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Successful treatment of perianal fistulas in two dogs with oclacitinib
奥拉替尼成功治疗2例犬肛周瘘
作者：Richard Harvey | Hollie Horton
翻译：王帆
Abstract
摘要
Perianal fistula (PAF) formation in dogs is a frustrating and painful disease, occurring primarily in German shepherd dogs. Ciclosporin has become the recommended treatment of choice yet may be associated with numerous adverse effects. This case report describes the successful treatment of two cases of PAF with oclacitinib.
犬肛周瘘(PAF)是一种令人沮丧和疼痛的疾病，主要发生在德国牧羊犬上。环孢素已成为推荐的治疗选择，但可能有许多副作用。本病例报告描述了用奥拉替尼成功治疗两例PAF。
KEYWORDS
关键词
dog, fistula, oclacitinib, perianal
犬，瘘道，奥拉替尼，肛周
INTRODUCTION
介绍
Perianal fistula (PAF) is a chronic, often progressive, idiopathic condition most commonly seen in middle-aged German shepherd dogs.The most frequent clinical signs are dyschezia associated with ulcers and sinus tracts around the anus. Pain and haemorrhage also may be noted. The disease affects the quality of life of both owner and pet.
肛周瘘(PAF)是一种慢性、常见渐进性、特发性疾病，最常见于中年德国牧羊犬。最常见的临床症状是排便困难伴有肛门周围溃疡和的瘘道。也可能伴有疼痛和出血。这种疾病会影响宠主和宠物的生活质量。
The histopathological features of the lesions are characterised by a predominantly mixed inflammatory infiltrate associated with periadnexal inflammation, furunculosis, hidradenitis and epithelium-lined sinus tracts.Immunopathological studies have demonstrated T-lymphocyte-mediated inflammation, a cytokine profile suggestive of an immune-mediated process, and reduction in interleukin (IL)-2 mRNA expression within lesional tissue after successful therapy with ciclosporin.
病变的组织病理学特征主要是混合炎症浸润，伴有附件周围炎症、疖病、汗腺炎和内衬上皮细胞的瘘道。免疫病理学研究已经证实了T淋巴细胞介导的炎症，一种提示免疫介导过程的细胞因子谱，以及环孢素治疗成功后病变组织中白细胞介素(IL)-2 mRNA表达的减少。
Notwithstanding a potentially immune-mediated aetiology, the disease is often refractory to treatment with prednisolone. Other treatments that have been reported, with variable responses, include metronidazole, azathioprine, mycophenolate mofetil, surgical excision of the lesions, cryotherapy, restricted diets and fluorescence light therapy. Human embryonic stem cell-derived mesenchymal stem cell treatment is being investigated as a potential therapy. Ciclosporin is currently regarded as the treatment of choice. However, its potential for a wide array of adverse effects warrants consideration of other immunomodulatory therapies, which may present fewer complications.
尽管该病可能有免疫介导的病因，但通常对泼尼松龙治疗无效。已有报道的其他治疗方法有不同的疗效，包括甲硝唑、硫唑嘌呤、吗替麦考酚酯、手术切除病变、冷冻疗法、限制饮食和荧光疗法。人们正在研究将人胚胎干细胞来源的间充质干细胞治疗作为一种潜在疗法。环孢素目前被认为是治疗首选。然而，其潜在的多种副作用值得考虑其他免疫调节疗法，这些疗法的并发症可能较少。
The successful use of oclacitinib in the management of perianal fistulas in two German shepherd dogs is reported herein.
本文报道使用奥拉替尼成功治疗两例德国牧羊犬肛周瘘。
CASE 1
病例1
An eight-year-old male German shepherd dog, weighing 46kg, was presented to this service for management of suspected PAF of 12months duration. Prior treatment with prednisolone (0.27mg/kg twice daily, per os) and a systemic antibacterial agent (cephalexin, 5.43mg/kg twice daily, p.o.) had been unsuccessful. The dog was found to be systemically healthy with lesions limited to the perianal skin. These consisted of a 1cm diameter sinus at the lower left aspect of the anus, and a small punctate sinus immediately dorsal to it. Rectal examination found a palpably normal rectum and normal anal sacs. Cytological findings from an impression smear made from discharge from the larger sinus included neutrophils and eosinophils, with a few cocci noted.
