本帖最后由 王帆 于 2021-12-23 14:57 编辑
Ear tip ulcerative dermatitis treated with oclacitinib in 25 dogs: a retrospective case series 奥拉替尼治疗25只犬的耳尖溃疡性皮炎:回顾性病例系列 Silvia Colombo* , Luisa Cornegliani†, Antonella Vercelli† and Alessandra Fondati‡
翻译：王帆
Background – Ear tip ulcerative dermatitis (ETUD) is an uncommon clinical reaction pattern in canine dermatology. The lesions are suggestive of vascular damage which may be caused by inflammatory or noninflammatory diseases, and often are idiopathic. Therapeutic options for ETUD include topical glucocorticoids or tacrolimus, pentoxifylline, vitamin E, doxycycline, tetracycline and niacinamide, sulfonamides, glucocorticoids, ciclosporin and surgical correction. Hypothesis/Objectives – The aims of this retrospective case series were to describe the clinical features and report response to treatment with oclacitinib in dogs with idiopathic, chronic ETUD. Animals – Twenty-five privately owned dogs with unilateral or bilateral ETUD. Methods and materials – Cases of ETUD which were poorly responsive to conventional therapy and subsequently treated with oclacitinib, are summarised. All cases were tested for leishmaniosis by serological examination [indirect fluorescent antibody test (IFAT) or enzyme-linked immunosorbent assay (ELISA)]. Histopathological examination was performed in two cases. Results – Serological results were negative for leishmaniosis in all dogs. Histopathological changes consistent with proliferative thrombovascular necrosis of the pinnae were documented in two cases. Oclacitinib, used at the standard dose range recommended for the treatment of canine atopic dermatitis, effectively resolved ETUD in 22 of 25 dogs within one to three months. Several of the dogs required prolonged use of twice daily dosing. Conclusions and clinical relevance – Oclacitinib should be included among the therapeutic options for ETUD, once infectious diseases have been ruled out. 摘要 背景 – 耳尖溃疡性皮炎(ETUD)是犬皮肤病学中不常见的临床反应模式。病变提示血管损伤，可能由炎性或非炎性疾病引起，通常为特发性。ETUD的治疗选择包括外用糖皮质激素或他克莫司、己酮可可碱、维生素 E、多西环素、四环素和烟酰胺、磺胺类药物、糖皮质激素、环孢素和手术矫正。 假设/目的 – 本回顾性病例系列的目的是描述特发性、慢性ETUD犬的临床特征，并报告对奥拉替尼治疗的反应。 动物 – 25只患有单侧或双侧ETUD的私家犬。 方法和材料 – 总结了对常规治疗反应不佳且随后接受奥拉替尼治疗的ETUD病例。所有病例均经血清学检查[间接荧光抗体试验(IFAT)或酶联免疫吸附试验(ELISA)]检测利什曼病。2例进行了组织病理学检查。 结果 – 所有犬的利什曼病血清学结果均为阴性。2例组织病理学变化记录为耳廓增生性血栓性血管坏死。奥拉替尼使用按照治疗犬特应性皮炎的标准推荐剂量范围，在1-3个月内，22/25只ETUD患犬得到有效缓解。一些犬需要长期使用，且每日两次给药。 结论和临床相关性 – 一旦排除感染性疾病，应将奥拉替尼纳入ETUD的治疗方案。
Introduction 介绍 Ear tip ulcerative dermatitis (ETUD) is an uncommon clinical reaction pattern in canine dermatology, suggestive of vascular damage. Histopathological changes may be inflammatory or noninflammatory, and may be associated with thrombus formation in some cases. Underlying disorders reported in association with canine ETUD include leishmaniosis, bartonellosis (Bartonella henselae), experimental infection by Rickettsia rickettsia, frostbite, cryoglobulinaemia and cryofibrinogenaemia and breedspecific (familial) vasculitides. In most cases, histopathological or immunopathological demonstration of vascular damage is lacking. Proliferative thrombovascular necrosis of the pinnae (PTVNP) is usually an idiopathic diagnosis characterised by histological features of vascular damage to small dermal arterioles, with or without fibrin thrombi. 耳尖溃疡性皮炎(ETUD)是犬皮肤科一种不常见的临床反应模式，提示血管损伤。组织病理学改变可能是炎性的，也可能是非炎性的，在某些病例中，可能与血栓形成有关。与犬ETUD相关的潜在疾病包括利什曼病、巴尔通体病(汉氏巴尔通体)、立克次体的实验性感染、冻伤、冷球蛋白血症和冷纤维蛋白原血症以及品种特异性(家族性)血管炎。在大多数病例中，没有使用组织病理学或免疫病理学证明发生血管损伤。耳廓增生性血栓性血管坏死(PTVNP)通常是一种特发性的诊断，其组织学特征是真皮小动脉血管损伤，伴有或不伴有纤维蛋白血栓。
