihistamines, and essential fatty acids. In allergic patients, glucocorticoids are typically used for acute incidences of pruritus or otitis. The efficacy of oclacitinib was compared to prednisolone in a prospective randomized controlled study. Prednisolone was prescribed at 0.5 to 1.0 mg/kg once daily for 6 days and then every other day for 28 days, and oclacitinib was prescribed at 0.4 to 0.6 mg/kg orally twice daily for 14 days and then once daily for 28 days. There was a rapid onset of reduced dermatitis and pruritus within 4 hours for both treatments. Mean reductions in pruritus and dermatitis scores were not significantly different between treatments except on day 14, when reductions were more pronounced for oclacitinib than prednisolone.

其他用于治疗犬的特应性皮炎和瘙痒的药物包括糖皮质激素、改良环孢素、洛基维特单抗、抗组胺药和必需脂肪酸。在过敏患者中，糖皮质激素通常用于瘙痒或耳炎的急性发作。在一项前瞻性随机对照研究中比较了奥拉替尼和泼尼松龙的疗效。泼尼松龙的剂量为每日1次，每次0.5 ~ 1.0 mg/kg，用药6日，之后隔日1次，用药28日;奥拉替尼的剂量为每日2次，每次0.4 ~ 0.6 mg/kg，用药14日，之后每日1次，用药28日。两种治疗方法均在4小时内迅速出现皮炎和瘙痒减轻。除第14日奥拉替尼组的瘙痒和皮炎评分平均降幅超过泼尼松龙组外，两组的瘙痒和皮炎评分平均降幅无显著差异。

 

The speed of action of oclacitinib was compared to that of glucocorticoids in a study using a model of itch in which research dogs were injected with IL-31 and then randomly allocated to receive either placebo, oclacitinib, oral prednisone, or intramuscular dexamethasone. Video surveillance was used to monitor and score pruritic behaviors in study animals. The results showed that prednisolone decreased pruritus when given 10 hours prior to observation, but when the treatment administration and observation were shortened to 1 hour, oclacitinib and dexamethasone were effective and prednisolone was not. Oclacitinib was effective within an hour, and the mean reduction of pruritus was greater than dexamethasone.

在一项使用瘙痒模型的研究中，研究者将研究犬注射IL-31，然后将其随机分配接受安慰剂、奥拉替尼、口服泼尼松或肌内注射地塞米松。采用视频监控对研究动物的瘙痒行为进行监测和评分。结果显示，观察前10 h给予泼尼松可减轻瘙痒，但将用药时间和观察时间缩短至1 h时，奥拉替尼和地塞米松均有效，而泼尼松无效。奥拉替尼在1小时内有效，瘙痒的平均降幅大于地塞米松。

 

Modified (microemulsion formulation) cyclosporine and topical tacrolimus (0.1% ointment) are calcineurin inhibitors used in the treatment of allergic and immune-mediated skin diseases. Generic cyclosporine with the wording “modified” is the equivalent of Atopica (dog product) and Neoral (human product). This formulation has better and more consistent absorption compared to the nonmodified formulation. Cyclosporine may take 2 to 4 weeks to relieve the symptoms of an allergic patient. The efficacy of oclacitinib was compared to oral-modified cyclosporine in a randomized controlled study that enrolled 226 dogs diagnosed with AD. Differences in efficacy were significant between groups in the first 28 days with oclacitinib group having less severe dermatitis and pruritus. These differences were no longer significant on day 56. Three times as many adverse events attributed to gastrointestinal signs were reported in the cyclosporine group compared to the oclacitinib group. The authors concluded that oclacitinib had faster efficacy and fewer adverse effects.

改良的(微乳制剂)环孢素和外用他克莫司(0.1%软膏)是钙调磷酸酶抑制剂，用于治疗过敏性和免疫性皮肤病。使用“改良”字样的通用环孢素相当于阿托皮卡(犬用产品)和Neoral(人用产品)。与未改性的配方相比，该配方具有更好和更一致的吸收。环孢素可能需要2 ~ 4周才能缓解过敏患者的症状。一项随机对照研究比较了奥拉替尼和口服改良环孢素的疗效，该研究纳入了226只诊断为AD的犬。在前28日内，奥拉替尼组的疗效有显著差异，其中皮炎和瘙痒的严重程度较轻。这些差异在第56天不再显著。环孢素组报告的胃肠道症状所致不良事件是奥拉替尼组的3倍。作者得出结论，奥拉替尼起效更快，不良反应较少。

 

Lokivetmab (Cytopoint) is a caninized monoclonal anti-IL-31 antibody that is labeled for use in AD and allergic dermatitis in dogs and is administered via a subcutaneous injection every 4 weeks. Lokivetmab is indicated for use in dogs with pruritus and is effective in 73% to 88% of dogs. Rarely, some dogs may produce antibodies against the product resulting in treatment-induced immunogenicity.

洛基维特单抗(赛妥敏)是一种犬源单克隆抗Il -31抗体，每4周皮下注射1次，用于治疗犬的AD和过敏性皮炎。洛基维特单抗适用于有瘙痒的犬，对73% ~ 88%的犬有效。罕见，一些犬可能产生针对产品的抗体，导致治疗诱导的免疫原性。

 

One study compared the efficacy of oclacitinib, prednisone, cyclosporine, and lokivetmab in a colony of atopic beagles challenged with allergen for a month while controlling environmental conditions and diet. In this study, in the first 2 weeks, the severity of dermatitis in the prednisone- and oclacitinibtreated dogs were significantly lower than the controls. At the end of 1 month of allergen exposure, the oclacitinib- and lokivetmab-treated dogs had less erythema than the other groups. Interestingly also, oclacitinib- and lokivetmab-treated dogs had higher cutaneous hydration than the controls suggesting that possibly these treatments may have a positive effect on skin barrier parameters.

一项研究在一群特应性皮炎比格犬中比较了奥拉替尼、泼尼松、环孢素和洛基维特单抗的疗效，这些比格犬接受过敏原刺激一个月，同时控制环境条件和饮食。在本研究中，在前2周，泼尼松和奥拉替尼治疗的犬的皮炎严重程度显著低于对照组。在过敏原暴露1个月结束时，奥拉替尼组和洛基维特单抗组的发红较其他组少。有趣的是，接受奥拉替尼和洛基维特单抗治疗的犬的皮肤含水量高于对照组，这表明这些治疗可能对皮肤屏障参数有积极影响。

 

Additional Outcomes Monitored

其他结果监测

Quality of life

生活质量

In an open retrospective study, oclacitinib significantly improved the quality of life for the majority of treated dogs. Client’s quality of life also improved as the dog needed fewer trips to the veterinarian, the clients’ sleep was less disrupted, and their dog’s overall behavior improved.

