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犬肛周瘘 临床表现、发病机制和治疗方法 Canine Perianal Fistulas Clinical Presentation, Pathogenesis, and Management
作者：Christine L. Cain, DVM
译者：王帆（巴哥控）
关键词 •犬科 •肛周瘘 •肛门疖病 •德国牧羊犬 •免疫介导 •环孢素A 重点 •犬肛周瘘是一种疼痛的溃疡或窦道病变，会自发性发生在肛门周围的皮肤上，会使患犬变得虚弱。 •中年德国牧羊犬最常患病，可能有遗传易感性，但其他纯种和混血犬也会出现肛周瘘。 •虽然解剖结构曾被认为是其发展诱因，但现在已经认识到免疫介导的发病机制。 •多年来，对犬肛周瘘的规范治疗方案已从手术治疗转变为长期药物管理。 •免疫调节药，特别是使用环孢素A，联用或不联用酮康唑，是治疗犬肛周瘘最常用的药物。 KEYWORDS •Canine •Perianal fistula •Anal furunculosis •German shepherd dog •Immune-mediated •Cyclosporin A KEY POINTS •Canine perianal fistulas are painful ulcers or sinus tracts that spontaneously occur in the skin around the anus and can be debilitating for affected dogs. •Middle-aged German shepherd dogs are most commonly affected and may have a genetic susceptibility, but other purebred and mixed-breed dogs also develop perianal fistulas. •Although anatomic factors were once believed to contribute to development, an immunemediated pathogenesis is now recognized. •Over the years, there has been a paradigm shift from surgical management to long-term medical management of canine perianal fistulas. •Immunomodulatory medications, in particular cyclosporin A with or without ketoconazole, are most commonly used for management of canine perianal fistulas. 介绍 INTRODUCTION 肛周瘘，也称为肛门疖病，是肛门周围皮肤自发性产生的疼痛的窦道或溃疡灶(图1)。德国牧羊犬易患肛周瘘，但其他纯种和混血犬也会发病。虽然肛周瘘的发生曾被认为与解剖结构有关，但目前认为这种病是免疫介导性疾病，尽管其发病机制尚未完全阐明。同样，虽然外科手术干预和纠正解剖结构因素曾经是治疗的主要内容，但目前治疗标准是使用药物管理犬肛周瘘。此病会使患犬变得虚弱，并且如果治疗无效，可能导致安乐死。快速准确的诊断和积极的药物治疗是成功治疗犬肛周瘘的关键。本文就肛周瘘的临床表现、发病机制、药物管理等方面的最新研究进展作一综述。 Perianal fistulas, also known as anal furunculosis, are painful sinus tracts or ulcers that spontaneously occur in the skin around the anus (Fig. 1). German shepherd dogs are predisposed to developing perianal fistulas, but other purebred and mixed-breed dogs also are affected. Although development of perianal fistulas was once believed related to anatomic conformation, the condition is now recognized as immune mediated, although the pathogenesis has not been fully delineated. Likewise, although surgical intervention and correction of anatomic factors were once the mainstays of therapy, medical management is the current standard of care for dogs with perianal fistulas. This condition can be debilitating for affected dogs and can result in euthanasia if not effectively managed. Rapid and accurate diagnosis and aggressive medical therapy are key to successful management of canine perianal fistulas. This article reviews current knowledge regarding the clinical presentation, pathogenesis, and medical management of perianal fistulas. 图1。一只7岁德国牧羊犬肛门周围有多个窦道。 Fig. 1. Multiple sinus tracts around the anus in a 7-year-old intact male German shepherd dog. 临床表现 CLINICAL PRESENTATION 肛周瘘患犬可能会在肛门周围的皮肤上出现一个或多个窦道性溃疡灶。一些病例中，溃疡可能又大又深或似火山口状。尽管肛周瘘一词在兽医医学文献中被广泛使用，但皮肤窦道通常不与直肠相通(如患有瘘道型克罗恩病的人)。由于病变部位和检查的不适感，犬主人可能发现不到病变,但可能会因为出现一些临床症状,如舔舐肛门、里急后重、便血或黏脓性分泌物(图2)，而带犬来就诊。肛周瘘和结肠炎之间的相关性已被证实,并且一些患犬也可能有软便或黏液样便、腹泻、排便次数增加的病史。 Dogs with perianal fistulas may present with a singleor multiple sinus tractsor ulcers in the skin around the anus. In some cases, ulcers may be large and deep or crateriform. Despite widespread use of the term, perianal fistula, in the veterinary medical literature, the cutaneous sinus tracts do not generally communicate with the rectal lumen (as is the case for humans with fistulizing Crohn’s disease). Due to the location and discomfort on examination, dog owners may not be aware of the lesions but may present their dog to the veterinarian due to associated clinical signs, such as licking around the anus, tenesmus, hematochezia, or mucopurulent discharge (Fig. 2). An association between perianal fistulas and colitis has been demonstrated, and some affected dogs also may have a history of soft or mucoid stools, diarrhea, and increased frequency of defecation.
图2。一只8岁德国牧羊犬肛周溃疡合并粘液脓性渗出物。这只犬也表现出严重的肌肉痉挛。 Fig. 2. Perianal ulcer with mucopurulent exudate in an 8-year-old intact male German shepherd dog. This dog also presented with severe tenesmus. 德国牧羊犬是最常见的患病犬种(据报道占病例总数的80%以上)，但一些其他品种，包括比格犬、边境牧羊犬、澳大利亚牧羊犬、爱尔兰长毛猎犬、切萨皮克海湾寻回犬、兰伯格犬、斯塔福斗牛㹴和混血犬中，也有患肛周瘘的报道。作者也诊断过一只美国斯塔福㹴(图3)、一只布列塔尼猎犬、一只软毛小麦㹴和混血犬种的肛周瘘。 German shepherd dogs are most commonly affected (reported to comprise more than 80% of the patient population4), but several other breeds, including the beagle, border collie, Australian shepherd, Irish setter, Chesapeake Bay retriever, Leonberger, Staffordshire bull terrier, and mixed-breed dogs, have also been reported to develop perianal fistulas. The author has also diagnosed perianal fistulas in an American Staffordshire terrier (Fig. 3), a Brittany spaniel, a soft-coated wheaten terrier, and mixed-breed dogs.