The exclusive involvement of the pinnal apex is clinically distinct and has been described so far only in PTVNP, leishmaniosis and the one case of bartonellosis. 在临床中，仅在PTVNP、利什曼病和一例巴尔通体病中描述病变仅出现在耳廓尖端。
Oclacitinib is a first-generation Janus kinase (JAK) inhibitor, approved in many countries to treat atopic dermatitis (AD) and allergic pruritus in dogs. Besides its antipruritic effect, which is mediated primarily by inhibition of signalling via the interleukin (IL)-31 receptor, oclacitinib also shows anti-inflammatory activity with in vitro inhibition of IL-2, IL-4, IL-6 and IL-13. A recent study demonstrated that oclacitinib, when used at doses higher than label guidelines, has immunosuppressive activity in vitro, with inhibition of T-cell proliferation and secretion of IL-2, IL-15, interferon-gamma (IFN-c), IL-18 and IL-10. Extra-label use of oclacitinib in dogs has been recently reported to be useful in various immune-mediated diseases, such as erythema multiforme, juvenile-onset ischaemic dermatopathy and one case of subepidermal blistering dermatosis. In addition, a case abstract described its favourable effect for canine idiopathic ear tip vasculitis not responsive to conventional therapy. The aims of this retrospective study were to describe the clinical features of 25 cases of idiopathic, chronic ETUD, and to report response to treatment with oclacitinib. 奥拉替尼是第一代Janus激酶(JAK)抑制剂，在许多国家被批准用于治疗犬的特应性皮炎(AD)和过敏性瘙痒。除了主要通过抑制白细胞介素(IL)-31受体信号传导的止痒作用外，奥拉替尼还表现出抗炎活性，在体外抑制IL-2、IL-4、IL-6和IL-13。最近的一项研究表明，当使用剂量高于标签用药时，奥拉替尼在体外具有免疫抑制活性，可以抑制T细胞增殖和IL-2、IL-15、干扰素- γ (IFN-c)、IL-18和IL-10的分泌。最近有报道称，奥拉替尼在犬身上的标签外使用在各种免疫介导性疾病中都有用，如多形红斑、幼犬发病的缺血性皮肤病和一例表皮下水疱性皮肤病。此外，一个案例摘要描述了其对常规治疗无效的犬特发性耳尖血管炎的疗效良好。本回顾性研究的目的是描述25例特发性慢性ETUD的临床特征，并报告奥拉替尼的治疗效果。
Methods and materials 方法和材料 Cases were identified by searching the clinical record databases of the authors and colleagues working in private practice in northern and central Italy, and Sardinia, from 2015 to 2019. Cases were included if they showed unilateral or bilateral ETUD as the only dermatological sign. Only dogs with complete medical records, including signalment, history and description of the clinical lesions, and which were treated with oclacitinib for at least four weeks, were included. Owners had been informed that oclacitinib is not licensed for treatment of ETUD. A minimum of six months follow-up time was required for inclusion, and information was collected regarding dose, duration of treatment, discontinuation of treatment, and relapses (VDDETable 1). 这些病例是通过搜索2015年至2019年在意大利北部和中部以及撒丁岛私人诊所工作的作者和同事的临床记录数据库确定的。将单侧或双侧ETUD作为唯一皮肤症状的病例纳入研究。只有具有完整的医疗记录，包括临床表现、病史和临床病变描述，并且使用奥拉替尼至少四周的犬被纳入研究。宠主已被告知，奥拉替尼不被许可用于治疗ETUD。纳入需要至少6个月的随访时间，并收集有关剂量、治疗持续时间、停止治疗和复发的信息(VDDETable 1)。