在一项公开的回顾性研究中，奥拉替尼显著改善了大多数治疗犬的生活质量。客户的生活质量也得到了改善，因为犬不需要去看兽医了，客户的睡眠受到的干扰减少了，他们的犬的整体行为也得到了改善。

 

Adverse events

不良事件

For managing pruritus, oclacitinib has less frequent side effects as compared with glucocorticoids and cyclosporine. Vomiting and diarrhea have been reported in the initial studies. Weight gain has been reported more often than weight loss in dogs on the medication (114 dogs gained 3.4% of body weight and anorexia in 0.9% of dogs).

与糖皮质激素和环孢素相比，奥拉替尼对于治疗瘙痒的副作用更少。在最初的研究中有呕吐和腹泻的报告。据报道，服用该药的犬体重增加的情况多于体重减轻的情况(114只犬体重增加3.4%，0.9%的犬出现厌食症)。

 

Demodicosis, pyoderma, and otitis were also reported in dogs receiving oclacitinib. A small study evaluated the management of otitis using twice-daily oclacitinib in 10 dogs with concurrent twice-daily topical application of enrofloxacin and Silvadene (Baytril Otic) for 14 days and reported a mean clinical score reduction of 81.7%. Histiocytomas, papillomas, and other cutaneous tumors have been reported in dogs receiving oclacitinib but do not appear to have increased incidence compared to dogs not receiving oclacitinib (16.5% on oclacitinib vs 12.8% not on oclacitinib).

在接受奥拉替尼治疗的犬中也报告了蠕形螨病、脓皮病和耳炎。一项小型研究评估了10只犬使用奥拉替尼治疗耳炎，同时每日2次外用恩诺沙星和磺胺嘧啶治疗14天，报告平均临床评分降低了81.7%。组织细胞瘤、乳头状瘤和其他皮肤肿瘤在接受奥拉替尼治疗的犬中已有报道，但与未接受奥拉替尼治疗的犬相比，其发病率似乎并未增加(奥拉替尼组为16.5%，未接受奥拉替尼组为12.8%)。

 

Evaluations of complete blood counts and serum biochemistries for patients on long-term oclacitinib reported mild leukopenia (most commonly neutropenia and rarely lymphopenia). Rare reports of changes in the serum biochemistry and urinalysis have been reported but do not often warrant cessation of therapy. In initial studies, symptoms of urinary tract infections were seen in 0.5% to 11.3% of dogs that were on chronic oclacitinib; however, quantitative bacterial cultures were not performed. A subsequent prospective study evaluated found no evidence of bacterial urinary tract infections in dogs on oclacitinib for up to 280 days. It is important to note that oclacitinib is not labeled for use in dogs < 12 months of age due to higher risk of pneumonia or demodicosis (Zoetis 2018). One of the authors (RM) has seen dogs develop hypothyroidism while on oclacitinib, but no study has specifically addressed the effect of oclacitinib on thyroid function.

对长期接受奥拉替尼治疗的患病动物进行的全血细胞计数和血清生化评估报告了轻度白细胞减少(最常见的是中性粒细胞减少，很少有淋巴细胞减少)。血清生化和尿液分析改变的报道很少，但通常不需要停止治疗。在最初的研究中，0.5% ~ 11.3%的长期服用奥拉替尼的犬出现了尿路感染症状。然而，未进行定量细菌培养。随后的一项前瞻性研究评估了服用奥拉替尼长达280天的犬，没有发现细菌性尿路感染的证据。需要注意的是，奥拉替尼未标明用于犬＜12月龄，因为肺炎或蠕形螨病风险较高(Zoetis 2018)。其中一名作者(RM)曾观察到犬在服用奥拉替尼时发生甲状腺功能减退，但没有研究专门探讨奥拉替尼对甲状腺功能的影响。

 

Need for antibacterial therapy

需要抗细菌治疗

In a retrospective study, the effect of oclacitinib on decreasing the need for antimicrobial therapy was examined and compared to other antipruritic therapies. The authors found that the odds of systemic antibacterial usage were significantly lower and odds of experiencing improvements in allergic dermatitis significantly higher for the oclacitinib group compared to other anti-pruritic therapies (eg, glucocorticoids, cyclosporine, and antihistamines). It is important to note that due to the retrospective nature of this study and the fact that limited information was provided regarding doses of the various treatments, it is possible that biases were introduced in the analysis of these patients. Regardless of the medication used, it is important to emphasize the need for a proactive approach in allergic patients as a way to minimize flares and ultimately minimize the development of infections. Atopic patients have lowgrade inflammation also while they are not clinically manifesting disease, thus some form of long-term sustainable control of the disease is very beneficial in minimizing flares and pyoderma.

在一项回顾性研究中，研究人员评估了奥拉替尼在减少抗菌治疗需求方面的效果，并与其他止痒疗法进行了比较。作者发现，与其他抗瘙痒疗法(如糖皮质激素、环孢素和抗组胺药)相比，奥拉替尼组全身性使用抗菌药物的概率显著较低，过敏性皮炎改善的概率显著较高。需要注意的是，由于本研究是回顾性的，并且提供的关于各种治疗剂量的信息有限，因此在对这些患病动物的分析中可能引入了偏倚。无论使用何种药物，重要的是要强调对过敏患病动物采取主动措施的必要性，以最大限度地减少发作并最终最大限度地减少感染的发生。特应性皮炎患病动物在没有临床表现的情况下也有低度炎症反应，因此使用某种形式长期持续控制疾病对减少发作和脓皮病非常有益。

 

Effect on epicutaneous sensitization

对表皮致敏影响

As atopic dogs are known to develop new sensitizations over time, the question of whether the administration of oclacitinib would influence sensitization to a novel allergen was addressed using a colony of atopic beagles. Dogs were exposed to a novel allergen (Bermuda grass) while receiving oclacitinib and the time to develop sensitization was significantly delayed compared to the control group. Whether this effect can be a significant benefit when applied to a proactive approach to AD will need to be evaluated longitudinally in dogs with natural disease.

