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本帖最后由 巴哥控 于 2019-8-10 09:42 编辑
犬缺血性皮肤病：177例病例分析回顾性研究（2005-2016）
Canine ischaemic dermatopathy: a retrospective study of 177 cases (2005–2016) 作者：
Katherine A. Backel*, Charles W. Bradley*, Christine L. Cain*, Daniel O. Morris*, Kyle H. Goldschmidt† and Elizabeth A. Mauldin*
翻译：王帆
背景: 犬缺血性皮肤病包含一些临床和组织学特征相似且机制不明的犬病组群。目前关于种群特性、进展和结果的信息非常少。
假设/目标: 本研究旨在通过组织病理学诊断的病例,报告缺血性皮肤病的临床特征和治疗结果(不包括家族性皮肌炎)。
动物: 2005年至2016年期间,177个做过组织病理学分析且符合纳入标准的病例,其中93个病例有完整病历。
方法和材料: 检索信息进行有针对性的调查并记录,创建评分系统去主观评估临床结果与疫苗相关的可能性。
结果: 在177例中,玩具贵宾犬、迷你贵宾犬、吉娃娃犬、马耳他犬、约克夏㹴犬和杰克罗素㹴犬的比例明显较多(P <0.001)。在93例历史数据中,皮肤活检的中位年龄为5岁(0.42-13岁),中位体重为7.3kg(范围1.32-50.3kg)。从45只犬身上发现(48.3%)病情可能与疫苗接种有关。年龄越小(P = 0.011)和体重越高(P = 0.003),以至于接种疫苗的可能性越大,呈正相关。体重<10 kg(P = 0.0045)和年龄越大(P = 0.0048),以至于预后越差,呈显著相关性。
结论和临床意义: 该研究为品种易感性提供支持,并识别潜在的预后因素。重要的是,超过一半的病例与疫苗无关,这表明有必要调查该病的其他潜在原因。
Background – Ischaemic dermatopathy encompasses a poorly understood subset of canine diseases that share similar clinical and histological features. Very little information is currently available regarding population characteristics, progression and outcome.
Hypothesis/objectives – This study aimed to describe the clinical features and therapeutic outcomes of ischaemia dermatopathy, excluding familial dermatomyositis, using cases diagnosed by histopathological analysis.
Animals – One hundred and seventy-seven cases submitted for histopathological analysis between 2005 and 2016 met inclusion criteria, of which 93 had complete medical records available.
Methods and materials – Both records and pointed surveys were used to retrieve information. Scoring systems were created to subjectively evaluate clinical outcomes and likelihood of a vaccine association.
Results – Of 177 cases, toy and miniature poodles, Chihuahuas, Maltese, Yorkshire terriers and Jack Russell terriers were significantly over-represented (P < 0.001). Of the 93 cases for which historical data were obtained, median age at skin biopsy was five years (0.42–13 years) and median body weight was 7.3 kg (range 1.32– 50.3 kg). The condition in 45 dogs (48.3%) was found likely to be associated with vaccination. Younger ages (P = 0.011) and higher body weights (P = 0.003) were positively correlated with greater likelihood of vaccination. Body weight <10 kg (P = 0.0045) and older ages (P = 0.0048) were significantly associated with worse outcomes.
Conclusions and clinical importance – This study provides support for breed predispositions and identifies potential prognostic factors. Importantly, over half of the cases were considered unlikely to be vaccine-associated, demonstrating the need to investigate other underlying causes of this condition.