一只8岁雄性德国牧羊犬，体重46公斤，因疑似持续12个月的PAF就诊于本院。之前治疗使用泼尼松龙(0.27mg/kg，每日2次，口服)和全身性抗生素(头孢氨苄，5.43mg/kg，每日2次，p.o.)治疗无效。该犬全身健康，病变局限于肛周皮肤。这表现为肛门左下方有一个直径1cm的瘘道，以及紧靠它的背侧的一个小点状瘘道。直肠检查可见直肠正常，肛门囊正常。大的瘘道分泌物的压片细胞学检查结果包括中性粒细胞和嗜酸性粒细胞，伴有少量球菌。
Treatment with ciclosporin (Atopica; Elanco) at 4.3mg/kg twice daily p.o. was prescribed, along with topical application of 0.1% tacrolimus ointment (Protopic; Astellas Pharma US, Inc.) twice daily. After six weeks of therapy, the owner reported no change and the dose of ciclosporin was increased to 6.5mg/kg twice daily. At re-examination three weeks later, a third, large lesion was found. Ciclosporin was suspended and mycophenolate mofetil (TEVA BV) was prescribed at a dose of 10.86mg/kg twice daily. Within one month the dog was nearing remission and a gradual reduction of medication was attempted. However, deterioration was reported and treatment was reinstituted at 10.86mg/kg twice daily, with an improvement again reported. After a further two months at this dose, marked deteriorated was seen and cephalexin (Rilexine; Virbac) at a dose of 25mg/kg twice daily was added, in addition to topical 0.1% tacrolimus applied twice daily. There was no response and the dog was presented with dyschezia,pain and tenesmus upon defaecation, and was described by the owners as ‘miserable’.
治疗使用环孢素(阿托皮卡)，剂量为4.3mg/kg，每日2次，口服，同时外用0.1%他克莫司软膏，每天两次。治疗6周后，宠主反馈无变化，将环孢素剂量增加至6.5mg/kg，每日2次。3周后复查，发现出现第3个大病变。停用环孢素，给予吗替麦考酚酯，剂量为10.86mg/kg，每日2次。在一个月内，犬接近缓解，并尝试逐渐减少用药。然而，反馈有恶化，并重新开始治疗，10.86mg/kg，每日两次，再次反馈有改善。继续使用该剂量2个月后，出现恶化，联用头孢氨苄，剂量为25mg/kg，每日2次，此外，外用0.1%他克莫司，每日2次。无效，且患犬出现排便困难、疼痛和里急后重，主诉“痛苦不堪”。
At this stage, the dog exhibited marked perineal erythema and hyperpigmentation and there were three deep fistulae, with sinus tracts apparent, one on the right and two, connected in the dermis, on the left (Figure 1a). The perineum was wet from continued licking. Options for management were discussed including azathioprine and an increased dose of ciclosporin. However, a short course of oclacitinib (Apoquel; Zoetis), at a dose of 1.125mg/kg twice daily, was prescribed based on recent reports of its efficacy for other immune-mediated skin diseases. Within four days the owners reported a decrease in dyschezia and an improvement in demeanour. Treatment was continued and within fourweeks the sinuses were closing, the perineum was dry and nonerythematous, and dyschezia had resolved. Haematological analysis revealed a complete blood count within normal reference ranges. After 12weeks of treatment, the prior lesions had scarred and both erythema and hyperpigmentation had resolved (Figure 1b). After six months, PAF remained in remission and a complete blood count revealed normal values. Accordingly, the dose of oclacitinib was reduced to 1.4mg/kg once daily.