众所周知，特应性皮炎犬随着时间的推移会产生新的致敏性，因此我们使用特应性皮炎比格犬来解决奥拉替尼是否会影响其对新型过敏原的致敏性这一问题。试验犬在接受奥拉替尼治疗时暴露于一种新型过敏原(百慕大草)，与对照组相比，发生致敏的时间显著延迟。我们需要在自然发病AD患犬中进行纵向评估，来说明当对AD患犬进行主动治疗时这种作用是否具有显著优势。

 

Long-Term Safety at Twice-Daily Administration

每日两次使用的长期安全性

The licensed dose of oclacitinib is 0.4 to 0.6 mg/kg twice daily for up to 2 weeks and then once daily. In some patients, the once-daily administration may not be sufficient to control clinical signs; thus, owners keep their animals on twice-daily administration for extended periods of time. One recently published study addressed the safety of a prolonged twice-daily administration regimen. In this retrospective study, 53 client-owned dogs with AD had received twice-daily administration of oclacitinib (0.5-mg/kg dose, median treatment duration was 113 days). Oclacitinib was generally well tolerated and effective in most of the treated dogs (excellent to good response in 72% of dogs). Pyoderma, gastrointestinal signs, and otitis externa were the most frequent adverse events reported. In this study, blood work was done in 35/53 dogs. Statistically significant decreases in mean leukocyte counts were noted with treatment, although counts were within the reference range for most individuals. Three dogs developed increased cholesterol and developed demodicosis. The authors of that study concluded that twice-daily long-term administration is well tolerated and effective in most dogs, but regular clinical evaluation and blood work are advisable.

奥拉替尼的许可剂量为每日2次，每次0.4 ~ 0.6 mg/kg，用药最多2周，之后每日1次。在一些患病动物中，每日一次给药可能不足以控制临床症状;因此，主人让他们的动物每天两次，延长时间。最近发表的一项研究探讨了每日2次长期给药方案的安全性。在这项回顾性研究中，53只患AD的家养犬接受了奥拉替尼每日两次给药(0.5 mg/kg剂量，中位治疗时间为113天)。奥拉替尼耐受性良好，对大多数接受治疗的犬有效(72%的犬有极好的反应)。脓皮病、胃肠道症状和外耳炎是最常见的不良事件。本研究对53只犬中的35只进行了血液检查。虽然大多数个体的白细胞计数在参考范围内，但治疗后平均白细胞计数在统计学上显著下降。3只犬出现胆固醇升高和蠕形螨病。这项研究的作者得出结论，每天两次长期给药对大多数犬是耐受性良好和有效的，但定期的临床评估和血液检查是可取的。

 

Oclacitinib and Neoplasia Concerns

奥拉替尼和肿瘤关系

Since the release of oclacitinib, there have been concerns regarding the incidence of malignancies in dogs receiving this drug. Some of the apprehension regarding oclacitinib and neoplasia has originated from reviewing the comparative use of JAK inhibitors in human medicine. When doing so, it is important to consider which JAK inhibitors oclacitinib is compared to, as the affinity of the various JAK pathways is different and what condition they are used to treat. Tofacitinib is an oral JAK1/JAK3 inhibitor with reduced JAK2 activity and has been used for the treatment of rheumatoid arthritis (RA), inflammatory bowel disease, transplant rejection, and psoriasis in humans.In humans with RA and other autoimmune diseases, independent of the type of treatment, there is an increased risk of certain malignancies. Another oral JAK1/JAK2 inhibitor, ruxolitinib, has been linked to increased incidence (17.1%) of basal cell carcinoma and squamous cell carcinoma compared to patients’ other therapies (2.7%).

自奥拉替尼上市以来，人们一直担心接受该药物的犬发生恶性肿瘤的情况。关于奥拉替尼和肿瘤的一些担忧源于对JAK抑制剂在人类医学中的比较应用进行的综述。这样做时，重要的是要考虑将奥拉替尼与哪种JAK抑制剂进行比较，因为各种JAK通路的亲和力不同，以及它们用于治疗什么疾病。托法替布是一种口服JAK1/JAK3抑制剂，JAK2活性降低，已被用于治疗人类类风湿性关节炎(RA)、炎性肠病、移植排斥和银屑病。在RA和其他自体免疫性疾病患者中，独立于治疗类型，某些恶性肿瘤的风险增加。与患者的其他疗法(2.7%)相比，另一种口服JAK1/JAK2抑制剂芦可替尼(ruxolitinib)与基底细胞癌和鳞状细胞癌的发病率增加(17.1%)相关。

 

The other area of attention regarding association of oclacitinib and neoplasia has come from some of the early field studies and published reports regarding neoplasia in treated dogs. Two dogs in the oclacitinib-treated group were withdrawn from the study due to suspected or confirmed malignant neoplasia and subsequently euthanized, including 1 dog that developed signs associated with a heart base mass after 21 days and 1 dog that developed a grade III mast cell tumor after 60 days of oclacitinib. One dog in the placebo group also developed a grade I mast cell tumor and was removed from the study. After completing the field studies, 239 dogs were enrolled in an unmasked (no placebo control), continuation therapy study receiving oclacitinib for a mean time of 372 days (range, 1 to 610 days). Of these 239 dogs, 6 dogs were euthanized because of suspected malignant neoplasms. The association between oclacitinib and tumor formation in these cases is not known. It is also important to point out that association is different from causation.

关于奥拉替尼与肿瘤形成的关系，另一个值得关注的领域来自于一些早期的现场研究和已发表的关于接受治疗的犬发生肿瘤的报告。奥拉替尼治疗组的2只犬因疑似或确诊恶性肿瘤而退出研究，随后对其实施了安乐死，其中1只犬在接受奥拉替尼治疗21天后出现了与心脏基底肿块相关的症状，1只犬在接受奥拉替尼治疗60天后出III级肥大细胞肿瘤。安慰剂组的一只犬也发生了I级肥大细胞肿瘤，并被从研究中移除。在完成现场研究后，239只犬被纳入一项非盲法(无安慰剂对照)的继续治疗研究，接受奥拉替尼治疗的平均时间为372天(范围，1 ~ 610天)。在这239只犬中，有6只犬因怀疑患有恶性肿瘤而被安乐死。在这些病例中，奥拉替尼与肿瘤形成之间的关联尚不清楚。同样重要的是要指出，关联不同于因果关系。

 

A study looked at a comparison of malignancies and nonmalignant skin masses in 339 allergic dogs receiving long-term (> 6 months) oclacitinib with age- and breed-matched control populations on other forms of allergy therapy. The incidence of malignancies in the oclacitinib group (16.5%) versus controls (12.8%) was not statistically different (P =0 .1742). The incidence of skin masses in the oclacitinib group (56.6%) versus controls (58.3%) was not statistically different (P = .6743). The age of death/euthanasia in the oclacitinib group (11.2 years; n = 80) versus controls (11.8 years; 72) was not statistically different (P = .2077). There was no statistical significance regarding the dose of oclacitinib on the cumulative incidence of malignancy or masses. These results are to some extent reassuring, but it is important to point out the limitation of a retrospective study and that euthanasia is typically done at primary care rather than a specialty practice.