图3。6岁已去势的美国斯塔福㹴犬出现肛门周围溃疡和窦道。这只犬也有慢性腹泻和炎症性肠病(结肠炎和直肠炎)的病史，已经内窥镜活检确诊。 Fig. 3. Multiple perianal ulcers and sinus tracts in 6-year-old castrated male American Staffordshire terrier dog. This dog also had a history of chronic diarrhea and inflammatory bowel disease (colitis and proctitis) confirmed via endoscopic biopsies. 肛周瘘是典型的成年发病。虽然发病年龄从青年到老年差异很大，但是中年犬最常发病。虽然认为未去势雄性德国牧羊犬比去势雄犬患病风险更高，但尚未证明有性别倾向性。 Perianal fistulas are typically adult onset. The age of onset can vary widely, from young adult to geriatric, although middle-aged dogs are most commonly affected. A definitive gender predisposition has not been demonstrated, although an increased risk in intact male German shepherd dogs compared with neutered male German shepherd dogs has been suggested. 诊断 DIAGNOSIS 肛周瘘有典型病变表现，而且在大多数情况下，仅凭临床表现就能诊断出来，特别是在德国牧羊犬身上。溃疡性肛周肿瘤(肛周腺瘤或肛周腺癌)和皮肤粘膜红斑狼疮(MCLE)是主要的鉴别诊断，但也应考虑其他导致肛周窦道的疾病。例如，肛门囊切除术后遗留的腺体组织可导致慢性肛周窦道，可被误诊为肛周瘘。德国牧羊犬也易患MCLE，在这种情况下也常见肛门或肛周病变。肛周瘘与MCLE通常在临床表现上有区别。肛周瘘是典型的界限分明的窦道或似火山口状溃疡，而MCLE更多与混合性糜烂、溃疡、红斑和结痂有关。有关犬MCLE更多信息，详见弗兰·巴诺维克的同本杂志文章《犬类皮肤红斑狼疮变异型新发现》。 Perianal fistulas are visually distinct and, in most cases, are diagnosed based on clinical presentation alone, especially in a German shepherd dog. An ulcerated perianal neoplasm (perianal adenoma or adenocarcinoma) and mucocutaneous lupus erythematosus (MCLE) are the primary rule-outs, but other conditions resulting in perianal draining tracts also should be considered. For example, glandular tissue left behind after an anal sacculectomy can result in chronic perianal draining tracts that can be misdiagnosed as perianal fistulas. German shepherd dogs are also predisposed to MCLE, and anal or perianal lesions are common in this condition. Perianal fistulas generally are clinically differentiated from MCLE. Perianal fistulas are typically sharply demarcated sinus tracts or crateriform ulcers, whereas MCLE is associated with more confluent erosions, ulcers, erythema, and crusts. For more information about canine MCLE, see Frane Banovic’s article, “Canine Cutaneous Lupus Erythematosus Newly Discovered Variants,” in this issue. 确诊犬肛周瘘时很少进行组织病理学检查，但可以考虑用于临床表现不常见的病例，或用于不常见的患病品种(如小体型犬种)。在克罗恩病引起的人肛周瘘患者中，可能转化为恶性，并且虽然在犬肛周瘘病例中没有记录，但这可能是慢性疾病病例首选组织病理学检查的一个原因。 Histopathology is rarely performed for diagnosis of canine perianal fistulas but can be considered in cases of unusual clinical presentation or in an uncommonly affected breed (such as a small breed dog). In humans with perianal fistulas due to Crohn’s disease, malignant transformation can occur and, although not well documented in dogs with perianal fistulas, could be a reason to prioritize histopathology in patients with chronic disease. 犬肛周瘘的组织病理学特征包括伴有或不伴有疖病的附件周围炎症、明显的汗腺炎、附件周围纤维化、溃疡以及真皮内形成上皮样排列的窦道。可在窦道内发现由中性粒细胞、淋巴细胞、浆细胞和巨噬细胞组成的炎症浸润。深部病变也可能与化脓性肉芽肿性蜂窝组织炎和淋巴样毛囊有关。如果临床很难区分肛周瘘和MCLE，皮肤活检进行组织病理学检查可能会有帮助。MCLE以富含淋巴细胞的界面性皮炎为特征，出现明显的基底细胞损伤。肛周瘘患犬的结肠组织活检能证明组织病理学上发生结肠炎。一项研究发现，18只肛周瘘患犬中有9只诊断为结肠炎的犬，组织病理学改变与结肠炎一致。 Histopathologic features of canine perianal fistulas include periadnexal inflammation with or without furunculosis, pronounced hidradenitis, periadnexal fibrosis, ulceration, and formation of epithelial-lined sinus tracts within the dermis. Inflammatory infiltrates, composed of neutrophils, lymphocytes, plasma cells, and macrophages, may be noted within sinus tracts.4 Deeper lesions also may be associated with pyogranulomatous cellulitis and lymphoid follicles. If clinical differentiation of perianal fistulas from MCLE is difficult, skin biopsies for histopathology may be helpful. MCLE is characterized by a lymphocyte-rich interface dermatitis with evidence of basal cell damage. Colonic biopsies from dogs with perianal fistulas may demonstrate histopathologic evidence of colitis; 1 study found histopathologic changes consistent with a diagnosis of colitis in 9 of 18 dogs with perianal fistulas. 除了对肛周皮肤的详细检查外，对怀疑有肛周瘘的犬的体格检查还应包括直肠检查。要进行这项检查可能需要镇静，这取决于患犬舒适度。对所有患犬应评估肛门狭窄程度，仔细触诊肛门囊，并观察肛门囊的表现。肛周瘘患犬可能出现的异常肛门囊，包括嵌塞、很难观察到或发生破裂，并且通常在肛门囊导管周围继发炎症反应和纤维化。作者曾在同一病例(一只中年德国牧羊犬)中遇到肛周瘘伴有肛门囊顶泌腺腺癌。这个病例表现为轻度增大、坚实、无法观察到的肛门囊，虽然肛周瘘经过药物治疗已经得到解决，但其肛门囊变化并不明显。 In addition to close examination of the perianal skin, the physical examination for dogs suspected of having perianal fistulas should include a rectal examination. Sedation may be required to accomplish this and is dependent on patient comfort level. All patients should be assessed for anal strictures, the anal sacs should be carefully palpated, and expression of the anal sacs should be attempted. Abnormalities of the anal sacs, including impaction, difficult expression, or rupture, may occur in patients with perianal fistulas and are usually secondary to inflammation and fibrosis in the region of the anal sac ducts. The author has encountered perianal fistulas and a concurrent apocrine gland adenocarcinoma of the anal sac in the same patient (a middle-aged German shepherd dog). This patient presented with a mildly enlarged, firm, and nonexpressible anal sac that did not markedly change despite resolution of the perianal fistulas with medical therapy. 