介绍
Introduction 缺血性皮肤病包含几种病因不同的临床综合征，但临床特征相同。以前，缺血性疾病被分为五种亚型:犬家族性皮肌炎(FDM)、非典型犬种的幼年发病性皮肌炎样疾病、狂犬疫苗注射后脂膜炎、疫苗相关性全身性缺血性皮肤病和全身性特发性缺血性皮肤病。
Ischaemic dermatopathy is a diagnosis that encompasses different clinical syndromes with common features and a wide range of possible aetiologies. Ischaemic diseases previously have been grouped into five subtypes: canine familial dermatomyositis (FDM), juvenile onset dermatomyositis-like disease in atypical breeds, post-rabies vaccine panniculitis, generalized vaccine-associated ischaemic dermatopathy and generalized idiopathic ischaemic dermatopathy.1
无论是全身性还是局灶性，皮肤症状包括脱毛、色素沉着或色素减退、皮屑、结痂和溃疡。病变最常见于疫苗注射部位和/或全身部位，包括耳廓边缘、尾尖、头部、面部和压力点。也经常在肢端分布，并以趾骨、爪垫和甲部病变为特征(甲发育不良和甲变形)。
Whether generalized or localized, cutaneous signs include alopecia, hyper- or hypopigmentation, scaling, crusts and ulcers. Lesions are found most commonly at vaccine sites and/or generalized areas including the pinnal margin, tip of the tail, head, face and pressure points. An acral distribution also is frequently observed and characterized by lesions on phalanges, paw pads and claws (onychodystrophy and onychomadesis).
缺血性皮肤病的组织学特征包括毛囊萎缩、少细胞性淋巴细胞浸润性界面性皮炎、真皮水肿/粘蛋白沉积、真皮胶原蛋白呈嗜酸性染色改变和血管束周围胶原蛋白呈现“污迹”样外观。这些变化被认为是患病组织发生了慢性缺氧/营养不良状态。
Histological features of ischaemic dermatopathy include follicular atrophy, a cell-poor lymphocytic interface dermatitis, dermal oedema/mucin deposition, and eosinophilic tinctorial changes to the dermal collagen and vascular tunics imparting a “smudged” appearance to the collagen. These changes are thought to represent a chronic oxygen-/nutrient-deficient state of the affected tissue.1,2
尽管在20世纪80年代中期就有发现，但从那时起很少有重点关注非家族性缺血性皮肤病的文章报道。虽然临床上很容易识别狂犬疫苗相关的病例，但关于真实的病例流行性、患病因素和临床结果的信息却很少。此外，在明显为疫苗诱发但尚未明确的病例中，对特发性缺血性皮肤病的了解更少。而且，对于疫苗相关和特发性病例的最佳治疗方案尚未得到仔细研究。据报道，己酮可可碱对FDM有效，虽然已发表的支持性数据很少，但已用于其他亚型的缺血性皮肤病的治疗。已报道的三例与疫苗相关的病例分析表明，己酮可可碱和维生素E联合用药治疗效果良好(其中两个病例短期使用了泼尼松)。两个病例分析描述了使用奥拉替尼治疗效果非常好。但也有报道表明，这些病例可能很难管理，有些病例需要联合免疫抑制剂治疗，而另一些病例仍在持续治疗。
Despite being recognized in the mid-1980s, very few primary publications since then have focused on nonfamilial variants of ischaemic dermatopathy.2–6 Although rabies vaccine-associated cases are relatively well recognized in clinical practice, there is a paucity of information regarding the true patient population, risk factors and clinical outcomes. Additionally, even less is known about idiopathic ischaemic dermatopathies in which an obvious vaccine trigger is not identified. Furthermore, optimal medical management of vaccine-associated and idiopathic cases has not been examined closely. Pentoxifylline has been reported to be effective in cases of FDM and is used for other subtypes of ischaemic dermatopathy, despite few published supportive data.7 Three cases of vaccine-associated disease were reported to respond well to therapy with pentoxifylline combined with vitamin E (and in two of these cases, short courses of prednisone).2 A report of two cases described excellent responses to oclacitinib.6 However, anecdotal reports suggest that these cases can be difficult to manage, with some requiring combination immunosuppressive therapy, and others progressing despite treatment.5,8
本研究的目的是更准确的描述种群特征，临床表现，和各种缺血性皮肤病亚型的预后特点，不包括FDM。此外，为了确定反应疾病严重程度和进展的风险因素和预后指标，努力将临床表现和治疗方法与预后结果相关联。根据临床观察，作者猜测患病种群大多数是小型犬种，特别是那些与疫苗相关疾病的犬种。此外，作者还假设，体重小于10公斤的犬，以及那些与疫苗明显不相关的犬，结果更糟。
The objectives of this study were to develop more accurate descriptions of the population characteristics, clinical presentations, and outcome features of the various subtypes of ischaemic dermatopathy, excluding FDM. Additionally, an effort was made to correlate clinical findings and treatment data with outcome patterns in order to identify risk factors and prognostic indicators for disease severity and progression. Based on clinical impressions, the authors hypothesized that small breeds would comprise the majority of the patient population, specifically of those dogs with vaccine-associated disease. Additionally, the authors hypothesized that dogs with a body weight <10 kg, and those without a strong vaccine association, would have worse outcomes.