一项研究比较了339只过敏犬的恶性肿瘤和非恶性皮肤肿块。研究对象为年龄和品种匹配的对照人群，并进行其他形式的过敏治疗。奥拉替尼组(16.5%)与对照组(12.8%)的恶性肿瘤发生率无统计学差异(P = 0.1742)。奥拉替尼组(56.6%)与对照组(58.3%)的皮肤肿块发生率无统计学差异(P = .6743)。奥拉替尼组死亡/安乐死的年龄(11.2岁;N = 80)与对照组(11.8年;72)差异无统计学意义(P = 0.2077)。奥拉替尼剂量对恶性肿瘤或肿块的累积发生率无统计学显著性。这些结果在一定程度上令人安心，但重要的是要指出回顾性研究的局限性，而且安乐死通常在初级保健机构进行，而不是在专科诊所进行。

 

In another published long-term safety study,the most diagnosed common malignancy in 247 client-owned dogs was mast cell tumors (MCT). Mast cell tumors are a common skin cancer in dogs in general and were the most common tumor also found in the study listed above that compared an oclacitinib and a control group of dogs treated with other therapies for AD. Mast cell tumors were also found to be the most frequent malignancy in the control group, with no significant difference in incidence or risk ratio between the groups. Breed predisposition is very important in neoplasia development, particularly in MCT, and in both of these studies, several breeds were overrepresented including Labrador Retrievers, Golden Retrievers, Staffordshire Terriers, and Boston Terriers, which all have been reported to have an increased incidence of MCT.

在另一项发表的长期安全性研究中，247只家养犬被诊断出的最常见的恶性肿瘤是肥大细胞肿瘤(MCT)。肥大细胞瘤是一种常见的犬皮肤癌，也是上面列出的研究中最常见的肿瘤，该研究比较了奥拉替尼和对照组犬的其他AD疗法。肥大细胞瘤也被发现是对照组中最常见的恶性肿瘤，两组之间的发病率或风险比无显著差异。品种易感性在肿瘤发展中非常重要，特别是在MCT中，在这两项研究中，几个品种的比例过高，包括拉布拉多猎犬，金毛猎犬，斯塔福德郡梗和波士顿梗，这些都被报道有增加的MCT发病率。

 

In a more recent publication, oclacitinib was evaluated for its effect on cytokines that support mast cell tumor growth, specifically, IL-8 and monocyte chemoattractant protein-1 (MCP-1) in 3 MCT cell lines (CoMS, CM-MC1, and VI-MC1). It was found that oclacitinib significantly decreased the release of IL-8 in the CoMS cell line and MCP-1 in the CoMS and VI-MC1 cell lines in clinically relevant concentrations and significantly decreased the proliferation of all 3 cell lines. These findings do not advocate using oclacitinib to treat mast cell tumors and further research is needed.

在最近发表的一篇文章中，研究者评估了奥拉替尼对3个MCT细胞系(CoMS、CM-MC1和VI-MC1)中支持肥大细胞肿瘤生长的细胞因子的影响，特别是IL-8和单核细胞趋化蛋白-1 (MCP-1)。我们发现，在临床相关浓度下，奥拉替尼显著降低了CoMS细胞系中IL-8和CoMS和VI-MC1细胞系中MCP-1的释放，并显著降低了3种细胞系的增殖。这些发现并不支持使用奥拉替尼治疗肥大细胞肿瘤，需要进一步研究。

 

The incidence of lymphoma in dogs on oclacitinib has also received attention, especially in genetically predisposed breeds. In the Lancellotti study comparing oclacitinib to other allergy therapies, the cumulative incidence of noncutaneous lymphoma did not meaningfully differ between the exposed group and the nonexposed group, and interestingly, no Labrador Retrievers or Golden Retrievers in either group had lymphoma. A previous study suggested a relationship between canine AD and cutaneous lymphoma; however, there were only 2 cases observed in the Lancellotti study for the entire 660 allergic dogs.

接受奥拉替尼治疗的犬的淋巴瘤发病率也受到了关注，尤其是在遗传易感的品种中。在比较奥拉替尼和其他过敏疗法的Lancellotti研究中，在暴露组和非暴露组之间，非皮肤淋巴瘤的累积发生率无显著差异，有趣的是，两组的拉布拉多猎犬或金毛猎犬均未患淋巴瘤。既往研究提示犬AD与皮肤淋巴瘤有关;而在整个660只过敏犬的Lancellotti研究中仅观察到2例。

 

 

In the previous long-term compassionate use oclacitinib study, the average time to detection of tumors was 7.9 months (range, 0.6 to 21.5 months), whereas the average time to detection of malignancy in the Lancellotti study was 24 months (range, 6.0 to 53.0 months). There is a report of a higher incidence of histiocytomas in patients receiving oclacitinib compared to patients receiving cyclosporine; however, the dogs receiving oclacitinib were significantly older (mean = 7.0 years) than dogs receiving cyclosporine (mean = 1.5 years). Furthermore, there was a significant difference in the duration of treatment between dogs with histiocytomas receiving oclacitinib (mean = 14.8 weeks) versus cyclosporin (mean = 4.8 weeks). In another study,14 the incidence of histiocytoma development in 283 dogs receiving oclacitinib was 3.9%. In the Lancellotti study, there were 19 histiocytomas identified in the oclacitinib group (5.6%) and 14 histiocytomas in the control group (4.4%), which was not statistically significant.