发病机制 PATHOGENESIS 德国牧羊犬肛周瘘的发病倾向最初被认为与解剖结构有关。据推测，一些结构特征有助于肛周瘘的形成，包括夹尾巴行为促进粪便潴留和肛周顶浆汗腺密度增加。夹尾巴行为被认为会产生一个温暖、潮湿的环境，导致慢性炎症和肛周腺和肛门腺的粪便菌群继发感染。没有夹尾巴行为的其他患肛周瘘的犬种，以及对抗菌药物单一治疗缺乏临床效果，使研究人员对这一解剖结构理论提出了质疑。 The predisposition to development of perianal fistulas in German shepherd dogs was initially believed related to anatomic conformation. Several conformational features were speculated to contribute to the development of perianal fistulas, including low tail carriage encouraging fecal retention and an increased density of perianal apocrine sweat glands. The low tail carriage was believed to produce a warm, humid environment, leading to chronic inflammation and secondary infection of perianal and anal glands with fecal flora. The occurrence of perianal fistulas in other dog breeds without low tail carriage, as well as the lack of a clinical response to antimicrobial therapy alone, led investigators to question this anatomic conformation theory. 逐渐地，浮现出犬肛周瘘发病机制是免疫介导性的可能。一项犬肛周瘘免疫学情况的早期研究调查，证明33只犬中有9只在植酸原刺激下淋巴细胞增殖反应迟钝。病变消退后，9只犬中有4只淋巴细胞增殖反应恢复正常。基于这一结果，研究人员认为淋巴细胞增殖反应的抑制可能是继发于肛周瘘的后天异常。最近的研究表明，肛周瘘很可能是由局部T细胞介导的炎症反应引起的。这一观点得到了研究的支持，研究表明，与对照组相比，肛周瘘患犬病变皮肤的血管周围有CD3+T淋巴细胞聚集，以及相关T细胞的表达增加，特别是与1型T辅助细胞相关的细胞因子mRNA表达增加。已证实在环孢素A治疗后，皮肤病变中的白细胞介素(IL)-2表达也有所下降。1型T辅助细胞对巨噬细胞的异常活化，也被认为在肛周瘘中起着重要作用。一项研究发现，与对照组相比，肛周瘘患犬的皮肤病变中基质金属蛋白酶(MMP)-9和MMP-13 mRNA表达增加。MMP -9和MMP13由活化的巨噬细胞产生，并且参与伤口愈合的早期阶段，主要通过下调细胞外基质。本研究的研究人员提出，损伤的伤口愈合，特别是不能在伤口早期修复，可能在顽固性溃疡和窦道中发挥作用。同样，MMP的上调可能在人的窦道性克罗恩病的发病机制中起重要作用，该病被认为与犬肛周瘘有关。 Gradually, a probable immune-mediated pathogenesis for canine perianal fistulas emerged. An early study investigating the immunologic status of dogs with perianal fistulas demonstrated a blunted lymphocyte proliferation response following stimulation with phytomitogens in 9 of 33 dogs with active disease. After lesion resolution, the lymphocyte proliferation response normalized in 4 of 9 dogs. Based on this result, the investigators suggested that the suppression of the lymphocyte proliferation response may be an acquired abnormality secondary to perianal fistulas. More recent work has demonstrated that perianal fistulas likely develop as a consequence of local T-cell–mediated inflammation. This is supported by studies demonstrating perivascular aggregates of CD3+ T lymphocytes within lesional skin of dogs with perianal fistulas as well as increased expression of T-cell–associated, in particular type 1 helper T-cell– associated cytokine mRNA in lesional skin of affected dogs compared with controls. A decrease in expression of interleukin (IL)-2 in lesional skin after cyclosporin A therapy has also been demonstrated. Abnormal macrophage activation by type 1 helper T cells has also been suggested to play a role in the development of perianal fistulas. One study found increased expression of matrix metalloproteinase(MMP)-9 and MMP-13 mRNA in lesional skin from dogs with perianal fistulas compared with controls. MMP-9 and MMP13 are produced by activated macrophages and are involved in the early stages of wound healing, primarily by degradation of the extracellular matrix. The investigators of this study proposed that impaired wound healing, in particular failure to initiate wound repair, may play a role in the persistence of ulcers and sinus tracts. Similarly, upregulation of MMPs may play a role in the pathogenesis of human fistulizing Crohn’s disease, which is proposed to be a correlate of canine perianal fistulas. 对肛门和肛周微生物的免疫应答功能失调也被认为是犬肛周瘘的发病机制之一。1988年进行的一项基于培养的研究显示，在手术切除瘘道时采集的组织样本中，最常被分离的是大肠杆菌、葡萄球菌、β溶血性链球菌和变形链球菌。研究人员得出结论，分离菌可能代表污染物，并且该微生物感染在肛周瘘发病过程中并不起主要作用。在2008年，House及其同事们研究了几种体外mRNA表达及功能的模式识别受体，这些受体均来自于肛周瘘患犬的血液中的单核/巨噬细胞。他们发现，与对照组相比，经微生物病原体相关分子模式刺激后，来自于肛周瘘患犬的巨噬细胞/单核细胞，NOD2模式识别受体的反应降低。这一结果提示犬肛周瘘可能存在先天免疫缺陷。与正常犬相比，肛周瘘患犬抗葡萄球菌IgG水平升高，并且有研究表明，肛周瘘患犬T细胞介导的皮肤粪便微生物抗原的反应失调。 A dysfunctional immune response to microbes in the anal and perianal regions also has been proposed to contribute to the pathogenesis of canine perianal fistulas. One culturebased study performed in 1988 from tissue samples collected at the time of surgical fistula excision showed that Escherichia coli, Staphylococcus sp, β-hemolytic streptococci, and Proteus mirabilis were isolated most frequently. The investigators concluded that the bacterial isolates likely represented contaminants and that microbial infection did not play a primary role in the development of perianal fistulas. In 2008, House and colleagues investigated mRNA expression and function of several pattern recognition receptors in vitro using monocyte/macrophages derived from the blood of dogs with perianal fistulas. They found evidence of a decreased response in the NOD2 pattern recognition receptor of macrophage/monocytes derived from dogs with perianal fistulas after stimulation with microbial pathogen-associated molecular patterns compared with controls. This result suggests a possible innate immunodeficiency in dogs with perianal fistulas. Dogs with perianal fistulas were also shown to have increased antistaphylococcal IgG compared with normal dogs and a dysregulated T-cell–mediated response to cutaneousor fecal microbial antigens in dogs with perianal fistulas has been proposed. 