Results 结果 Information from the medical records of 25 dogs were included in the study, including four dogs reported upon previously. There were six dachshunds, five Jack Russell terriers, four mongrels, three Rhodesian ridgebacks and one each of the following breeds: Dalmatian, French bulldog, Chihuahua, Labrador retriever, Alaskan malamute, Maltese and Epagneul Breton. Ages ranged between one and 13 years, with a mean age of 5.19 years and a median age of 5 years. There were 17 males, three of which were castrated and eight females, four of which were spayed. Thirteen dogs had pendulous pinnae, five dogs had folded pinnae, three dogs had erect pinnae, and pinnal conformation was unknown in four mixed-breed dogs. 研究纳入了25只犬的医疗记录，其中包括4只之前报道过的犬。其中有6只腊肠犬、5只杰克罗素㹴、4只杂交犬、3只罗得西亚脊背犬，以及以下各一种犬种:大麦町犬、法国斗牛犬、吉娃娃犬、拉布拉多猎犬、阿拉斯加雪橇犬、马尔济斯犬和布列顿犬。年龄范围为1 - 13岁，平均年龄为5.19岁，中位年龄为5岁。有17只雄性，其中3只已去势，8只雌性，其中4只已绝育。13只垂耳犬，5只折耳犬，3只立耳犬，4只杂交犬的耳廓结构未知。
None of the dogs had a history of vaccination or any other pharmacological intervention within six months before the onset of ETUD. Concurrent diseases reported by the owners were Addison’s disease in one dog and AD in five dogs. Five dogs, including four of the atopic dogs, presented with bilateral erythematous/ceruminous otitis externa (OE); of the four atopic dogs with OE, two also showed unilateral auricular haematoma. Previous noneffective treatments included pentoxifylline (15 mg/ kg orally twice daily) in 11 dogs, topical glucocorticoids in six dogs, prednisolone or methylprednisolone (1 mg/kg p.o. once daily) in six dogs, doxycycline (5 mg/kg p.o. twice daily) in one dog, topical 0.1% tacrolimus in one dog and skin glue (cyanoacrylate) application in one dog. 在ETUD发病前的6个月内，没有犬有接种疫苗或任何其他用药史。一只犬的宠主报告有并发艾迪森病，5只犬报道并发AD。5只犬(包括4只特应性皮炎患犬)出现双侧红斑/耵聍性外耳炎(OE)，4只特应性皮炎患犬有OE，2只犬也有单侧耳血肿。之前无效的治疗包括11只犬用过己酮可可碱(15毫克/公斤，口服每天两次),6只犬外用过糖皮质激素,6只犬用过泼尼松龙或甲基泼尼松龙(1毫克/公斤，口服，每天一次),1只犬用过多西环素(5毫克/公斤，口服每天两次),1只犬外用过0.1%他克莫司，1只犬外用过皮肤粘合剂。
General physical examination was unremarkable in all cases and, with the exception of five dogs with OE, pinnal lesions were the only abnormality. The onset of ETUD was recorded as occurring one to 24 months before presentation (mean 5.1 months, median 3 months). In 16 of 25 cases, lesions appeared three months or less before presentation. Nine of 25 dogs showed ear pruritus/pain, including four dogs with allergic OE. The majority (24 of 25 dogs) had bilateral lesions, with erythema, erosions, ulcerations and crusting involving the tips of the pinnae, with a typical wedge-shape pointing towards the ear canal (Figure 1a,b). The length of the lesions, measured from the ear tip, varied from 0.5 to 5 cm. Intermittent bleeding was reported in 21 of 25 cases. Cytological examination of otic material was performed in five dogs with OE and yielded Malassezia yeast in high numbers in three dogs and normal findings (corneocytes) in two dogs. Leishmaniosis was ruled out for all dogs by means of indirect immunofluorescence antibody testing (IFAT) or enzyme-linked immunosorbent assay (ELISA). Histopathological examination was performed in two cases and confirmed the diagnosis of PTVNP (Figure 2). 除了5只犬有OE外，所有病例全身体格检查均未见异常，耳廓病变是唯一的异常。ETUD的发病时间为发病前1 - 24个月(平均5.1个月，中位数3个月)。在25例中，有16例在3个月或更短的时间内出现病变表现。25只犬中有9只出现耳部瘙痒/疼痛，包括4只过敏性OE患犬。大多数(25只犬中有24只)有双侧病变，伴有耳廓尖部红斑、糜烂、溃疡和结痂，呈典型的指向耳道的楔形(图1a,b)。病变的长度，从耳尖测量，从0.5到5厘米不等。25例中有21例报道有间歇性出血。对5只OE犬的耳分泌物进行细胞学检查，3只犬有大量马拉色酵母菌，2只犬细胞学检查正常（角化细胞）。通过间接免疫荧光抗体检测(IFAT)或酶联免疫吸附试验(ELISA)，所有犬均排除利什曼病。2例进行组织病理学检查，确诊为PTVNP(图2)。
