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Oclacitinib therapy in two cats with refractory proliferative and necrotising otitis externa
奥拉替尼治疗两只难治性增生性坏死性外耳炎患猫
Tim Chan | Sandra Nogueira Koch2 | Samuel Devine | Ekaterina Mendoza-Kuznetsova
翻译：王帆
Abstract
摘要
Feline proliferative and necrotising otitis externa (PNOE) is a rare immunemediated condition, usually self-limiting or responsive to immunosuppressants such as topical tacrolimus. This case report describes two cats with refractory PNOE that responded successfully to oclacitinib. One cat also had middle ear involvement and the other cat had extra-auricular dermatitis.
猫增生性坏死性外耳炎(PNOE)是一种罕见的免疫介导性疾病，通常自限性或对免疫抑制剂(如外用他克莫司)有反应。本病例报告描述了2只难治性PNOE猫对奥拉替尼成功有效。1只猫有中耳患病，另1只猫有耳外皮肤病变。
INTRODUCTION
介绍
Feline proliferative and necrotising otitis externa (PNOE) is a rare T-cell-mediated condition of unknown aetiology, usually self-limiting or responsive to immunosuppressants, such as topical tacrolimus. Clinically, it presents as dark, adherent crusts in the concave pinna and external ear canal. Variants of PNOE include additional extra-auricular dermatitis and middle ear involvement. These forms of PNOE may justify the use of systemic immunosuppressants as reported in one cat that responded to ciclosporin, systemic prednisolone and topical tacrolimus.
猫增生性坏死性外耳炎(PNOE)是一种罕见的病因不明的T细胞介导的疾病，通常自限性或对免疫抑制剂(如外用他克莫司)有反应。临床上表现为耳廓凹面和外耳道内的深色附着性结痂。PNOE的变型包括耳外皮肤病变和中耳患病。这些形式的PNOE可能证明使用全身性免疫抑制剂是合理的，正如报道的那样，有一只猫对环孢素、全身性泼尼松龙和外用他克莫司有反应。
Oclacitinib is a Janus kinase-1 (JAK1) inhibitor that affects the signalling pathway of cytokines involved in pruritus and allergic dermatitis. At doses exceeding the labelled amount, oclacitinib was found to inhibit T-cell proliferation and activation in dogs. Despite not being labelled for use in cats, anecdotal case reports have suggested that oclacitinib may have therapeutic benefits for various immune-mediated and autoimmune diseases in dogs and cats.To the best of the authors' knowledge, oclacitinib has not been reported previously as a treatment for PNOE. Herein, we describe two cats with PNOE that responded poorly or incompletely to tacrolimus, ciclosporin or prednisolone, yet responded rapidly and completely to oclacitinib.
奥拉替尼是Janus激酶-1 (JAK1)抑制剂，可影响参与瘙痒和过敏性皮炎的细胞因子的信号通路。研究发现，在超剂量标签剂量时，奥拉替尼可抑制犬的T细胞增殖和活化。尽管奥拉替尼是未被批准为用于猫的药物，但有零星病例报告提示，奥拉替尼可能对犬和猫的各种免疫介导性和自体免疫性疾病有治疗作用。据作者所知，奥拉替尼用于PNOE的治疗之前尚未见报道。在此，我们描述了两只患有PNOE的猫，它们对他克莫司、环孢素或泼尼松龙反应不佳或不完全，但对奥拉替尼反应迅速且完全。
CASE 1
病例1
A 6-month-old intact male Ragdoll cat presented to the Foster Hospital for Small Animals at the Cummings School of Veterinary Medicine at Tufts University with a three-month history of recurrent ear infections. Previous unsuccessful treatments included oral antibiotics and topical otic medication (see Table S1a). At initial presentation, the cat had dark-brown, adherent crusts that occluded both external ear canals. Microscopy of otic debris did not reveal ectoparasites and ear cytological results demonstrated cocci bacteria. A presumptive diagnosis of PNOE with secondary bacterial infection was made. Both ears were treated with an ear cleaner (Epi-Otic Advanced; Virbac) once weekly and tacrolimus 0.1% ointment (Protopic; Astellas Pharma) once daily. At the same visit, the cat was diagnosed with early-onset hypertrophic cardiomyopathy.