因为这些研究的提出，在1990年代末和2000年代初,医学界已越来越关注微生物种群特征(微生物群)，通过非培养方法和微生物种群的变化之间的复杂的相互作用和促进疾病。皮肤和/或肠道微生物群的变化被认为有助于化脓性汗腺炎的发生(在人医也有与犬肛周瘘相关的提出)，尽管还没有很好地建立这种联系。肠道菌群失调已被很好地描述与人医炎症性肠病有关，并且通过粪便移植操纵肠道菌群可能在改善人克罗恩病和溃疡性结肠炎的临床症状方面有效。探索皮肤和肠道微生物种群可能在犬肛周瘘方面发挥作用,作者和他的同事们已经完成了一个德国牧羊犬肛周瘘的皮肤和直肠微生物的纵向评估,之前和在接受免疫调节治疗环孢素A和酮康唑(这项研究由宾夕法尼亚州费城佩恩兽医中心的一项内部拨款资助)。临床表现正常的德国牧羊犬作为对照组;目前正在进行数据分析。 Since these studies were performed in the late 1990s and early 2000s, there has been an increasing focus in the medical community on characterization of microbial populations (the microbiome) via non–culture-based methods and on the complex interplay between shifts in microbial populations and the promotion of disease. Shifts in the cutaneous and/or intestinal microbiome have been proposed to contribute to the development of hidradenitis suppurativa (also proposed as a human correlate of canine perianal fistulas), although this link has not been well established. Intestinal dysbiosis has been well described in association with inflammatory bowel disease in humans, and manipulation of the intestinal microbial flora via fecal transplantation may be effective at ameliorating the clinical signs of Crohn’s disease and ulcerative colitis in humans. To explore the role that cutaneous and intestinal microbial populations may play in canine perianal fistulas, the author and colleagues have completed a longitudinal evaluation of the cutaneous and rectal microbiome in German shepherd dogs with perianal fistulas, both prior to and while receiving immunomodulatory therapy with cyclosporin A and ketoconazole (the study was funded by an internal grant from the Penn Vet Center for Host-Microbial Interactions, Philadelphia, Pennsylvania). Clinically normal German shepherd dogs were sampled as a control population; data analysis currently is in progress. 据报道，一些肛周瘘患犬有食物副反应。一项关于有皮肤病变患犬的食物副反应研究报道了肛周瘘和食物副反应之间的显著关系，但是只研究了4只肛周瘘患犬，而且都是德国牧羊犬。三项研究报告了一种新奇蛋白日粮在肛周瘘患犬中的临床疗效，在一项研究中，在手术切除窦道和双侧肛门囊后，长期饲喂鱼和土豆日粮。在第二项研究中，只给犬饲喂鹿肉和土豆或鱼和土豆日粮，但同时也开始服用甲硝唑，外用0.1%他克莫司软膏和口服泼尼松，疗程为16周。在第三项研究中，给犬饲喂商品化的羊肉和米饭或素食，但同时也给犬口服泼尼松，初始剂量为免疫抑制剂量，随后疗程逐渐减量。尽管作者经常推荐使用新奇蛋白或水解蛋白处方日粮进行食物排除试验，作为诊断肛周瘘患犬的一部分，但从现有文献中尚不清楚，仅通过控制饮食，有多少病例能达到长期的疾病缓解。 An adverse food reaction has been reported for some dogs with perianal fistulas. One study of adverse food reactions in dogs with dermatologic signs reported a significant association between perianal fistulas and adverse food reaction, but only 4 dogs with perianal fistulas were included and all were German shepherd dogs. Three studies reported a positive clinical response to a novel protein diet in dogs with perianal fistulas; in 1 study,a fish and potato diet was fed longterm after surgical excision of sinustracts and bilateral anal sacculectomy. In the second study, dogs were fed an exclusive venison and potato or fish and potato diet but also received metronidazole initially as well as topical tacrolimus 0.1% ointment and a tapering course of oral prednisone for 16 weeks. In the third study, dogs were fed a commercially available lamb and rice or vegetarian diet but concurrently received a tapering course of oral prednisone at an initial immunosuppressive dose. Although the author regularly recommends an elimination diet trial using a prescription novel protein or hydrolyzed protein diet as part of the diagnostic work-up for dogs with perianal fistulas, it is unclear from the available literature how many dogs may achieve long-term disease remission with dietary control alone. 遗传因素 GENETIC BASIS 德国牧羊犬品种与肛周瘘的紧密联系表明其遗传易感性。一些研究探索了德国牧羊犬患病的潜在遗传风险因素。在英国和芬兰的德国牧羊犬种群中发现，II型MHC等位基因DLA-DRB1*00101与肛周瘘风险增加之间存在联系。有纯合DLA-DRB1*00101等位基因的犬可能在年轻时(小于8岁)发生肛周瘘。主要组织相容复合体(MHC) II型分子参与抗原呈递和T细胞活化。因此，与MHC等位基因的关联进一步支持这种疾病的T细胞介导的发病机制。全基因组关联研究了21只患病德国牧羊犬和25只未患病德国牧羊犬,随后对英国和芬兰的患病和未患病德国牧羊犬的相关潜在单核苷酸多态性基因分型，发现可能与ADAMTS16 和CTNND2基因区域相关。CTNND2基因区域也与人的克罗恩病和溃疡性结肠炎有关，提示人炎性肠病和犬肛周瘘的潜在共同发病机制。另一项研究调查了德国牧羊犬肛周瘘几种模式识别受体的编码基因。该研究未能识别任何与肛周瘘相关的模式识别受体单核苷酸多态性编码基因，但与其他犬种相比，德国牧羊犬(患病的和未患病的)呈现限制性模式识别受体基因型。德国牧羊犬的限制性模式识别受体基因型可能影响该品种的先天免疫功能。 