方法和材料
Methods and materials 对宾夕法尼亚大学兽医学院的组织病理学数据库进行了全面的电子搜索，以获取2005年至2016年间包含关键词“缺血性”或“缺血性皮肤病”的报告。如果组织学描述和/或书面诊断与皮肤缺血性疾病一致，则选择病例。排除标准包括诊断为FDM(不包括目前报道的所有品种)和继发于原发性皮肤病(如皮肤瘤变、反应性组织细胞增多症)的缺血性改变。初步共发现282例。然后由两位作者检查每个病例的所有载玻片。
A comprehensive electronic search of a histopathology database at the School of Veterinary Medicine of the University of Pennsilvania for reports generated between 2005 and 2016 containing the key words “ischaemic” or “ischaemic dermatopathy”, was performed. Cases were then selected if the histological description and/or written diagnosis was consistent with cutaneous ischaemic disease. Exclusion criteria included a diagnosis of FDM (excluding all currently reported breeds) and ischaemic changes secondary to a primary skin disease (e.g. cutaneous neoplasia, reactive histiocytosis). A total of 282 cases were initially identified. All slides from each case were then examined by two authors.
确诊缺血性皮肤病需要，存在附件萎缩(“毛囊萎缩”)，同时伴有一个或多个以下的组织学特点:(1)少细胞性界面性模式,(2)胶原蛋白模糊不清,(3)血管炎或血管病变(无血管分布或内皮细胞缺失)和/或(4)淋巴性浆细胞性皮炎或脂膜炎。(图1)。
A diagnosis of ischaemic dermatopathy was conferred by the presence of adnexal atrophy (“faded follicles”) with one or more of the following histological characteristics: (1) cell-poor interface pattern, (2) collagen smudging, (3) vasculitis or vasculopathy (loss of vascular distinction or endothelial cells) and/or (4) lymphoplasmacytic dermatitis or panniculitis. (Figure 1).
图1。照片为第101例缺血性皮肤病病例的皮肤组织病理学特征。
(a)轻度皮肤真皮层炎症反应和水肿，伴有明显的毛囊萎缩(faded follicles)和明显的玻璃膜(箭头所指)。(b)高倍镜下明显的玻璃膜(箭头)。(c)高倍镜下的真皮表皮交界处。少细胞性界面性改变，伴浅表真皮水肿和真皮胶原纤维的细节缺失。基底层角质细胞空泡样变性伴细胞凋亡(arrows)和局灶性表皮下开裂(arrowhead)。基底层角质细胞凋亡(arrows)。HE染色，40倍 (a)和400倍 (b,c)。
Figure 1. Photomicrographs showing histopathological features of ischaemic dermatopathy in skin from Case 101.
(a) Mild dermal inflammation and oedema with marked follicular atrophy (faded follicles) with a prominent glassy membrane (arrows). (b) Higher magnification highlighting glassy membrane (arrows). (c) Higher magnification of dermoepidermal junction. Cell-poor interface change with superficial dermal oedema and loss of detail in dermal collagen fibres. Vacuolar degeneration of basal keratinocytes with apoptosis (arrows) and focal subepidermal cleft (arrowhead). Apoptotic keratinocytes are located in basal layer (arrows). Haematoxylin and eosin, *40 (a) and *400 (b,c).