在之前的奥拉替尼长期同情用药研究中，至检出肿瘤的平均时间为7.9个月(范围，0.6 ~ 21.5个月)，而在Lancellotti研究中，至检出恶性肿瘤的平均时间为24个月(范围，6.0 ~ 53.0个月)。有报道称，接受奥拉替尼治疗的患者组织细胞瘤的发生率高于接受环孢素治疗的患者。然而，接受奥拉替尼治疗的犬的年龄(平均= 7.0岁)显著大于接受环孢素治疗的犬(平均= 1.5岁)。此外，接受奥拉替尼(平均= 14.8周)和环孢素(平均= 4.8周)的组织细胞瘤犬的治疗持续时间有显著差异。在另一项研究中14，在接受奥拉替尼治疗的283只犬中，组织细胞瘤的发生率为3.9%。在Lancellotti研究中，奥拉替尼组发现19例组织细胞瘤(5.6%)，对照组发现14例组织细胞瘤(4.4%)，差异无统计学意义。

 

From the current data available, the incidence of malignancies and age of death in patients receiving oclacitinib long-term is not statistically different from patients receiving other long-term treatments for AD. Veterinarians should still continue to follow precaution and monitor patients for the development of neoplasia as each patient’s immune system is different. One of the authors (RM) has seen several young dogs receiving oclacitinib develop numerous fast-growing histiocytomas, some of which were behaving very aggressively. Whether this was caused by oclacitinib or would have occurred regardless of circumstances is unknown.

从现有数据来看，长期接受奥拉替尼治疗的患病动物的恶性肿瘤发生率和死亡年龄与接受其他AD长期治疗的患病动物无统计学差异。兽医应继续遵循预防措施，并监测患病动物的肿瘤发展，因为每个患者的免疫系统是不同的。其中一名作者(RM)已经看到几只接受奥拉替尼治疗的幼犬发生了许多快速生长的组织细胞瘤，其中一些表现得非常具有攻击性。目前尚不清楚这是由奥拉替尼引起，还是无论情况如何都会发生。

 

Oclacitinib Use for Allergic Skin Disease in Other Species

其他物种使用奥拉替尼治疗过敏性皮肤病

Use in feline atopic skin syndrome

猫特应性皮肤综合征的使用

Oclacitinib is not labeled for use in cats. At present, there are 4 peer-reviewed reports of oclacitinib safety and/or efficacy for feline atopic skin syndrome (Table 3). Adverse events reported included anemia, vomiting, and an increase in ALT, creatinine, BUN, and soft stool in Giardia-positive individuals. The pharmacokinetics of orally administered oclacitinib in cats is described in 6 cats, and plasma levels of 28 cats have been reported. Compared to dogs, oclacitinib was absorbed and eliminated more rapidly with greater individual variability in plasma levels and appears to have a greater dose and/or frequency requirement. Improvements in dermatitis and pruritus are not correlated to plasma levels.

奥拉替尼未标明用于猫。目前，关于奥拉替尼治疗猫特应性皮肤综合征的安全性和/或疗效，有4份同行评议的报告(表3)。报告的不良事件包括贫血、呕吐，以及一例贾第虫阳性病例的ALT、肌酐、BUN升高以及软便。在6只猫中描述了口服奥拉替尼的药代动力学，并报告了28只猫的血浆水平。与犬相比，奥拉替尼的吸收和消除速度更快，血浆水平的个体差异较大，似乎对剂量和/或频率的要求较高。皮炎和瘙痒的改善与血浆水平无关。

 

Doses ranged from 0.25 mg/kg, PO, every 24 hours to 2 mg/kg, PO, every 12 hours (Table 3). The safety of oclacitinib was investigated in a prospective, placebo-controlled study. In this study, 20 cats receiving oclacitinib at 1 or 2 mg/kg, PO, every 24 hours for 28 days demonstrated no significant differences in mean complete blood count,nor urinalysis parameters compared to the placebo group at 7, 14, and 28 days of treatment. Mean serum chemistry values were not significantly different than placebo on these treatment days, except fructosamine elevation to high normal in treatment groups on day 7.

剂量范围从每24小时1次的0.25 mg/kg口服剂量至每12小时1次的2 mg/kg口服剂量(表3)。我们在一项前瞻性、安慰剂对照研究中研究了奥拉替尼的安全性。在这项研究中，20只猫每24小时接受1或2 mg/kg PO的奥拉替尼，持续28天，在治疗的第7、14和28天，与安慰剂组相比，平均全血细胞计数和尿液分析参数没有显著差异。除第7天各治疗组果糖胺升高至正常高值外，这些治疗日的平均血清化学值与安慰剂无显著差异。

 

Fatal toxoplasmosis has been reported in a feline immunodeficiency virus-positive cat receiving oclacitinib. Toxoplasmosis has been reported also in cats receiving cyclosporine. For the efficacy and doses of oclacitinib used in feline studies, see Table 3.

已报告一例免疫缺陷病毒阳性患猫使用奥拉替尼治疗出现致命性弓形虫病。在接受环孢素治疗的猫中也有弓形虫病的报告。奥拉替尼在猫的研究中的疗效和剂量见表3。

 

Given safety and efficacy data are limited to fewer than 100 cats and 28 days of dosing, it is prudent to limit oclacitinib to cats failing approved or conventional therapies for feline atopic skin syndrome or those receiving medications that contraindicate their use. Chronic oclacitinib monotherapy has been anecdotally reported as safe within the aforementioned dosing ranges, without significant serologic, hematologic, or urinary abnormalities. Given that long-term safety data are not presently available, it is prudent to perform serologic and hematologic evaluation, urinalysis, and physical examination prior to therapy and routinely.

考虑到安全性和疗效数据仅限于不到100只猫，并且用药28天，因此谨慎的做法是将奥拉替尼仅限用于常规疗法治疗无效的FASS患猫，或者对正在使用的药有禁忌症的患猫。据报道，在上述剂量范围内，奥拉替尼慢性单药治疗是安全的，没有显著的血清学、血液学或泌尿学异常。鉴于目前尚未获得长期安全性数据，因此谨慎做法是在治疗前和常规治疗前进行血清学和血液学评估、尿液分析和体格检查。

 

Use in equine allergic skin diseases

马过敏性皮肤病的使用

Anecdotally, oclacitinib maleate has been used off-label by equine veterinarians and several specialists to relieve pruritus in horses for both insect bite hypersensitivity (IBH) and AD. Pharmacokinetics of oclacitinib in horses following a single intravenous (n = 4; 0.25 mg/kg, IV) and oral dose (6; 0.2 mg/kg) showed that the half-life (t1/2) was similar for both routes (9 to 10 hours) and longer than dogs suggesting that once a day dosing should maintain plasma concentrations. Oclacitinib was evaluated in 6 horses at a dose comparable to the approved dosage in dogs as a single dose (0.5 mg/kg). The estimated t1/2 was 7.5 to 8 hours further supporting a longer half-life than what is reported in dogs supporting the once a day dosing.