The strong association of perianal fistulas with the German shepherd breed suggests a genetic susceptibility. A few studies have explored potential genetic risk factors for the disease in German shepherd dogs. An association between the class II MHC allele DLA-DRB1*00101 and increased risk of development of perianal fistulas has been found in populations of German shepherd dogs from the United Kingdom and Finland. Dogs homozygous for the DLA-DRB1*00101 allele may develop perianal fistulas earlier in life (at <8 years of age). Class II molecules of the major histocompatibility complex (MHC) are involved in antigen presentation and T-cell activation; thus, an association with an MHC allele further supports a T-cell–mediated pathogenesis for this disease. A genome-wide association study of 21 affected German shepherd dogs and 25 unaffected German shepherd dogs, followed by genotyping of potentially associated single nucleotide polymorphisms in cohorts of affected and unaffected German shepherd dogs in the United Kingdom and Finland, found a potential association with the ADAMTS16 and CTNND2 gene regions. The CTNND2 gene region also has been associated with human Crohn’s disease and ulcerative colitis, suggesting a potential shared pathogenesis for human inflammatory bowel disease and canine perianal fistulas. Another study investigated genes encoding for several pattern recognition receptors in German shepherd dogs with perianal fistulas. This study failed to identify any single nucleotide polymorphisms in genes encoding for pattern recognition receptors associated with perianal fistulas but did show restricted pattern recognition receptor genotypes in German shepherd dogs (both affected and unaffected) versus other dog breeds. The restricted pattern recognition receptor genotypes in German shepherd dogs may influence innate immune function in this breed. 人医相关性 HUMAN CORRELATES 提出人医的两种疾病，化脓性汗腺炎和瘘道型克罗恩病,与犬肛周瘘的相关性。像犬肛周瘘一样，患这两种疾病都会疼痛和虚弱，会降低患者生活质量。治疗这两种疾病都很有挑战性:目前还没有发现普遍有效的治疗方法，并且经常复发。 Two human conditions, hidradenitis suppurativa and fistulizing Crohn’s disease, have been proposed as correlates of canine perianal fistulas. Like perianal fistulas in dogs, both of these conditions are painful and debilitating and can have a negative impact on quality of life of patients. Management of both of these conditions is challenging: no universally effective therapy has been identified and relapses are common. 化脓性汗腺炎主要在皱褶皮肤处(腋窝、腹股沟、肛周和乳房处) 出现结节、脓肿、窦道、疤痕。化脓性汗腺炎最初被认为与犬肛周瘘有潜在相关性，因为组织病理学特征相似，包括疖病、汗腺炎和形成上皮排列的窦道。化脓性汗腺炎的发病机制尚未完全阐明，但可能是一种具有遗传易感性的免疫性疾病。皮肤或肠道微生物群的改变可能在发病机制中起作用。危险因素包括肥胖、吸烟、代谢性综合征、激素影响和糖尿病，与炎性肠病也有关联。化脓性汗腺炎的药物管理包括使用局部或全身使用抗菌素(抗炎和/或免疫特性调节的潜在帮助比直接针对微生物更大)、维A酸、全身或局部使用皮质类固醇、细胞因子定向治疗(肿瘤坏死因子抑制剂[TNF]或IL-1)。 Hidradenitis suppurativa is associated with nodules, abscesses, sinus tracts, and scarring, primarily in intertriginous regions (axilla, groin, perianal region, and mammary region).Hidradenitis suppurativa was initially proposed as a potential correlate of canine perianal fistulas because of similar histopathologic features, including furunculosis, hidradenitis, and formation of epithelial-lined sinus tracts. The pathogenesis of hidradenitis suppurativa has not been fully elucidated, but it is likely an immunemediated condition with a genetic susceptibility. Alterations in cutaneous or intestinal microbiota may play a role in the pathogenesis. Risk factors include obesity, smoking, metabolic syndrome, hormonal influences, and diabetes mellitus; an association with inflammatory bowel disease has also been suggested. Medical management of hidradenitis suppurativa involves use of topical or systemic antimicrobials (potentially helpful for anti-inflammatory and/or immunomodulatory properties more so than direct targeting of microbes), retinoids, systemic or intralesional corticosteroids, and cytokine-directed therapies (inhibitors of tumor necrosis factor [TNF] or IL-1). 克罗恩病常见肛周临床表现，预计有25%至33%的克罗恩病患者发病。结肠或直肠疾病患者发生肛周瘘更为常见，瘘道表现可能是单一的(有一个外开口的单一瘘道)或复杂的(多个瘘道、肛周脓肿或肛门/直肠狭窄)。与犬的典型疾病不同，这些是真正的瘘道，与肠腔相通。克罗恩病肛周瘘的发病机制尚不完全清楚，但已证明是涉及上皮向间质转化，以及MMPs和促炎细胞因子的上调。遗传易感性，以及皮肤和/或肠道菌群的改变，可能在人类肛周瘘的发生中发挥作用。与犬肛周瘘一样，克罗恩病的治疗方法也发生了转变，从主要的外科治疗转向了联合药物治疗。成功治疗克罗恩病通常需要多种外科和药物治疗方法。迄今为止，最有效的药物治疗方法是细胞因子定向治疗(TNF或IL-12/IL-23抑制剂)、间质干细胞注射和辅助抗菌剂(但是单独使用抗菌剂不能有效解决瘘道)。 Perianal manifestations of Crohn’s disease are common, estimated to affect 25% to 33% of Crohn’s disease patients. Perianal fistulas are more common in patients with colonic or rectal disease and may be simple (a fistulous tract with a single external opening) or complex (multiple fistulous tracts, perianal abscesses, or anal/rectal stricture). Unlike the typical disease in dogs, these are true fistulas that communicate with the intestinal lumen. The pathogenesis of perianal fistulas in Crohn’s disease is not fully understood but has been shown to involve epithelial-to-mesenchymal transition and up-regulation of MMPs and proinflammatory cytokines. Genetic susceptibility, as well as alterations in the cutaneous and/or intestinal microbiota, may play a role in development of perianal fistulas in humans. Like canine perianal fistulas, there has been a shift in management of fistulizing Crohn’s disease from primarily surgical intervention to incorporation of medical therapies. Successful management of fistulizing Crohn’s disease usually necessitates multimodal surgical and medical approaches. To date, the most efficacious medical therapies are cytokine-directed therapies (inhibitors of TNF or IL-12/IL-23), intrafistula mesenchymal stem cell injections, and adjunctive antimicrobials (although antimicrobials alone are not effective for resolution of fistulas). 