所有符合这些组织学纳入标准的病例均纳入分析以确定种群特征。只有由美国兽医皮肤病学学院的兽医提交的病例才进行临床描述、治疗和预后分析。之所以这样做，是因为认为这样可以提供更好的一致性的病变描述。为了获取数据，我们从皮肤组织病理学报告中收集信息，并针对每个病例向提交的临床医生发送书面调查和所需的医疗记录(图S1)。
All cases meeting these histological inclusion criteria were included in the analysis to define population characteristics. Only cases submitted by veterinarians who were members of the American College of Veterinary Dermatology were analysed for clinical descriptions, treatment and outcome data. This was done because it was assumed that it would provide better consistency in lesion descriptions. For data capture, information was collected from skin biopsy histopathological reports, a written survey and a request for medical records was sent to the submitting clinician for each case (Figure S1).
病例特征描述(年龄、性别、品种)、体重、病史调查或同期疾病、当前/最近使用的药物、体格检查、病变分布和描述、全身症状(包括发热、嗜睡、食欲减退、虚弱、呕吐、腹泻、咳嗽、呼吸用力、跛行、神经学异常、疼痛、淋巴结异常和打喷嚏/鼻分泌物)、诊断性测试/实验室检查(全血细胞计数、生化分析)、免疫记录(免疫时间和类型)、治疗(使用的药物和剂量)疗效(主观描述)。已知时，所有用于治疗的药物都记录为每日剂量。为了本研究的目的，“疫苗注射部位”被定义为一个独立的、单侧特异性病变描述，位于体侧/大腿/臀部或肩部/胸侧。如果病历中没有记载病史调查或体格检查结果，则认为是数据缺失。如果没有获得临床和历史数据，或者没有记录至少3个月内的复诊信息，病例将不被列入最终分析。
Case signalment (age, sex, breed), weight, historical or concurrent diseases, current/recent medications, physical examination findings, location and description of lesions, systemic signs (including fever, lethargy, inappetence, weakness, vomiting, diarrhoea, coughing, respiratory effort, lameness, neurological abnormalities, pain, lymphadenopathy and sneezing/nasal discharge), diagnostic tests/ laboratory data (complete blood count, biochemical analysis), vaccine history (timing and type of vaccine given), treatments (drugs and doses used) and outcome data (subjective descriptions) were recorded. When known, all medications used for treatment were recorded as dose per day. For the purposes of this study a “vaccination site” was defined as a discrete, unilateral lesion specifically described on the flank/thigh/hip or shoulder/lateral thorax. If a historical or physical examination finding was not noted in the medical record, it was considered to be a missing datum. Cases were excluded from end-point analysis if clinical and historical data were not obtained or if a follow-up period of at least three months was not recorded.
创建了一个疫苗评分标准来评估每个病例与最近的疫苗接种相关的可能性。(表1).较高的数字表明疾病与接种疫苗有关的可能性较高。
A vaccine scoring rubric was created to evaluate the likelihood of each case being associated with a recent vaccination. (Table 1). Higher numbers indicated higher likelihood of disease being associated with vaccination.