在这一阶段，患犬表现出明显的会阴部发红和色素沉着，有3个深瘘道，瘘道明显，右侧1个，左侧2个，真皮层中相连(图1a)。会阴部因为持续舔而变湿。讨论了治疗方案，包括硫唑嘌呤和增加环孢素剂量。然而，根据最近关于其对其他免疫介导性皮肤病的疗效的报告，选择短期使用奥拉替尼(爱波克)，剂量1.125mg/kg，每日2次。四天内，宠主反馈排便困难减轻，行为改善。继续治疗，4周内，瘘道闭合，会阴部干燥且无发红，排便困难缓解。血液学分析显示全血细胞计数在正常参考值范围内。12周治疗后，之前的病变有瘢痕，发红和色素沉着都已消退(图1b)。6个月后，PAF持续缓解，全血细胞计数正常。因此，奥拉替尼剂量降低至每日1次，每次1.4mg/kg。
CASE 2
病例2
A 5.5-year-old neutered female German shepherd dog, weighing 27kg, was referred to the soft-tissue surgery service with a five-week history of perineal licking, repeated crouching while defaecating, dyschezia and perianal lesions suspected to be a traumatic wound. Previous treatments with amoxicillin-clavulanic acid (Synulox; Zoetis) at 9.25mg/kg twice daily for two weeks had no effect. Perianal fistulation was suspected on the basis of history, examination and rectal examination. The case then was referred to the dermatology service.
一只5.5岁已绝育雌性德国牧羊犬，体重27kg，因持续5周的舔舐会阴、反复蹲着排便、排便困难和怀疑为创伤性肛周病变的病史，被转诊到软组织外科。用药史阿莫西林-克拉维酸(速诺) 9.25mg/kg，每日2次，连续2周无效。根据病史、检查及直肠检查，怀疑为肛周瘘。该病例随后被转诊至皮肤科。
At the examination, there were several fissures with sinus tracts around the anus, with a large fissure on the left, which extended around the ventral anus. There was erythema and hyperpigmentation, and the perineum was wet from continued licking (Figure 2a). Rectal examination was painful for the dog, and the anal sacs were palpably normal. Treatment options were discussed and oclacitinib was instituted at 0.88mg/kg twice daily.
检查时，肛门周围有多处开裂伴瘘道，左侧开裂较大，延伸至肛门腹侧。有发红和色素沉着，会阴因持续舔舐而湿润(图2a)。犬直肠检查疼痛，肛囊明显正常。讨论治疗方案，给予奥拉替尼0.88mg/kg剂量，每日2次。
At re-examination after three weeks, the fistulas had healed and perineal swelling had resolved. The owners reported that tenesmus was still noted, yet crouching to defaecate and licking of the perineum had ceased. Rectal examination was accepted by the dog and a thickened anal ring palpated. The anal sacs again were palpably normal. Haematological analysis revealed a complete blood count within normal reference ranges. The oclacitinib dose was reduced to 0.59mg/kg in the evening, while the morning dose was maintained at 0.88mg/kg; additional improvement was noted after sevenweeks on this regimen, at which time there was minimal evidence of licking or tenesmus. By 10weeks, the erythema and hyperpigmentation had resolved and the lesions remained in remission (Figure 2b). At the time of writing, the dog was receiving 0.59mg oclacitinib twice daily and the owner reported that the dog remained normal.
3周后复查，瘘道愈合，会阴肿胀消退。宠主反馈，里急后重的感觉仍存在，但蹲着排便和舔会阴部的行为已经停止。犬接受直肠检查，可触诊到肛环增厚。肛门囊再次可见正常。血液学分析显示全血细胞计数在正常参考值范围内。奥拉替尼晚上的剂量减至0.59mg/kg，早上剂量维持在0.88mg/kg。采用该方案治疗7周后观察到进一步改善，当时几乎没有舔舐或里急后重。到10周时，发红和色素沉着已消退，病变仍处于缓解状态(图2b)。撰写本文时，犬正在接受每日2次、每次0.59mg奥拉替尼治疗，宠主反馈患犬持续正常。
DISCUSSION
讨论
Oclacitinib is a first-generation Janus kinase (JAK)1 inhibitor approved for the treatment of canine atopic dermatitis (cAD). It has the potential to inhibit the activation of receptors for several cytokines involved in autoimmunity, such as IL-2, IL-15, interferon (IFN)-α and IFN-γ. At higher doses (equivalent to approximately 3–4mg/kg), oclacitinib has immunomodulatory effects on T-cell proliferation in addition to cytokines. It has been reported to be effective in a number of immunemediated dermatoses, such as hyperkeratotic erythema multiforme, cutaneous lupus erythematosus and pemphigus vulgaris.