Figure 1. Case 5. Bilateral ear tip ulcerative dermatitis involving the right (a) and left (b) pinna. 图1。病例5。双侧耳尖溃疡性皮炎，右耳廓(a)和左耳廓(b)病变。
Figure 2. Clinical presentation of ear tip ulcerative dermatitis in (a) Case 3 and (b) Case 16. 图2。耳尖溃疡性皮炎(a)病例3和(b)病例16的临床表现。
Oclacitinib was initiated in all dogs at 0.4–0.6 mg/kg twice daily. In 22 cases the dose was reduced to once daily administration after two weeks. In two cases, administration was continued twice daily for two months. In one of these cases, lesions did not improve and treatment was changed to pentoxifylline and topical 0.1% tacrolimus, with complete resolution. In the other case, lesions improved only partially and complete resolution was achieved with ciclosporin. In a third case, administration was continued twice daily for one month with complete resolution, followed by a relapse when the dose was reduced to once daily. This dog was subsequently lost to follow-up. In total, complete resolution of ETUD was achieved in 22 of 25 dogs within one to three months of treatment. 所有犬奥拉替尼的初始剂量为0.4-0.6毫克/公斤，每天两次。在22例中，两周后剂量减少到每日一次。其中两例持续每日给药两次，持续两个月。在其中一个病例中，病变没有改善，治疗方案改变为己酮可可碱和外用0.1%他克莫司，完全缓解。在另一个病例中，病变仅部分改善，联用环孢素后完全缓解。在第三个病例中，每天给药两次，持续一个月，完全缓解，当剂量减少到每天一次时复发。这只犬随后失联。总的来说，在治疗一到三个月内，25只犬中有22只的ETUD得到了完全缓解。
Four of the oclacitinib-treated dogs relapsed within one month after treatment was discontinued. In one dog, reinstitution of oclacitinib therapy induced remission, and the dog remained on this treatment long-term. A second dog was treated surgically (conchectomy), and two cases were lost to follow-up. Concurrent treatment was prescribed for five dogs affected by OE: three dogs with Malassezia otitis received a topical gel containing betamethasone, florfenicol and terbinafine (Osurnia, Dechra Veterinary Products; Shresbury, UK) topically applied twice at one week interval. Two dogs with erythematous otitis and normal cytological examination received a topical preparation containing triamcinolone and salicylic acid (Recicort, Dechra Veterinary Products) once daily for two weeks. 停用奥拉替尼治疗的四只犬在一个月内复发。在一只犬中，重新接受奥拉替尼治疗得到缓解，并且这只犬长期接受这种治疗。另一只犬接受手术治疗(耳尖切除术)，2例失联。5只OE患犬同时接受治疗:3只马拉色菌性耳炎患犬外用含有倍他米松、氟苯尼考和特比萘芬的耳膏，一周两次。两只红斑性耳炎患犬且细胞学检查正常，外用含有曲安奈德和水杨酸的耳部产品，每天一次，持续两周。
Discussion 讨论 The observations presented here suggest that oclacitinib may be useful in the management of ETUD. Twentytwo of 25 dogs presenting with ETUD responded completely to oclacitinib. Four of these dogs relapsed when oclacitinib therapy was withdrawn, and one required long-term treatment with oclacitinib to maintain remission. 这里提出的观察结果表明，奥拉替尼可能在ETUD的管理中是有效的。25只出现ETUD的犬中有22只对奥拉替尼完全有效。其中4只犬在停用奥拉替尼治疗后复发，1只需要长期服用奥拉替尼以维持缓解。