使用两个独立的系统评估病例疗效(表2和表3)。创建这两个系统的目的是对病例的严重程度提供最客观的评估，并帮助确定预后因素。首先，为了反映每个病例实现临床控制的难度，我们创建了一个治疗评分来评估所选择的医疗治疗的程度。该评分系统适用于回顾性目的从系统先前报告的异位性皮炎。少数药物添加到这个方案(咪唑硫嘌呤、来氟米特)和每只犬的所有剂量的最大剂量(表2)。计算治疗评分,分数高的表示的使用更多的治疗药物和免疫抑制药物更有效。其次，为了最好地评估长期疗效，建立了一个基于死亡/安乐死记录的(如果与缺血性疾病有关)或最后治疗记录的(如果患犬最后一次就诊时仍然活着)的终点评分系统。死亡原因与缺血性疾病无关的病例根据死亡前最后一次就诊时使用的药物进行评分(表3)。分数高表明疗效更好。
Case outcomes were evaluated using two separate systems (Tables 2 and 3). Both systems were created in an effort to provide the most objective assessment of case severity and to help identify prognostic factors. First, to reflect difficulty in achieving clinical control in each case, a treatment score was created to evaluate the extent of chosen medical therapy. The scoring system was adapted for retrospective purposes from systems previously reported for atopic dermatitis.9–11 A few drugs were added to this scheme (azathioprine, leflunomide) and all doses were scored as the maximum dose that each dog received (Table 2). Treatment scores were cumulative, meaning a higher treatment score indicated the use of a greater number of medications and more potent immunosuppressive agents. Second, in order to best represent long-term outcomes, an end-point scoring system was created based on recorded death/euthanasia (if related to the ischaemic disease) or last recorded medical therapy if the dog was alive at last contact with the client. Cases that died for reasons unrelated to ischaemic disease were scored based on medications being used at last contact before death (Table 3). A higher number indicated a better outcome.
统计分析
Statistical analysis A statistical software program (JMP 14.2, SAS Institute Inc.; Cary, NC, USA) was used to generate descriptive statistics for breed, sex, weight and disease characteristics, and examine relationships between selected variables. A one sample proportion test was conducted for each breed within the 177 cases to determine if the proportion differed from the target proportion calculated for the same breeds included in the histopathology database (81,525 of 125,567 total cases). Relationships between case signalments and scoring metrics were analysed using one-way ANOVA. Bivariate analysis was used to determine an association between case signalment and scoring metrics.
结果
Results Two hundred and eighty-two cases were initially identified from the histopathology database. Of those, 177 met inclusion criteria and were used for breed and signalment data. This equated to 0.14% (177 of 125,567) of all cases where biopsies were submitted during that time period. Of the 177 cases, records and/or surveys were obtained from 93 cases for historical data and analysis.
特征描述
Signalment 177例中，皮肤活检时平均年龄为5岁(范围为0.33-14岁)。78例雌性(44.6%;61例已绝育，17例未绝育），95例雄性(54.8%;67例已去势，28例未去势)，4例性别未知。共有43个品种。最多的是杂交犬(177只中有45只;25.4%），其次是吉娃娃犬(177只中有12只;6.8%)、杰克罗素㹴(177只中有12只;6.8%)、玩具及小型贵宾犬(177只中有12只;6.8%）、约克夏㹴(177只中的7只;4%)、腊肠犬(177只中有7只;4%）和马尔济斯犬(177只中有5只;2.8%))。表S1列出了所有品种。进行活检的病例种群仅作参考,以下品种更具代表性:吉娃娃犬(P < 0.0001)、中国冠毛犬(P < 0.0001)、马尔济斯犬(P < 0.0001)、玩具和迷你贵宾犬(P < 0.0001)、猎鼠犬(P < 0.0001)、舒柏奇犬(P < 0.0001)、约克夏㹴(P = 0.0003)、玩具猎狐㹴(P = 0.0007)和杰克罗素㹴(P = 0.001)。93例中有77例记录了体重，并获得了其他记录。中位体重7.3 (1.32-50.3)kg，其中有49例体重 (63.6%)<10 kg。
Of the 177 cases, the median age at time of skin biopsy was five years (range 0.33–14 years). There were 78 females (44.6%; 61 spayed, 17 intact) and 95 males (54.8%; 67 neutered and 28 intact), four were unknown sex. There were 43 breeds represented. Mixed breed dogs were the largest group (45 of 177; 25.4%), followed by Chihuahuas (12 of 177; 6.8%), Jack Russell terriers, (12 of 177; 6.8%), toy and miniature poodles, (12 of 177; 6.8%), Yorkshire terriers (seven of 177; 4%), Dachshunds (7 of 177; 4%) and Maltese terriers (five of 177; 2.8%)). All breeds are listed in Table S1. Using the patient population of the biopsy service as a reference, the following breeds were significantly over-represented: Chihuahuas (P < 0.0001), Chinese crested dogs (P < 0.0001), Maltese terriers (P < 0.0001), toy and miniature poodles (P < 0.0001), rat terriers (P < 0.0001), schipperkes (P < 0.0001), Yorkshire terriers (P = 0.0003), toy fox terriers (P = 0.0007) and Jack Russell terriers (P = 0.001). Body weight was recorded in 77 of 93 cases for which additional records were obtained. The median weight was 7.3 (1.32–50.3) kg, with 49 of 77 (63.6%) being <10 kg.