据报道，马来酸奥拉替尼已被马兽医和几名专科医师标签外使用，用于缓解马的昆虫咬伤超敏反应(IBH)和AD的瘙痒。奥拉替尼在马单次静脉给药后的药代动力学(n = 4;0.25 mg/kg，静脉注射)和口服剂量(6;0.2 mg/kg)表明两种给药途径的半衰期(t1/2)相似(9 ~ 10小时)，且比犬的半衰期更长，提示每天给药一次应维持血浆浓度。在6匹马中评估了奥拉替尼，其剂量与单次给药(0.5 mg/kg)时在犬中的批准剂量相当。估计的t1/2为7.5 ~ 8小时，进一步支持较长的半衰期比支持一天一次给药的犬。

 

The efficacy and safety of 2 oral doses (0.1 and 0.25 mg/kg, q 24 h, was evaluated compared to a placebo control group. Fifty-eight horses were randomized into the treatment groups (placebo, n = 19; 0.1 mg/kg, 19; and 0.25 mg/kg, 21) Horses were evaluated based on PVAS and clinical lesional scoring and all had clinical signs consistent with allergic dermatitis. No significant difference (P ≤ .0938) was found for 0.25-mg/kg dosing compared to placebo at all time points. Lesional scoring was also not significantly different (P ≤ .136). Adverse events and clinical pathology revealed no effects that appeared clinically significant or biologically important. Although many practitioners and specialists have used oclacitinib off label at 0.25 mg/kg, every 24 hours, further controlled clinical studies are needed to fully evaluate the efficacy and safety of oclacitinib in horses with atopic dermatitis or other allergic condition.

与安慰剂对照组比较，评估两种口服剂量(0.1和0.25 mg/kg，每24小时1次)的疗效和安全性。58匹马被随机分配到治疗组(安慰剂，n = 19;0.1 mg/kg, 19例;21)根据PVAS和临床皮损评分对马进行了评估，所有马的临床症状均符合过敏性皮炎。在所有时间点，0.25 mg/kg剂量与安慰剂相比没有显著差异(P≤0.0938)。病灶评分也没有显著差异(P≤.136)。不良事件和临床病理学显示没有临床显著或生物学重要的影响。虽然许多医师和专科医师已超说明书使用奥拉替尼(每24小时0.25 mg/kg)，但仍需要进一步的临床对照研究来充分评估奥拉替尼在患特应性皮炎或其他过敏性疾病的马中的疗效和安全性。

 

 

Use for Nonallergic/ Atopic

非过敏症/非特应性皮炎使用

Disease Autoimmune/immune-mediated diseases

自体免疫病/免疫介导病

Oclacitinib’s immunemodulatory effects on numerous cytokines have prompted investigation of its use in nonallergic, cytokine-mediated inflammatory, and autoimmune- or immune-mediated diseases in dogs either as monotherapy or an adjunctive treatment. Oclacitinib was used at 0.4 to 0.7 mg/kg twice daily, along with a tapering regimen of oral prednisolone to manage ischemic dermatopathy in 4 dogs. Other case reports for use in ischemic dermatopathy showed a positive response when oclacitinib was used at 0.6 mg/kg twice daily for 60 days and then once daily.

奥拉替尼对多种细胞因子的免疫调节作用促使研究将其用于犬的非过敏性、细胞因子介导的炎症以及自体免疫或免疫介导的疾病(单药治疗或辅助治疗)。奥拉替尼每日2次，剂量为0.4 ~ 0.7 mg/kg，同时口服泼尼松龙逐渐减量，以治疗4只犬的缺血性皮肤病。用于缺血性皮肤病的其他病例报告显示，奥拉替尼以每日2次、每次0.6 mg/kg的剂量用药60天，之后改为每日1次，治疗结果有效。

 

Oclacitinib was used as monotherapy for the control of a presumed autoimmune subepidermal blistering dermatosis, and complete resolution was obtained at 0.5 mg/kg twice daily after 2 weeks. Relapse was observed when the regimen was reduced to once daily. Oclacitinib was also useful in a case of drug-induced-pemphigus vulgaris at 0.5 mg/kg twice daily.

奥拉替尼作为单一疗法用于控制假定的自体免疫性表皮下大疱性皮肤病，并在2周后以0.5 mg/kg每日两次的剂量获得完全缓解。当治疗方案减少到每天一次时，观察到复发。奥拉替尼也适用于药物诱发性天疱疮，剂量为0.5 mg/kg，每日两次。

 

In a retrospective study,52 cases diagnosed with ulcerative ear tip dermatosis nonresponsive to conventional therapy responded to oclacitinib at 0.4 to 0.6 mg/kg within 1 to 3 months (22/25 dogs). Several of the dogs required prolonged use of twice-daily dosing.

在一项回顾性研究中，52例诊断为溃疡性耳尖皮肤病，对常规治疗无反应的病例(22/25只犬)在1至3个月内对0.4至0.6 mg/kg的奥拉替尼有效。其中几只犬需要长期服用每日两次的剂量。

 

Oclacitinib was used to treat hyperkeratotic erythema multiforme in 2 cases with rapid improvement when used at 0.6 to 0.9 mg/kg twice daily. Oclacitinib also provided temporary relief in a case of inherited sensory and autonomic neuropathy, heritable neuropathy, and idiopathic rhinitis. These reports are few in number and the information is limited by the format of abstracts presented at meetings. Collectively, in these case reports, dogs were treated with 0.4 to 1 mg/kg twice daily for at least 2 weeks followed by either long-term twice-daily administration or a reduction to once-daily administration. Topical 0.1% oclacitinib has been used to treat canine keratoconjunctivitis sicca (KCS), and its efficacy has been compared to that of 0.1% topical tacrolimus. Topical 0.1% oclacitinib twice daily was not effective in controlling the ocular signs of KCS in dogs, and its use is not justified.