化脓性汗腺炎和瘘道型克罗恩病与犬肛周瘘的临床特征相同。已证明化脓性汗腺炎和克罗恩病的发病机制有相似之处，尤其在病变组织中过滤出的T辅助细胞-17。未来的研究应该重点在于更好地描述这3种疾病的潜在病因上，并可能有助于指导未来治疗方法的发展，比如针对特定细胞因子的抗体，用于治疗犬肛周瘘。 Both hidradenitis suppurativa and fistulizing Crohn’s disease share clinical features with canine perianal fistulas. Similarities in the pathogenesis of hidradenitis suppurativa and Crohn’s disease have been demonstrated,in particular in filtration of diseased tissue by type 17 T helper cells. Future studies should focuson better characterization of the underlying etiology of these 3 conditions and may help direct the development of future therapies, such as antibodies targeting specific cytokines, for perianal fistulas in dogs. 手术治疗 SURGICAL MANAGEMENT 对犬肛周瘘手术治疗的全面回顾超出了本文的讨论范围。随着越来越多的人认识到免疫介导疾病发病机制，相应的护理标准也从外科治疗转向药物管理。已经描述了几种外科手术方法，包括整体手术切除(通常与双侧肛门囊切除术一起进行)，然后进行外科重建、激光切除、冷冻外科手术和尾根部切除术。有一项研究报道，通过手术切除残存窦道、双侧肛门囊切除术和囊切除术，随后采用免疫调节疗法结合泼尼松和咪唑硫嘌呤或环孢素A联合或不联合酮康唑,能很好的控制肛周瘘。另一项研究报告，33只犬中有29只在进行肛周瘘切除术、双侧肛门囊切除术以及日粮改为鱼和土豆后，治疗全部有效(看不到窦道或溃疡)。这29只犬中有6只继续表现出临床症状，如舔舐肛周、里急后重、腹泻或便秘。肛周瘘手术修复的潜在并发症包括伤口开裂、病变复发(一项研究中有超过50%的犬会复发)，可能与未能控制潜在的免疫介导性炎性反应、大便失禁和肛门狭窄有关。 A comprehensive review of surgical management of canine perianal fistulas is beyond the scope of this article. With the increasing recognition of an immune-mediated pathogenesis for the disease, there was a corresponding shift in standard-of-care from surgical intervention to medical management. Several surgical procedures have been described, including en bloc surgical excision (usually performed together with bilateral anal sacculectomy) followed by surgical reconstruction, laser excision, cryosurgery, and amputation at the tail base.One study reported good control of perianal fistulas using a combination of immunomodulatory therapy with prednisone and azathioprine or cyclosporin A with or without ketoconazole followed by surgical excision of remaining sinus tracts, bilateral anal sacculectomy, and cryptectomy. Another study reported a complete response (lack of visible sinus tracts or ulcers) in 29 of 33 dogs after en bloc surgical resection of perianal fistulas, bilateral anal sacculectomy, and diet change to a fish and potato diet. Six of these 29 dogs continued to exhibit clinical signs, such as perianal licking, tenesmus, diarrhea, or constipation. Potential complications of surgical repair of perianal fistulas include dehiscence, lesion recurrence (reported in more than 50% of dogs in one study), likely related to the failure to control the underlying immune-mediated inflammation, fecal incontinence, and anal stricture. 药物管理 MEDICAL MANAGEMENT 注射间充质细胞 Mesenchymal Stem Cell Injections 将间充质干细胞直接注射到瘘管中，已被证明对克罗恩病患者有效。间充质干细胞具有免疫调节活性，如降低T淋巴细胞和树突状细胞的增殖和活化，增加T调节细胞的产量。Ferrer及其同事已经报道了一小部分犬的间充质干细胞注射治疗犬肛周瘘的效果。6只患有肛周瘘的犬，在标准剂量环孢素A治疗失败的情况下，给予至少6个月的治疗，被纳入一项标签外试验，并在肛周病变内接受单次人类胚胎间充质干细胞注射。注射后随访6个月;所有犬在注射干细胞后3个月，窦道或溃疡都有消退。两例术后6个月肛周瘘复发。虽然间充质干细胞注射是治疗犬肛周瘘的一种很有前途的治疗方法，但是还需要更多的对照研究来将这些结果应用于更多患犬，并确定注射的最佳频率。 Injections of mesenchymal stem cells, administered directly into fistulas, have been shown effective for humans with fistulizing Crohn’s disease.1 Mesenchymal stem cells have immunomodulatory activity, such as decreasing proliferation and activation of T lymphocytes and dendritic cells and increasing production of T-regulatory cells. The efficacy of mesenchymal stem cell injections for canine perianal fistulas has been reported for a small number of dogs by Ferrer and colleagues. Six dogs with perianal fistulas that had failed therapy with cyclosporin A at standard dosing for a minimum of 6 months of administration were enrolled in an open-label trial and received a single injection of human embryonic stem cell–derived mesenchymal stem cells within perianal lesions. The dogs were followed for 6 months postinjection; all dogs had resolution of sinus tracts or ulcers by 3 months after injection of stem cells. Two dogs had recurrence of perianal fistulas by 6 months postinjection.10 Although mesenchymal stem cell injections are a promising treatment option for canine perianal fistulas, additional controlled studies are needed to apply these results to larger populations of affected dogs as well as to determine the optimal frequency of injections. 抗菌素 Antimicrobials 抗菌素本身似乎不能有效治疗犬肛周瘘。根据作者的经验，许多犬在出现肛周瘘的临床症状时接受了抗菌素治疗，但病情仍在继续发展。一些研究报道了甲硝唑联合其他疗法(硫唑嘌呤、他克莫司软膏、泼尼松和新奇蛋白日粮)治疗犬肛周瘘。除对厌氧菌和原虫有活性外，甲硝唑还可能具有抗炎活性，包括促进T调节细胞分化。这种抗炎活性可能有助于治疗免疫介导性疾病，但甲硝唑单独治疗肛周瘘的效果目前尚不清楚。 