临床表现
Clinical presentation 在93例犬中，79例(85%)最常见病变表现为脱毛。其他常见的病变包括结痂(65.5%)、皮屑(57%)、红斑(44.1%)、糜烂/溃疡(38.7%)和色素沉着(36.6%)。瘙痒也很常见，93只犬中有32只(34.4%)出现瘙痒。其他病变较少(表S2)。病变部位中位数为4个(范围1 ~ 13个)。13只犬只有一个病灶;其中9例为疫苗注射部位病变，2例位于耳廓，1例位于尾部，1例位于躯干。与所有病例相比，不包括只接种疫苗部位的病变，只有一个局灶病变的犬体重更重(平均15.4公斤)，年龄更大(平均7.3岁)。总体而言，93例中61例(65.59%)的病灶最常见于耳廓，43例(46.3%)的病灶位于疫苗注射部位，39例(41.94%)位于眼周/面部(见表S3和图2)。93只犬中有20只(21.5%)嗜睡，12只(13%)发烧，12只(13%)食欲不振，6只(6.5%)跛行等全身症状。
Alopecia was the most common lesion noted in 79 of 93 dogs (85%). Other common lesions included crust (65.5%), scale (57%), erythema (44.1%), erosions/ulcers (38.7%) and hyperpigmentation (36.6%). Pruritus also was common, noted in 32 of 93 dogs (34.4%). Other lesions were noted in fewer numbers (Table S2). The median number of lesion sites was four (range one to 13). Thirteen dogs had a single lesion; of these, nine were vaccination site lesions, two were found on pinna, one on the tail and one on the trunk. Excluding vaccine-site-only lesions, dogs with one local lesion had greater body weights (mean = 15.4 kg) and were older (mean = 7.3 years of age) compared to all cases. Overall, lesions were most commonly found on the pinnae in 61 of 93 cases (65.59%), at vaccination sites in 43 (46.3%), and periocular/face in 39 (41.94%) (see Table S3 and Figure 2). Systemic signs were reported in 29 of 93 dogs (31.2%). The most frequently reported were lethargy in 20 of 93 dogs (21.5%), fever in 12 (13%), inappetance in 12 (13%) and lameness in six (6.5%).
图2。两只缺血性皮肤病患犬的临床病变照片。
(a,b)病例166:脱毛区瘢痕化伴色素沉着，以及眼周和颞区的色素沉着。耳缘呈扇形和锯齿状，粘附厚的皮屑/结痂。(b,c)病例137:耳廓凹面的对称性溃疡。脱毛区环形瘢痕化和颅骨背侧色素沉着。趾骨色素沉着、红斑、脱毛。
Figure 2. Clinical images from two dogs with ischaemic dermatopathy.
(a,b) Case 166: Coalescing foci of scarring alopecia with hyperpigmentation and hypopigmentation in the periocular region and temporal region. Scalloped and notched ear margin with thick adherent scale/crust. (b,c) Case 137: Symmetrical ulcers on the concave pinnae. Annular focus of scarring alopecia and hyperpigmentation on the dorsal calvarium. Hyperpigmentation, erythema and alopecia on the phalanges.