2例应用奥拉替尼治疗过度角化性多形红斑，0.6 ~ 0.9 mg/kg, 2次/ d，症状迅速改善。奥拉替尼还使1例遗传性感觉和自主神经病变、遗传性神经病变和特发性鼻炎得到暂时缓解。这些报告数量很少，而且资料受到会议摘要格式的限制。总之，在这些病例报告中，犬被给予每日两次0.4 ~ 1 mg/kg治疗至少2周，之后要么长期每日两次给药，要么减少到每日一次给药。外用0.1%奥拉替尼治疗犬干燥性角结膜炎(KCS)，并与外用0.1%他克莫司进行疗效比较。0.1%奥拉替尼每日2次外用不能有效控制犬KCS的眼部症状，使用它是不合理的。

 

In cats, effective control of nonallergic cutaneous inflammatory conditions with oclacitinib is limited to a publication57 of a 13-year-old cat with pemphigus foliaceus (1 mg/kg, PO, q 12 h). A 50% clinical improvement was observed after 7 days and was maintained at a dose of 0.5 mg/kg, PO, every 12 hours. Oclacitinib (1 mg/kg, PO, q 12 to 24 h) failed to control urticaria-pigmentosa-like mastocytic dermatitis in a 14-month-old cat.

在猫中，奥拉替尼对非过敏性炎性皮肤病的有效控制仅限于一只13岁的落叶型天疱疮猫(1mg /kg, PO，每12小时)。7天后观察到50%的临床改善，并保持0.5 mg/kg, PO，每12小时的剂量。奥拉替尼(1mg /kg, PO, q 12 ~ 24 h)未能控制14月龄猫的荨麻疹-色素样肥大细胞性皮炎。

 

Oclacitinib for Neoplastic Conditions

奥拉替尼治疗肿瘤疾病

The use of oclacitinib in dogs diagnosed with neoplastic conditions is highly debated. Oclacitinib primarily inhibits JAK1-dependent cytokine receptor complexes involved in allergic inflammation; however, it has less effect on JAK2, JAK3, and TYK2. Indeed, retrospective analysis of the long-term use of oclacitinib in atopic dogs reveals no increased risk for neoplasia development. More recently, treatment of a single case of canine cutaneous epitheliotropic T-cell lymphoma with oclacitinib (0.7 mg/kg, q 12 h) resulted in partial remission for 3 months with marked histological cytoreduction of neoplastic cells. The authors reported that the dose was welltolerated and posed fewer potential adverse effects than traditional chemotherapy protocols, although the dog did not achieve complete remission.

奥拉替尼在诊断为肿瘤的犬中的应用存在很大争议。奥拉替尼主要抑制参与过敏性炎症的JAK1依赖性细胞因子受体复合物;然而，它对JAK2、JAK3和tyk2的影响较小。事实上，对特应性皮炎犬长期使用奥拉替尼的回顾性分析表明，发生肿瘤的风险并未增加。最近，奥拉替尼(0.7 mg/kg，每12小时1次)治疗了一个犬皮肤趋上皮T细胞淋巴瘤病例，结果在3个月内部分缓解，肿瘤细胞在组织学上显著减少。作者报告，与传统化疗方案相比，该剂量的耐受性良好，潜在的不良反应较少，但犬没有达到完全缓解。

 

Aberrant JAK/signal transducer and activator of transcription (STAT) signaling within hematologic and solid tumors has been implicated as a driver of tumor growth. One study evaluated oclacitinib coadministration with other chemotherapeutics (4 dogs received carboplatin and 5 received doxorubicin). Tumors treated included recurrent anal sac adenocarcinoma, oral malignant melanoma with pulmonary metastasis, distal radial osteosarcoma without metastasis, and oral malignant melanoma for the carboplatin group and pulmonary metastasis from appendicular osteosarcoma and 1 dog with recurrent abdominal myxosarcoma for the doxorubicin group. No unexpected toxicities occurred, and the incidence of adverse events with combination therapy was not increased. The authors concluded that oclacitinib was well tolerated when given in combination with carboplatin or doxorubicin but had no observable effect on tumor inhibition.

血液肿瘤和实体肿瘤中异常的JAK/信号转导和转录激活因子(STAT)信号被认为是肿瘤生长的驱动因素。一项研究评估了奥拉替尼与其他化疗药物的联合用药(4只犬接受卡铂治疗，5只犬接受多柔比星治疗)。卡铂组治疗的肿瘤包括复发性肛门囊腺癌、口腔恶性黑色素瘤伴肺转移、桡骨远端骨肉瘤无转移、口腔恶性黑色素瘤，多柔比星组治疗的肿瘤包括阑尾骨肉瘤肺转移和1只复发性腹腔黏液肉瘤犬。未发生非预期毒性，联合治疗的不良事件发生率未增加。作者得出结论，奥拉替尼与卡铂或多柔比星联用时，耐受性良好，但对抑制肿瘤无明显作用。

 

Additional investigation into oclacitinib’s antitumor effects is warranted since constitution activation of JAK/STAT pathway leads to increased tumor proliferation, survival, invasion, and metastasis.61 JAK1/2 inhibitors that have been used in clinical trials for treating various hematologic cancers in humans and in vitro experiments have shown that JAK1/2 inhibitors can successfully inhibit canine lymphoma cell growth in vitro in a dose-dependent manner. The antitumor properties of oclacitinib are not known at this time and are worth investigating.

由于JAK/STAT通路的结构激活导致肿瘤增殖、存活、侵袭和转移增加，因此有必要对奥拉替尼的抗肿瘤作用进行进一步的研究JAK1/2抑制剂已被用于治疗人类各种血液学癌症的临床试验和体外实验，结果表明JAK1/2抑制剂可以在体外以剂量依赖的方式成功抑制犬淋巴瘤细胞的生长。奥拉替尼的抗肿瘤特性目前尚不清楚，值得进一步研究。

 

Use in Nondomestic Animals

非家养动物的使用

Oclacitinib has been administered to treat pruritus to 3 captive Andean bears (Tremarctos ornatus) diagnosed with alopecia syndrome with a rapid response at 0.5 mg/kg twice daily initially and then tapered to 0.2 to 0.4 mg/kg once daily as maintenance.

奥拉替尼已被用于治疗3只诊断为脱毛综合征的圈养安第斯熊(Tremarctos ornatus)的瘙痒，最初的剂量为0.5 mg/kg，每天两次，反应迅速，然后逐渐减少到0.2至0.4 mg/kg，每天一次作为维持。

 

Where Do We Go From Here?