Antimicrobials alone do not seem effective for management of perianal fistulas in dogs. In the author’s experience, many dogs are treated with antimicrobials at the time of onset of clinical signs of perianal fistulas but continue to experience disease progression. A few studies have reported use of metronidazole in combination with other therapies (azathioprine, tacrolimus ointment, prednisone, and novel protein diet) for treatment of dogs with perianal fistulas. In addition to activity against anaerobic bacteria and protozoa, metronidazole may also have anti-inflammatory activity, including promotion of T-regulatory cell differentiation. This anti-inflammatory activity may aid in treatment of immune-mediated diseases, but the efficacy of metronidazole alone for treatment of perianal fistulas is unknown at this time. 免疫调节剂 Immunomodulatory Agents 用于治疗犬肛周瘘的几种免疫调节剂已有报道，包括口服泼尼松(初始免疫抑制剂量)、硫唑嘌呤、环孢素A(单独或联合酮康唑)、外用他克莫司和霉酚酸酯。钙调神经磷酸酶抑制剂(环孢素A和他克莫司)疗效最好;这些内容在后文会提到。在一项对患肛周瘘的德国牧羊犬的研究中，27只犬中有9只(33.3%)的病变完全得到解决。由于需要持续使用免疫调节剂进行管理，以及长期使用皮质类固醇的副作用风险，作者通常不使用皮质类固醇来管理犬肛周瘘。在另一项由Harkin及其同事进行的研究中，对14只肛周瘘患犬单独使用硫唑嘌呤进行治疗。经过16周的治疗，14只犬中有8只(57%)的病灶完全消退。据笔者所知，在兽医文献中，关于霉酚酸酯治疗肛周瘘的报道仅有一篇，这只犬接受了四周的治疗，但病情没有好转。 Several immunomodulatory agents have been reported as treatments for canine perianal fistulas, including oral prednisone (at initial immunosuppressive doses), azathioprine, cyclosporin A (alone or in combination with ketoconazole), topical tacrolimus, and mycophenolate mofetil. The best evidence of efficacy is for calcineurin inhibitors (cyclosporin A and tacrolimus); these are discussed later. In 1 study of German shepherd dogs with perianal fistulas treated with a tapering course of oral prednisone (at an initial immunosuppressive dose of 2 mg/kg/d) and a commercially available novel protein diet for up to 16 weeks, complete lesion resolution was noted in 9 of 27 dogs (33.3%). Due to the need for ongoing administration of immunomodulatory agents for management, as well as the risk of side effects with long-term administration of corticosteroids, the author does not typically use corticosteroids for management of canine perianal fistulas. In another study by Harkin and colleagues, 14 dogs with perianal fistulas were treated with azathioprine alone. After 16 weeks of therapy, 8 of 14 dogs (57%) achieved complete resolution of lesions. To the author’s knowledge, there is only a single report of the use of mycophenolate mofetil for the management of perianal fistulas in the veterinary literature; this dog was treated for 4 weeks without improvement in lesions. 钙调磷酸酶抑制剂（环孢素A和他克莫司） Calcineurin Inhibitors (Cyclosporin A and Tacrolimus) 环孢素A和他克莫司是一种免疫调节剂，通过与细胞内抑制钙调蛋白的环蛋白-1结合而发挥作用。钙调神经素的这种抑制作用可以阻止活化T细胞核因子的去磷酸化，以及随后抑制产生促炎细胞因子，如IL-2。IL-2的产生减少导致T淋巴细胞的生长和活化减少。 Cyclosporin A and tacrolimus are immunomodulatory agents that work by binding to the intracellular protein cyclophilin-1, which inhibits calcineurin. This inhibition of calcineurin prevents the dephosphorylation of nuclear factor of activated T cells and subsequent production of proinflammatory cytokines, such as IL-2. Decreased production of IL-2 leads to decreased growth and activation of T lymphocytes. 多项研究支持环孢素A治疗犬肛周瘘的疗效，包括随机和对照临床试验。在一项随机临床试验中，对患有肛周瘘的德国牧羊犬使用环孢素A和安慰剂进行对比，在20只接受环孢素A治疗16周的犬中，有17只(85%)的犬的病变完全消退。接受环孢素A治疗4周后，犬的平均总表面积和病灶深度分别提高了78%和62%。 Several studies have supported the efficacy of cyclosporin A for treatment of canine perianal fistulas, including randomized and controlled clinical trials. In a randomized clinical trial comparing cyclosporin A with a placebo in German shepherd dogs with perianal fistulas, complete lesion resolution was reported in 17 of 20 dogs (85%) receiving cyclosporin A after 16 weeks of treatment. Mean total surface area and depth of lesions improved by 78% and 62%, respectively, after 4 weeks of therapy in dogs receiving cyclosporin A. 环孢素A治疗犬肛周瘘的剂量差异很大，从每24小时1.5 mg/kg到每12小时10 mg/kg不等。总的来说，较高的剂量效果好，但所有犬都没有接受相同剂量的环孢素A治疗(有些服用未修饰环孢素A)，并且有些病例环孢素A与食物一起服用。改良或微乳化环孢素A制剂在犬体内具有较好的生物利用度，应在所有情况下优先使用。犬体内环孢素A的生物利用度也会因食物的存在而降低，最好空腹服用(例如：餐前或餐后2小时)。 Cyclosporin A doses investigated for treatment of canine perianal fistulas vary widely—from 1.5 mg/kg every 24 hours to 10 mg/kg every 12 hours. In general, higher doses were associated with improved outcome, but all dogs were not treated with the same formulation of Cyclosporin A (some received nonmodified cyclosporin A) and cyclosporin A was administered with food in some cases. Modified or microemulsified formulations of cyclosporin A have superior bioavailability in dogs and should be used preferentially in all cases. Bioavailability of cyclosporin A in dogs is also reduced by the presence of food and it is best administered on an empty stomach (ie, 2 hours prior to or after a meal). 环孢素A价格高，特别是在高剂量或更大的犬，可能因此受限。酮康唑联合环孢素A可抑制肝细胞色素P450微酶对环孢素A的代谢，通过抑制肠道p糖蛋白提高生物利用度(从而减少环孢素A向肠腔的转运)。这两种药联合用药可使环孢素A的生物利用度提高75%或更多，这取决于酮康唑的剂量，并可使环孢素的剂量减少。环孢素A(剂量的1-5.5毫克/公斤/天)联合酮康唑(剂量为5.1-11毫克/公斤/天)，在临床试验中被证实有效，病变全都得到缓解，治疗16周93%的犬有效, 治疗3到10周100%的犬有效,治疗67%的犬平均恢复周期在13.9周。 