病史资料
Historical data 93例中，35例(38%)报告在确诊时有同期疾病存在。最近诊断或同期疾病见表4。80例正在接受药物治疗的病例中，有25例在报告发布时正在服药。报道的药物要么是抗寄生虫预防性药物，或用于治疗同期疾病的药物。药物包括左旋甲状腺素(1)、咪唑硫嘌呤(1)、苯丁酸氮芥(1)、泼尼松/泼尼松龙(5)、水飞蓟素(1)、胰岛素(1)、苯巴比妥(1)、阿替洛尔(1)、卡洛芬(2)、美洛昔康(1)、速尿(1)、羟嗪(1)、己酮可可碱(1)、外用耳药(4)、各种抗寄生虫药[塞拉菌素(1)、伊维菌素(3)、阿福拉那(1)、吡虫啉/莫昔克丁(1)、磺胺二甲嘧啶(1)]、止痛药(曲马多(1)、美索巴莫(1)]、各种抗生素[阿莫西林(1)、阿莫西林-克拉维酸(4)、头孢维星(1)、克林霉素(1)、恩诺沙星(2)、甲硝唑。对所有药物使用没有临床可疑症状。由于数据不完整，无法计算药物评分。
Of the 93 cases, 35 (38%) had reported concurrent disease(s) at diagnosis. Recently diagnosed or concurrent medical conditions are shown in Table 4. In 80 cases where concurrent medication use was reported, 25 were being administered medication at the reported time of onset. Medications reported were either antiparasitic preventatives or being used for management of concomitant diseases. Medications included levothyroxine (one case), azathioprine (one), chlorambucil (one), prednisone/prednisolone (five), milk thistle (one), insulin (one), phenobarbital (one), atenolol (one) carprofen (two), meloxicam (one), furosemide (one), hydroxyzine (one), pentoxifylline (one), topical ear medications (four), various antiparasitics [selamectin (one), ivermectin (three), afoxolaner (one), imidacloprid/moxidectin (one) sulfadimethoxine (one)], pain medications [tramadol (one), methocarbamol (one)] and various antibiotics [amoxicillin (one), amoxicillin-clavulanic acid (four), cefovecin (one), clindamycin (one), enrofloxacin (two), metronidazole (one)]. No clinical suspicion was noted for any medications used. Due to incomplete data, medication scores could not be calculated.
疫苗评分
Vaccine scores 疫苗评分平均为2分。为便于分析，认为疫苗评分< 2分(1或0)的病例不太可能与疫苗有关。93例(51.6%)中有48例疫苗得分< 2。疫苗评分更高的相应体重也更重(P = 0.0029, r2 = 0.96)和年龄更年轻(P = 0.0110, r2 = 0.07)。两个病变部位——颅骨背侧(33个观察点)和趾部(16个观察点)——与疫苗的相关性显著降低(分别为1.39,P = 0.003和1.18,P = 0.0151)。较低的疫苗评分对应全身症状表现更多，但这种关系没有统计学意义(P = 0.116)。未评估单个病例全身症状的影响。病例有无同期疾病的疫苗评分之间也无明显差异。疫苗评分与病变部位总数之间无明显相关性。只有玩具贵宾犬(n = 6)的疫苗评分在病例种群中显著升高(平均疫苗得分= 4,P = 0.0005)。
The average vaccine score was two. For the purposes of analysis, cases with a vaccine score < 2 (1 or 0) were considered unlikely to have an association with a vaccine. A vaccine score < 2 was calculated for 48 of 93 (51.6%) cases. Higher vaccine scores were positively correlated with higher body weights (P = 0.0029, r2 = 0.96) and younger ages (P = 0.0110, r2 = 0.07). Two lesion sites – the dorsal calvarium (33 observations) and digits (16 observations) – were significantly less likely to be associated with vaccination (mean 1.39, P = 0.003 and mean 1.18, P = 0.0151, respectively). A lower vaccine score was associated with a greater number of systemic signs, but this relationship was not statistically significant (P = 0.116). The effects of individual systemic signs were not evaluated. Vaccine scores were not significantly different between cases with concurrent disease and those without; nor were vaccine scores significantly associated with the total number of lesional sites. Only toy poodles (n = 6) had a significantly higher vaccine score when compared to the case population (mean vaccine score = 4, P = 0.0005).