一只6月龄的未去势雄性布偶猫被送到塔夫茨大学卡明斯兽医学院的福斯特小动物医院，有3个月的反复耳部感染史。既往不成功的治疗包括口服抗生素和外用耳药(见表S1a)。最初就诊时，这只猫有黑褐色的附着性结痂，阻塞了双侧外耳道。耳分泌物显微镜检查未发现外寄生虫，耳细胞学结果显示球菌。我们做出了PNOE继发细菌感染的推测性诊断。双耳均使用洗耳液(耳漂、维克)和0.1%他克莫司软膏，每日1次。同时，猫被诊断为早发型肥厚型心肌病。
Follow-up 15weeks later revealed marked improvement of lesions besides small crusts in both horizontal ear canals. Treatment was changed to compounded tacrolimus 0.1% otic suspension (Wedgewood Pharmacy) to facilitate medication delivery. The cat achieved complete remission (CR) of lesions in the left ear and partial remission (PR) in the right ear 15 weeks later. Tacrolimus was discontinued for the left ear and reduced to every-other-day (EOD) for the right. However, sixweeks later, PNOE relapsed in the left ear and tacrolimus was subsequently restarted daily for the left ear.
15周后随访，除双侧水平耳道有小结痂外，病变明显改善。治疗改为0.1%他克莫司复方混悬液，以方便给药。15周后，猫左耳病变完全缓解(CR)，右耳病灶部分缓解(PR)。左耳停用他克莫司，右耳减少至隔日1次。然而，6周后，左耳PNOE复发，随后左耳重新开始每日服用他克莫司。
There was no improvement by 15weeks of the reinstated tacrolimus course. Computed tomography (CT) and video-otoscopy revealed crusts in the left horizontal canal that extended into the middle ear (Figure 1a,b). Material in the left middle ear obtained via curettage was histologically consistent with PNOE (Figure S1). Generic modified ciclosporin (Gengraf; Abbvie) 6.8mg/kg/day per os (p.o.) was started, and sixweeks later tacrolimus suspension was switched back to the ointment. However, sevenweeks after starting ciclosporin, lesions in the left ear continued to worsen (Figure 2a). Systemic treatment options were limited as a result of the cat's progressive hypertrophic obstructive cardiomyopathy, so a total ear canal ablation and bulla osteotomy was planned.
恢复他克莫司疗程15周时无改善。计算机断层扫描(CT)和视频耳镜检查显示，左侧水平耳道内有结痂，结痂延伸至中耳(图1a,b)。刮除术获得的左中耳材料在组织学上与PNOE一致(图S1)。仿制改良环孢素6.8mg/kg/d口服，6周后将他克莫司混悬液更换为软膏。然而，在开始使用环孢素后7周，左耳病变继续恶化(图2a)。由于猫的进行性肥厚型梗阻性心肌病，全身性治疗选择有限，因此计划行全耳道消融和鼓泡截骨术。
Before surgery, ciclosporin was discontinued and oclacitinib (Apoquel; Zoetis) was trialled (1.5mg/kg p.o.every 12h) based on previous pharmacokinetic and safety studies in cats.9,10 After twoweeks, the owner reported marked improvement, and the surgery was cancelled. Following 12weeks of oclacitinib therapy, examination revealed almost CR. A small, adherent crust was found in the left concave pinna (Figure 2b) and the tympanic membrane was well-visualised. Tacrolimus was withdrawn while oclacitinib was continued at the same dose. One year later, both ears were in CR (Figure 2c). A small ceruminolith developed in the left horizontal ear canal. Regular complete blood counts (CBC) and serum chemistries did not reveal abnormalities. Oclacitinib was tapered to 1.5mg/kg once a day and PNOE remained in CR.