ETUD is a clinical reaction pattern which may be observed in dogs as a consequence of localised vasculitis or noninflammatory vasculopathy. Clinical signs include wedge-shaped ulcers (usually bilateral) affecting the ear tips. ETUD presenting as the sole clinical lesion may be caused by a limited number of diseases, including PTVNP and leishmaniosis. Recently, a single case of ETUD resulting from Corynebacterium ulcerans infection also was reported. PTVNP was originally described by Griffin and subsequently discussed in two review papers under the synonym “pinnal margin vasculopathy”. PTVNP has been described as an idiopathic syndrome, clinically characterised by wedge-shaped devitalisation and necrosis of the distal pinnae.Histopathological features include fibrinoid degeneration and thickening of small dermal arteriole walls, and fibrin thrombi. Secondary changes may include mixed inflammatory infiltrates, ulceration, haemorrhage and dermal fibrosis. The pinnal cartilage may be necrotic. ETUD是一种临床反应模式，可能在犬身上观察到的局灶性血管炎或非炎性血管病变的结果。临床症状包括耳尖的楔形溃疡(通常是双侧)。ETUD可能是少数疾病的唯一的临床表现，包括PTVNP和利什曼病。最近也报道了一例由溃疡棒状杆菌感染引起的ETUD。PTVNP最初是由Griffin描述的，随后在两篇综述论文中讨论了其同义词“耳廓边缘血管病变”。PTVNP被描述为一种特发性综合征，临床特征是耳廓远端呈楔形失活和坏死。组织病理学特征包括纤维蛋白样变性、真皮小动脉壁增厚和纤维蛋白血栓形成。继发的改变可能包括混合炎症浸润、溃疡、出血和真皮纤维化。耳廓软骨可能坏死。
In Mediterranean countries, the major differential diagnosis for PTVNP is leishmaniosis, and this diagnosis was ruled out in all dogs by negative ELISA or IFAT serological testing. None of the dogs had a history of vaccination or drug administration within six months of the onset of ETUD, although recent vaccination and deworming with fenbendazole have been reported as potential predisposing factors for PTVNP. Dachshunds and Rhodesian ridgeback dogs seem to be predisposed, and in this case series there were six dachshunds and three Rhodesian ridgebacks. A familial vasculopathy has been reported in Jack Russell terrier dogs, with alopecia and ulcerations affecting bony prominences of the head and limbs, as well as the ear tips and footpads and onset of lesions shortly after routine vaccination in several cases.In the present case series, five Jack Russell terrier dogs were included which showed only ETUD lesions and had no history of vaccination within six months of the onset of the lesions. 在地中海国家，PTVNP的主要鉴别诊断为利什曼病，ELISA或IFAT血清学检测均阴性，排除了该诊断。虽然最近的疫苗接种和芬苯达唑驱虫被报道为PTVNP的潜在诱发因素，但在发生ETUD的6个月内，没有犬有接种疫苗或用药史。腊肠犬和罗得西亚脊背犬似乎有品种倾向性，在这篇病例系列中，有6只腊肠犬和3只罗得西亚脊背犬。家族性血管病变已在杰克罗素㹴犬中有报告，头部和四肢骨突处脱毛和溃疡，耳尖和爪垫也有病变，在几个病例中在常规疫苗接种后不久出现病变。在本病例系列中，包括5只表现为ETUD病变且在发病6个月内没有接种疫苗史的杰克罗素㹴犬。
When the pinnal conformation was evaluated, 18 of 25 dogs had either pendulous or folded pinnae, suggesting that dogs with the tip of the pinnae directed downwards may be affected more commonly than dogs with erect ears. In this case series, five dogs were concurrently affected by OE, and continuous trauma resulting from pruritus and head shaking may have contributed to the pathogenesis of ETUD. An otoscopic and cytological examination should always be performed in dogs presenting with ETUD. 当评估耳廓结构时，25只犬中有18只垂耳或折耳，这表明耳廓尖端下垂的犬可能比立耳犬更容易患病。在本病例系列中，5只犬同时患有OE，瘙痒和甩头造成的持续创伤可能是ETUD的发病原因之一。出现ETUD的犬应进行耳镜和细胞学检查。