奥拉替尼是第一代Janus激酶(JAK)1抑制剂，已被批准用于治疗犬特应性皮炎(cAD)。它具有抑制多种参与自身免疫的细胞因子受体活化的潜能，如IL-2、IL-15、干扰素(IFN)-α和IFN-γ。较高剂量(相当于约3 ~ 4mg/kg)时，奥拉替尼除了对细胞因子有免疫调节作用外，还对T细胞增殖有免疫调节作用。据报道，它对多种免疫介导皮肤病有效，如角化过度型多形红斑、皮肤红斑狼疮和寻常型天疱疮。
The exact mechanism of oclacitinib's effect on PAF is not known. Given its demonstrated immunosuppressive effects and prior observations that ciclosporin reduces IL-2 mRNA expression in PAF lesions, it could be hypothesised that oclacitinib mediates its positive effect by suppressing inflammatory mediators and lymphocyte function.
奥拉替尼对PAF作用的确切机制尚不清楚。鉴于其已证实的免疫抑制作用和先前观察到的环孢素降低PAF病变中IL-2 mRNA的表达，可以假设奥拉替尼通过抑制炎症介质和淋巴细胞功能介导其积极作用。
Based on the cases described here and positive outcomes reported for use of oclacitinib at twice the label dose for long-term management of cAD, this drug might be expected to produce fewer adverse effects than ciclosporin or azathioprine when used for management of PAF. However, additional studies will be needed to confirm the responses reported here, to determine the ideal induction dose regime for PAF, and to assess whether long-term control is possible at lower doses. Furthermore, if oclacitinib is to be used for longterm management of immune-mediated skin diseases at doses higher than those reported in previous clinical trials, studies also should focus on adverse event reporting and recommendations for laboratory monitoring.
根据本文描述的病例和使用2倍标签剂量的奥拉替尼长期治疗cAD的有效结果，预期该药物用于治疗PAF时产生的副作用可能比环孢素或硫唑嘌呤少。然而，我们需要开展更多研究来证实本文报告的缓解情况，确定PAF的理想诱导剂量方案，并评估是否有可能在较低剂量下实现长期控制。此外，如果奥拉替尼要以高于既往临床试验报告的剂量长期治疗免疫介导皮肤病，研究还应关注副作用报告和实验室监测建议。
In summary, this report describes the successful management of PAF in two dogs. The cases demonstrate a rapid and sustained response, albeit to a higher dose than that labelled for the treatment of cAD.
总之，本报告描述了两只犬PAF的成功治疗。这些病例显示出快速和持续的效果，但剂量高于治疗cAD的剂量。
FIGURE 1 German shepherd dog. Case 1. (a) Before oclacitinib therapy, there are severe perianal lesions consistent with fistula formation; perineal erythema, hyperpigmentation and three deep sinuses are visible. (b) After 12weeks of oclacitinib therapy, the erythema and hyperpigmentation have resolved, and there are no sinus lesions remaining.
图1德国牧羊犬。病例1。(a)在奥拉替尼治疗前，肛周病变严重持续伴有瘘道;会阴发红、色素沉着、三个可见的深瘘道。(b)经奥拉替尼治疗12周后，发红和色素沉着消失，无瘘道病变。
FIGURE 2 German shepherd dog. Case 2. (a) Before oclacitinib therapy, there is erythema, sinus formation and purulent discharge, and the surrounding area is wet from persistent licking. (b) After 10weeks of oclacitinib therapy, the erythema and hyperpigmentation have resolved, and there are no sinus lesions remaining.
图2德国牧羊犬。病例2。(a)奥拉替尼治疗前，有发红、瘘道和脓性分泌物，周围因持续舔舐而潮湿。(b)奥拉替尼治疗10周后，发红、色素沉着消失，无瘘道病变。
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发表于 2023-6-2 14:23:21
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