术前停用环孢素，并尝试使用奥拉替尼(每12小时1.5mg/kg口服)是基于之前在猫身上的药代动力学和安全性研究。两周后，患猫的病情明显好转，手术被取消。奥拉替尼治疗12周后，检查显示几乎为CR。在左侧耳廓凹处发现一个小的黏附性结痂(图2b)，鼓膜清晰可见。停用他克莫司，奥拉替尼以相同剂量继续用药。1年后，双耳均达到CR(图2c)。左侧水平耳道一小块耵聍。常规全血细胞计数(CBC)和血清化学检查未发现异常。奥拉替尼逐渐减量至每日1次1.5mg/kg, PNOE仍维持在CR状态。
CASE 2
病例2
A 5-month-old cryptorchid male domestic medium-hair cat presented to the emergency service at the College of Veterinary Medicine at the University of Minnesota with a 2-week history of pyrexia, hyporexia, lethargy, progressive skin lesions and pruritus unresponsive to previous therapies (Table S1b). The cat tested negative for feline immunodeficiency and leukaemia viruses. Examination revealed multifocal crusts and plaques in the ears (Figure 2d), face (Figure 3a), head, trunk, ventral abdomen and extremities. Otoscopy was limited as a consequence of ear canal stenosis. Ear and skin cytological evaluation revealed mixed inflammatory cells and rare cocci and bacilliform bacteria. Skin scrapings were negative for ectoparasites. Serum chemical analysis was unremarkable, and CBC showed mild neutrophilia and eosinophilia.
一只5月龄隐睾雄性家养中毛猫到明尼苏达大学兽医学院急诊室就诊，该猫有2周的发热、厌食、嗜睡、进行性皮肤病变和对既往治疗无反应的瘙痒病史(表S1b)。猫的免疫缺陷和白血病病毒检测呈阴性。检查显示耳部(图2d)、面部(图3a)、头部、躯干、腹部和四肢有多灶性结痂和斑块。耳镜检查由于耳道狭窄而受到限制。耳部和皮肤细胞学检查显示混合炎症细胞和罕见的球菌和杆菌。皮肤刮片未检出体外寄生虫。血清化学分析无明显异常，全血细胞计数显示轻度中性粒细胞和嗜酸性粒细胞增多。
A presumptive diagnosis of PNOE with extraauricular involvement was made, and ear and skin biopsies were taken. The cat was hospitalised and prednisolone (PrednisTab; Lloyd) 1.3mg/kg/day p.o., buprenorphine (Buprenex; Indivior Inc.) 0.03mg/kg p.o. every 8h and fluid therapy were initiated. The cat was discharged twodays later after systemic signs improved and prednisolone was continued at home. Histopathological results confirmed PNOE with extraauricular involvement (Figure S2) and topical tacrolimus 0.1% (Protopic; Astellas Pharma) every 12h was started.
患猫被推定诊断为PNOE伴耳外患病，并进行了耳部和皮肤活检。猫被送进了医院，并接受了泼尼松龙(剂量：1.3毫克/公斤/天p.o，丁丙诺啡(剂量：每8小时0.03mg/kg，并开始液体治疗。两天后，猫全身症状改善后出院，继续在家接受泼尼松龙治疗。组织病理学结果证实了伴耳外患病的PNOE(图S2)和外用0.1%他克莫司每12小时1次。
Twelve days later, lesions and pruritus worsened. Skin and ear cytological results showed neutrophils and numerous cocci, and skin culture revealed Staphylococcus aureus and Enterococcus faecium. Prednisolone was increased to 2 mg/kg/day and amoxicillin-clavulanate (Clavamox; Zoetis) 18 mg/kg p.o. every 12 h, compounded gabapentin suspension 9.8 mg/kg p.o. every 8–12 h, and gentamicin, clotrimazole and mometasone otic suspension (Mometamax; Merck) every 12 h were initiated. Tacrolimus was continued. By Day (D)26, lesions improved marginally yet severe pruritus persisted. Cytological results revealed persistent infection. Prednisolone dosing was increased to 4.3 mg/kg/day.