Histological evaluation of lesional tissues was performed in only two dogs, and this is a limitation of this retrospective evaluation. The diagnosis of a vascular disease requires histological confirmation. However, biopsies of the pinna are difficult to acquire. The procedure requires general anaesthesia and may result in permanent deformity to the pinna. Pathological changes of the arterioles may be difficult to appreciate when ulceration, inflammation and fibrosis obscure the vascular lesions. Other diagnostic tests proposed to evaluate vascular diseases are the D-Dimer and C-protein assays and ear pinnae dermal blood flow determination by laser Doppler flowmeter. Unfortunately, these tests were not performed on the cases reported in this series. 仅对两只犬病变组织进行了组织学评估，这是本次回顾性评估的一个局限性。血管疾病的诊断需要组织学证实。然而，对耳廓的活组织检查很难获得。手术需要全身麻醉，可能导致耳廓永久畸形。当溃疡、炎症和纤维化掩盖血管病变时，小动脉的病理变化可能很难判断。其他用于评估血管疾病的诊断试验包括D -二聚体和C-蛋白检测和激光多普勒流量计测定耳廓真皮血流。不幸的是，没有对本系列中报告的案例执行这些测试。
Therapeutic options for pinnal vascular lesions may include topical glucocorticoids or tacrolimus for mild cases, or systemic drugs such as pentoxifylline, vitamin E, doxycycline, tetracycline and niacinamide, sulfonamides, glucocorticoids and ciclosporin for more severe lesions. The most severe cases may require surgical correction. The dogs presented in this report had all been treated previously with one or more of these drugs, without improvement. 针对耳廓血管病变的治疗选择可能包括，病变轻的病例外用糖皮质激素或他克莫司，或病变更严重的全身性用药，如己酮可可碱、维生素E、多西环素、四环素和烟酰胺、磺胺类药物、糖皮质激素和环孢素。最严重的病例可能需要手术矫正。在本报告中的犬都曾接受过一种或多种药物治疗，但没有改善。
In a recent case series, complete responses to oclacitinib were reported for four cases of canine juvenile onset ischaemic dermatopathy which had been refractory to conventional therapies. Despite the uncertainty regarding oclacitinib’s mechanism of action for the treatment of ischaemic dermatopathy, it is hypothesised that it may be effective by inhibiting type I interferons. In people, JAK inhibitors are registered for the treatment of many autoimmune and immune-mediated conditions.A recent publication reports the efficacy of tofacitinib, a JAK3 and JAK1 inhibitor, in giant cell arteritis, which is a chronic immune-mediated condition affecting the vascular walls. Tofacinib effectively inhibited proliferation of lesional T cells in the vessel wall and production of IFN-c, IL-17 and IL-21. 在最近的一系列病例中，有4例常规治疗顽固性幼年发病缺血性皮肤病患犬的报道，使用奥拉替尼能完全缓解。尽管奥拉替尼治疗缺血性皮肤病的作用机制尚不明确，但据推测，它可能通过抑制I型干扰素而发挥疗效。在人医中，JAK抑制剂被注册用于治疗许多自身免疫性和免疫介导性疾病。最近发表的一篇文章报道了托法替尼，一种JAK3和JAK1抑制剂，对巨细胞动脉炎的疗效，巨细胞动脉炎是一种影响血管壁的慢性免疫介导性疾病。托法替尼能有效抑制病变的血管壁T细胞增殖及IFN-c、IL-17和IL-21的产生。
In conclusion, oclacitinib effectively resolved clinical signs of ETUD in 22 of 25 dogs within one to three months, and should be included among the therapeutic options for treatment of this condition once infectious diseases have been ruled out. 总之，在1 - 3个月内，奥拉替尼有效地解决了25只犬中22只的ETUD临床症状，一旦排除了感染性疾病，应将其纳入该疾病的治疗方案。
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发表于 2021-11-25 15:19:44
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感谢提醒，晚一些更改