The cost of cyclosporin A, particularly at higher doses or for larger dogs, may be prohibitive. Administration of cyclosporin A with ketoconazole can inhibit metabolism of cyclosporin A by hepatic cytochrome P450 microenzymes as well as improve bioavailability via inhibition of intestinal P-glycoprotein (thus decreasing transport of cyclosporin A to the intestinal lumen). Coadministration of the 2 drugs can improve cyclosporin A bioavailability by 75% or more, depending on the ketoconazole dose, and allow cyclosporin A dose reduction. The combination of cyclosporin A (at doses of 1 mg/kg/d to 5.5 mg/kg/d) and ketoconazole (at doses of 5.1 mg/kg/d to 11 mg/kg/d) was shown effective in clinical trials with complete lesion resolution in 93% of dogs in 16 weeks, 100% of dogs in 3 to 10 weeks, and 67% of dogs with a mean time to resolution of 13.9 weeks. 作者经常使用初始剂量为2 mg/kg/d至4 mg/kg/d的环孢素A和初始剂量为5 mg/kg/d至10 mg/kg/d的酮康唑联合治疗犬肛周瘘。当停止免疫调节治疗时，可发生复发。因此，在病变完全消退后(通常需要8-12周的治疗)，作者缓慢地将环孢素A和酮康唑的有效剂量和剂量频率降低到最低。作者没有对这些患者进行常规的环孢素A血药浓度监测，因为环孢素A血药浓度与临床反应相关性不强。 The author regularly uses the combination of cyclosporin A at initial doses of 2 mg/kg/d to 4 mg/kg/d and ketoconazole at initial doses of 5 mg/kg/d to 10 mg/kg/d for treating perianal fistulas in dogs. Relapses can occur when immunomodulatory therapy is discontinued.For this reason, after complete resolution of lesions (which generally requires 8–12 weeks of therapy), the author slowly tapers cyclosporin A and ketoconazole to the lowest effective dosing and dose frequency. The author does not routinely perform cyclosporin A blood level monitoring in these patients because cyclosporin A blood levels do not correlate well with clinical response. 0.1%他克莫司软膏也被证明对犬肛周瘘有效，尽管还没有进行随机对照临床试验。在1篇报告中，对10只犬使用他克莫司治疗，0.1%软膏每日两次用于肛周皮肤，持续16周，5只犬病变完全消退。他克莫司比环孢素A更适合外用，因为它的分子量更小，可以改善表皮的吸收。由于可能与使用不适有关，作者最常见的建议是给病变较轻的犬外部使用他克莫司软膏，或给口服环孢素A完全或部分消退后病情较重的犬(最常与酮康唑联用)。一些犬可能会转换为单独外用他克莫司软膏维持，以防止肛周瘘复发(图4)。 Tacrolimus 0.1% ointment has also been shown effective for treatment of canine perianal fistulas, although randomized controlled clinical trials have not been performed. In 1 report of 10 dogs treated with tacrolimus, 0.1% ointment applied to the perianal skin twice daily for 16 weeks, 5 dogs achieved complete resolution of lesions. Tacrolimus is more appropriate for topical application than cyclosporin A because of its smaller molecular weight, leading to improved absorption through the epidermis. Because of the discomfort that may be associated with application, the author most commonly recommends topical tacrolimus ointment for dogs with mild lesions or for dogs with more severe lesions after complete or partial resolution with oral cyclosporin A (most often in combination with ketoconazole). Some dogs may be transitioned to topical tacrolimus ointment alone for maintenance to prevent relapses of perianal fistulas (Fig. 4). 其他药物管理的注意事项 Other Considerations for Medical Management 急性肛周瘘患犬会疼痛，尤其是排便时。应该考虑使用粪便软化剂，并且有些病例可能需要灌肠，以缓解里急后重。疼痛管理应优先考虑有活动性病变的犬，但在制定疼痛管理计划时，应考虑使用阿片类激动剂等止痛剂可能导致便秘的情况。一些肛周瘘患犬会因为持续的疾病、肛门狭窄等并发症的发展或长期的管理费用而被安乐死。因此，犬肛周瘘的早期诊断和积极的医疗管理是关键。根据作者的经验，对慢性病变患者的管理可能更具挑战性，这些患者可能更难以接受药物治疗。未来的研究应该关注更好地阐述这个疾病的遗传和免疫发病机理,评估影响犬和主人的生活质量(见Chiara Noli的同本杂志文章《皮肤病患宠及其主人生活质量的评估》),和开发有针对性的药物治疗。 Dogs with active perianal fistulas can be painful, particularly on defecation. Stool softeners should be considered, and, in some cases, enemas may be necessary to ease tenesmus. Analgesia should be prioritized for dogs with active lesions but the potential for constipation with use of some analgesics, such as opioid agonists, should be considered when formulating a pain management plan. Some dogs with perianal fistulas are euthanized due to unremitting disease, development of complications such as anal stricture, or expense of long-term management. For these reasons, early diagnosis and aggressive medical management of canine perianal fistulas are key. In the author’s experience, management of patients with chronic lesions can be more challenging and these patients can be more refractory to medical therapy. Future studies should focus on better characterizing the genetics and immunopathogenesis of this disease, assessing quality of life of affected dogs and their owners (see Chiara Noli’s article, “Assessing Quality of Life for Pets with Dermatologic Disease and their Owners,” in this issue), and developing targeted medical therapies.
图4。图1 的7岁德国牧羊犬的肛周窦道已痊愈。口服环孢素A和酮康唑治疗，使其达到病变改善，然后改用0.1%他克莫司软膏。应用他克莫司软膏后，临床症状持续缓解12个多月。 Fig. 4. Complete resolution of perianal sinus tracts in the 7-year-old German shepherd dog picturedin Fig. 1. This dog was treated withoral cyclosporin A and ketoconazole to the point of lesion resolution,then transitioned to topical tacrolimus 0.1% ointment.Clinical remission has been maintained for more than 12 months with application of tacrolimus ointment.
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