12天后，皮肤病变及瘙痒加重。皮肤和耳部细胞学结果示中性粒细胞和大量球菌，皮肤培养示金黄色葡萄球菌和屎肠球菌。泼尼松龙增加至2 mg/ (kg·d)和阿莫西林-克拉维酸盐(复方加巴喷丁混悬液9.8 mg/kg，口服，每8 ~ 12小时1次;庆大霉素克霉唑莫米松混悬液(每12小时给药1次。继续服用他克莫司。第(D)26天，皮肤病变略有改善，但重度瘙痒持续存在。细胞学结果提示持续性感染。泼尼松龙剂量增加至4.3 mg/ (kg·d)。
On D40, as PNOE continued to progress (Figures 2e, 3b), oclacitinib (Apoquel; Zoetis) 0.5mg/kg p.o. every 12h was prescribed. Prednisolone was tapered to 1mg/kg p.o. every other day. In twodays, the owner reported significant improvement in lethargy and pruritus. After twoweeks of oclacitinib therapy, lethargy and pruritus had resolved and cutaneous lesions improved significantly. Oclacitinib and topicals were continued while all other systemic medications including prednisolone were discontinued at fiveweeks, 35days after starting oclacitinib. Seven weeks after starting oclacitinib, CR was achieved (Figures 2f, 3c). Oclacitinib was tapered to 0.5mg/kg once daily and discontinued twoweeks later along with all topicals, and the cat continued to be in CR. No adverse effects were noticed during treatment. Bi-weekly CBC and serum chemistries were unremarkable.
在D40，随着PNOE继续进展(图2e、3b)，奥拉替尼0.5mg/kg，口服，每12小时1次。泼尼松龙减量至每隔一天1mg/kg p.o.。在两天内，主人报告嗜睡和瘙痒有显著改善。奥拉替尼治疗2周后，嗜睡和瘙痒缓解，皮肤病变显著改善。奥拉替尼和外用药物继续用药，而包括泼尼松龙在内的所有其他全身性用药在5周(奥拉替尼开始用药后35日)时停用。奥拉替尼开始用药后7周，患猫达到CR(图2f, 3c)。奥拉替尼减量至0.5mg/kg, 1次/天, 2周后连同所有外用药物一起停药，猫继续处于CR状态。治疗期间未发现不良反应。两周的全血细胞计数和血清化学检查结果无显著差异。
Fourteen days after oclacitinib discontinuation, the cat developed pruritus resulting from Demodex gatoi infestation. Fluralaner spot-on (Bravecto; Merck) successfully eliminated the infestation. There was no recurrence of PNOE at a 4-month follow-up and the cat was reported healthy by the owners, 18months after his last exam.
停用奥拉替尼14天后，猫因戈托伊蠕形螨感染而出现瘙痒。使用氟雷拉纳成功进行蠕形螨病管理。经过4个月的随访，PNOE无复发，18个月后主人报告猫健康。
DISCUSSION
讨论
To the best of the authors' knowledge, this is the first description of successful treatment of feline PNOE with oclacitinib.
据作者所知，这是第一次描述用奥拉替尼成功治疗猫PNOE。
Proliferative and necrotising otitis externa is an idiopathic condition driven by T lymphocytes. As a Janus kinase (JAK) 1 inhibitor, oclacitinib blocks the signalling pathway of proinflammatory cytokines. In dogs, oclacitinib exerts a dose-dependent inhibition of spontaneous T-cell proliferation; a high dose of 3–4mg/kg every 12h causes immunosuppressive effects by significantly reducing the secretion of clonal activator and proinflammatory cytokines. It is not known if there is the same effect of oclacitinib on T cells in cats. The authors suspect that a similar influence on lymphocyte activation and proliferation led to remission in the cats described herein. However, the exact mechanism of oclacitinib's actions on the pathogenesis of PNOE remains unknown.