到此，我们何去何从？

The last 10 years have allowed us to accumulate a lot of experience with oclacitinib, and we continuously explore new uses and discover its usefulness for a variety of diseases ranging from inflammatory to immune mediated. We have learned about the safety, efficacy, and speed of action of oclacitinib compared to glucocorticoids. Instinctively we had assumed that injectable glucocorticoids would be faster than an oral medication, but the current evidence proves the opposite.

在过去的10年里，我们积累了很多关于奥拉替尼的经验，我们不断探索新的用途，并发现它对从炎症到免疫介导的各种疾病的有用性。与糖皮质激素相比，我们已经了解了奥拉替尼的安全性、有效性和作用速度。我们本能地认为注射糖皮质激素会比口服药物更快，但目前的证据证明了相反的情况。

 

A topic of debate is whether oclacitinib has clinically appreciable anti-inflammatory properties and how they would compare to glucocorticoids. While initially oclacitinib was considered a quick drug to stop itch, we now realize how blocking the signaling of so many cytokines involved in allergic inflammation affects a cascade of events that affect inflammation and not just pruritus. Yet, no study has specifically addressed this topic in a controlled fashion. Another question is whether oclacitinib could be of help for stenotic ear canals in allergic patients, a presentation for which the majority of dermatologists rely on glucocorticoids to decrease the swelling and inflammation. Proper studies are needed to address both of these questions. Topical formulations could also be of interest in the future, not only for ocular diseases but possibly also for ear disease and localized conditions like pododermatitis.

具有争论的一个话题是，奥拉替尼是否具有临床上明显的抗炎特性，以及与糖皮质激素相比效果如何。虽然最初认为奥拉替尼是一种快速止痒的药物，但我们现在认识到，阻断了与过敏性炎症相关的这么多细胞因子的信号传导，不仅是对瘙痒相关的级联反应有影响，同样也影响了炎症相关的级联反应。然而，没有任何研究以受控的方式专门探讨这一主题。另一个问题是奥拉替尼是否对过敏症患犬的耳道狭窄有帮助，对于过敏症患犬的耳道狭窄，大多数皮肤科医师依赖糖皮质激素减轻肿胀和炎症。需要适当的研究来解决这两个问题。外用制剂在未来也可能受到关注，不仅用于眼部疾病，还可能用于耳部疾病和足皮炎等局部疾病。

 

We have learned how to best educate owners and fellow clinicians to increase their comfort level with the use of this medication. Education on the different types of JAK inhibitors is particularly important to avoid lumping oclacitinib in the same group as JAK2 inhibitors. Prompting owners to use the medication as prescribed is equally important since, with higher doses, possible unwanted effects on JAK2 may occur. As the effect of oclacitinib on the various JAKs is concentration dependent and an issue of threshold, frequency of administration besides dose is important. Most case reports on the use of oclacitinib for autoimmune cases required twice-daily administration for extended periods of time to keep the diseases into remission highlighting the ability to immunosuppress by giving the medication more frequently and selecting the high end of the approved dose. As clinicians, we need to continue to be observant to provide the best care for our patients to maximize benefits and minimize unwanted adverse effects. Oclacitinib has proven to be a great tool in our armamentarium and has opened countless opportunities for an alternative option to the use of glucocorticoids.

我们已经学会了如何最好地教育宠主和临床医师同行，以增加他们使用这种药物时的舒适度。关于不同类型JAK抑制剂的教育尤其重要，以避免将奥拉替尼与JAK2抑制剂归为同一组。提示宠主按处方用药同样重要，因为较大剂量可能会对JAK2产生有害作用。由于奥拉替尼对各种JAK的作用具有浓度依赖性和阈值问题，因此除剂量外，给药频率也很重要。在使用奥拉替尼治疗自体免疫病的病例报告中，大多数需要长时间每日2次给药，以使疾病保持缓解，这凸显了更频繁给药和选择批准剂量的高端的免疫抑制能力。作为临床医师，我们需要继续观察，为患病动物提供最佳治疗，以最大限度地增加获益，最大限度地减少不必要的不良反应。奥拉替尼已被证明是我们设备中的一个伟大工具，并为糖皮质激素的替代治疗提供了无数机会。

 

 

 

 

Figure 1—Atopic dermatitis results from a combination of skin barrier damage and a skewed immune response to epicutaneously presented allergens. The inflammatory response is dynamic. Keratinocytes shape the immune response through the secretion of cytokines and contribute to the recruitment of lymphocytes by releasing chemokines. The initial Th2 response is important for the IgE production and supports a mastocytic and eosinophilic inflammation while later on other lymphocytic populations (Th1, Th17, and Th22) play a role. TARC = Thymus and activation-regulated chemokine. TSLP = Thymic stromal lymphopoietin.

图1 .特应性皮炎是由皮肤屏障损伤和对经皮呈递的过敏原的偏态免疫反应共同引起的炎症反应是动态的。角质形成细胞通过分泌细胞因子塑造免疫应答，并通过释放趋化因子促进淋巴细胞的募集。最初的Th2反应对IgE的产生很重要，并支持肥大细胞性和嗜酸性粒细胞性炎症，之后其他淋巴细胞群体(Th1、Th17和Th22)也发挥作用。TARC =胸腺和活化调节趋化因子。TSLP =胸腺基质淋巴生成素。

 

 

 

Figure 2—Relationship between drug exposure and inhibition of cytokine function. The blue line shows the concentration of oclacitinib needed to inhibit the listed Janus kinase 1 (JAK1)–dependent cytokines. The potency of oclacitinib toward cytokines can be illustrated by generating dose-response curves that show the inhibitory effects of increasing concentrations of oclacitinib on cytokine function. Half maximal inhibitory concentration (IC50) can be determined from these curves, indicating the concentration of oclacitinib that inhibits the function of that cytokine by 50%. (Adapted from Incorporating Apoquel® chewable tablets into practice. In: Clinician’s Forum, a Clinician’s Brief supplement; 2022. Sponsored by an educational grant from Zoetis. Reprinted with permission from Embark Veterinary, Inc.)

图2药物暴露与细胞因子功能抑制之间的关系。蓝线显示抑制列出的Janus激酶1 (JAK1)依赖性细胞因子所需的奥拉替尼浓度。奥拉替尼对细胞因子的效力可以通过绘制剂量-反应曲线来说明，该曲线显示了增加奥拉替尼浓度对细胞因子功能产生的抑制作用。可以从这些曲线确定半量抑制浓度(IC50)，即能抑制50%的该细胞因子的功能时的奥拉替尼浓度。

 

 

 

 

 

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