增生性坏死性外耳炎是一种由T淋巴细胞驱动的特发性疾病。奥拉替尼作为Janus激酶(JAK) 1抑制剂，可阻断促炎细胞因子的信号通路。在犬中，奥拉替尼对自发性T细胞增殖具有剂量依赖性抑制作用;每12小时3-4mg/kg的高剂量通过显著减少克隆激活剂和促炎细胞因子的分泌产生免疫抑制作用。目前尚不清楚奥拉替尼对猫的T细胞是否有同样的作用。作者怀疑对淋巴细胞活化和增殖的类似影响导致了本文中描述的猫的缓解。然而，奥拉替尼在PNOE发病机制中的确切作用机制仍不清楚。
The two cats described herein had unusual and severe forms of PNOE that showed no or minimal response to tacrolimus, ciclosporin and/or glucocorticoids. These two cases support consideration of oclacitinib as an alternative or adjunctive treatment for PNOE, especially in refractory and/or extra-auricular cases. Additionally, off-label use of oclacitinib can be justified when systemic steroids or ciclosporin are contraindicated or ineffective.
本文描述的两只猫有罕见和严重的PNOE形式，对他克莫司、环孢素和/或糖皮质激素无反应或轻微反应。这两个病例支持考虑将奥拉替尼作为PNOE的替代或辅助治疗，特别是对于难治性和/或耳外病变病例。此外，当全身性类固醇或环孢素有禁忌证或无效时，奥拉替尼的标签外用药是合理的。
Both cats tolerated oclacitinib well and did not develop clinicopathological abnormalities. Although the source of D.gatoi in Case 2 could not be confirmed, it was likely to have been the result of exposure to stray cats in the household, and unlikely to have been associated with oclacitinib or steroids.
2只猫对奥拉替尼耐受性良好，未出现临床病理异常。虽然病例2的戈托伊蠕形螨来源无法确定，但很可能是家中流浪猫的暴露结果，不太可能与奥拉替尼或类固醇相关。
This case report has some limitations. In Case 1, formulations of tacrolimus (branded ointment versus compounded suspension) could have different efficacies despite both forms being initially effective. The material obtained by blind curettage is suspected to have come from the middle ear, yet it is possible that it originated from the external ear canal. Furthermore, assessment of the cat's response to oclacitinib using CT was not performed owing to the high anaesthetic risks. Nonetheless, given the cat's otoscopic findings and clinical remission, the authors believe that oclacitinib completely resolved the lesions in the external and middle ears. In Case 2, the initial administration of oral steroids and tacrolimus may have contributed to the cat's improvement. However, the cutaneous lesions continued to progress despite high doses of steroids and rapidly regressed once oclacitinib was started, supporting the belief that oclacitinib was primarily responsible for the improvement. Moreover, although spontaneous resolution of PNOE is reported, it was less likely in these cases owing to the recurrent and chronic courses.
本病例报道有一定局限性。在病例1中，他克莫司的配方(品牌软膏和复合混悬液)可能具有不同的疗效，但两种剂型最初都有效。盲刮法获得的材料疑似来自中耳，但也有可能来自外耳道。此外，由于麻醉风险高，未使用CT评估猫对奥拉替尼的反应。尽管如此，鉴于猫的耳镜检查结果和临床缓解，作者认为奥拉替尼完全缓解了外耳和中耳的病变。在病例2中，最初口服类固醇和他克莫司可能有助于猫的改善。然而，尽管使用了大剂量类固醇，皮肤病变仍继续进展，并且在奥拉替尼开始用药后迅速消退，这支持奥拉替尼是皮肤病变改善的主要原因这一观点。此外，虽然有PNOE自发消退的报道，但由于这些病例的复发性和慢性病程，PNOE自发消退的可能性较小。
In summary, this report describes the successful management of PNOE with oclacitinib in two cats. Both cats improved clinically and achieved stable remission on oclacitinib in Case 1 and sustained effect after oclacitinib cessation in Case 2. Despite lacking safety and pharmacokinetic studies in cats, oclacitinib should be considered as a therapeutic alternative for controlling PNOE, especially if classical therapies are ineffective or contraindicated.
总之，本报告描述了奥拉替尼对两只猫PNOE的成功治疗。2只猫在接受奥拉替尼治疗后均有临床改善，病例1达到稳定缓解，病例2在奥拉替尼停药后持续有效。尽管缺乏安全性和猫的药代动力学研究，但奥拉替尼应被考虑作为控制PNOE的替代治疗，尤其是在经典疗法无效或禁忌的情况下。
FIGURE 1 Case 1: A single computed tomography (CT) slice of the skull and video-otoscopic images of the left ear canal. (a) CT image before oclacitinib administration. Note soft tissue attenuating material extending into the dorsolateral compartment of the left tympanic bulla (arrowhead). (b) Video-otoscopic image before oclacitinib administration. Note abundant debris and thick, adherent crusts. The tympanic membrane is obscured by the crusts. (c) The same ear after a 22-week course of oclacitinib. Note mild debris and resolution of the adherent crusts.
图1病例1:头颅单层计算机断层扫描(CT)和左耳道视频耳镜图像(a)奥拉替尼给药前的CT图像。注意软组织衰减物质延伸到左鼓室的背外侧室(箭头)。(b)奥拉替尼给药前的视频耳镜图像。注意大量碎屑和厚的附着性结痂。鼓膜被结痂遮蔽。(c)奥拉替尼22周疗程后的相同耳朵。注意到轻微的碎屑和附着性结痂的缓解。
 FIGURE 2 Proliferative and necrotising otitis externa (PNOE) affecting the concave pinna in Case 1 (a, b, c) and Case 2 (d, e, f). (a) Case 1: Left concave pinna before oclacitinib administration (current treatments at the time were ciclosporin and tacrolimus). Note massive adherent necrotic crust occluding the ear canal. (b) Case 1: The same ear after threemonths of oclacitinib treatment. Note a residual adherent lesion (arrowhead). (c) Case 1: The same ear after fivemonths of oclacitinib therapy in complete clinical remission. (d) Case 2: Right concave pinna at initial presentation. Note erythematous scaly plaques and adherent crusts extended into the ear canal. (e) Case 2: During disease progression before oclacitinib administration (current treatments at the time were prednisolone and tacrolimus). Note proliferative plaques and necrotic adherent crusts completely occluded the ear canal. (f) Case 2: After a seven-week course of oclacitinib, all lesions resolved with only mild ceruminous debris present.
图2病例1 (a、b、c)和病例2 (d、e、f)中累及耳廓凹面的增生性坏死性外耳炎(PNOE)。(a)病例1:奥拉替尼给药前的左耳廓凹面(当时的治疗方案是环孢素和他克莫司)。可见大量粘附性坏死性结痂阻塞了耳道。(b)病例1:奥拉替尼治疗3个月后仍为同一耳。注意残留的粘连病变(箭头)。(c)病例1:同耳接受奥拉替尼治疗5个月后临床完全缓解。(d)病例2:初次就诊时右侧耳廓凹面。注意到发红皮屑斑块和粘附的结痂延伸到耳道。(e)病例2:奥拉替尼给药前疾病进展期间(当时的当前治疗是泼尼松龙和他克莫司)。注意增生的斑块和坏死的粘附性结痂完全堵塞了耳道。(f)病例2:奥拉替尼7周疗程后，所有病变均消退，仅残留轻度蜡样碎片。
FIGURE 3 Case 2: Extra-auricular proliferative and necrotising otitis externa (PNOE) affecting the face. (a) At initial presentation. Note erythematous scaly plaques and necrotic adherent crusts around the left eye. (b) During disease progression before administration of oclacitinib (current treatments at the time were prednisolone and tacrolimus). Note progression of the proliferative plaques, necrotic adherent crusts and hypotrichosis. (c) After a seven-week course of oclacitinib in complete clinical remission.
图3病例2:累及面部的耳外增生性坏死性外耳炎(PNOE)(a)初次就诊时。注意左眼周围的发红皮屑斑块和坏死的附着性结痂。(b)在奥拉替尼给药前的疾病进展期间(当时的治疗方法是泼尼松龙和他克莫司)。注意增生性斑块、坏死性附着结痂和少毛的进展。(c)经过7周奥拉替尼疗程后达到完全临床缓解。
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发表于 2024-6-2 23:10:05
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