治疗
Treatments 在报道的80例治疗中，73例(91.3%)使用了己酮可可碱。使用的平均剂量为47.12 mg/kg/天(范围:18-112.5 mg/kg/天)。其次最常用的药物是糖皮质激素(80例中41例)。其中，41人(44%)中有18人使用的相当于泼尼松的剂量大于1 mg/kg/ day(初始剂量)。其他常用药物包括93例中的33例维生素E(35.5%)和环孢素(平均初始剂量:5.52 mg/kg/d)， 93例中的16例(17.2%)。所有的治疗方法报告见表S4。
Of the 80 cases for which treatment use was reported, 73 (91.3%) were treated with pentoxifylline. The mean dose used was 47.12 mg/kg/day (range: 18–112.5 mg/ kg/day). The next most common drugs used were corticosteroids (in 41 of 80 cases). Of these, 18 of 41 (44%) used a prednisone-equivalent dose greater than 1 mg/kg/ day (initial dose). Other common medications included vitamin E in 33 of 93 cases (35.5%) and ciclosporin (mean initial dose: 5.52 mg/kg/day), in 16 of 93 cases (17.2%). See Table S4 for all treatments reported.
治疗评分
Treatment scores 大于3个月的复诊病例62例纳入终点评分计算;然而，其中三例患犬的治疗评分无法计算。在计算的59例患者中，平均治疗评分为82.73，中位数为60(范围为0-380)。59例中40例(67.8%)治疗评分<100,16例(27.1%)介于100 - 200之间，3例(4.8%)为>200(240,300,380)。当治疗评分与临床特征比较时，只有胸骨病变(n = 42)与较高的治疗评分显著相关(95.04,P = 0.005)。全身病变部位数量与治疗评分呈正相关(P = 0.029, r2 = 0.08)。在所有品种中，只有迷你杜宾(n = 2)的平均治疗评分显著高于其他品种(240,P = 0.0008)。治疗评分与活检时的体重或年龄无显著差异。
There were 62 cases with follow-up greater than three months which were included in the calculation of endpoint scores; however, treatment scores could not be calculated in three of these cases. Of the 59 calculated, the mean treatment score was 82.73, and the median was 60 (range 0–380). Scores of <100 were calculated in 40 of 59 cases (67.8%), whereas 16 cases (27.1%) scored between 100 and 200 and three cases (4.8%) scored >200 (240, 300, 380). When treatment scores were compared to clinical characteristics, only pinnal lesions (n = 42) were significantly associated with higher treatment scores (95.04, P = 0.005). The number of systemic signs was positively correlated with higher treatment scores (P = 0.029, r2 = 0.08). Of all breeds, only miniature pinschers (n = 2) had a significantly higher mean treatment score than other breeds (240, P = 0.0008). Treatment scores did not vary significantly with weight or age at time of biopsy.
终点评分
End-point scores 在62例复诊时间超过3个月或在任何时间点实施安乐死/死亡的病例中指定了终点评分(1-6)。终点评分数越高，结果越好。平均得分为3.35分。62例患者中，有一半(31例)的终点评分被认为是“好”或更好，而其中21例(33.9%)的终点评分被认为是“一般”或更差，并且仍然使用至少一种免疫抑制剂进行控制。62例中有10例(16.1%)因与缺血性疾病相关的问题而实施安乐死，其中5例因与皮肤病变同时发生的严重全身疾病而实施安乐死。全身性疾病包括吸入性肺炎、肺叶扭转和多发性关节病、不明原因的肝病、蛋白质丢失性肠病和未分类的中枢神经系统疾病，以及蛋白质丢失性肾病(一年后实施安乐死)。10例中有3例因治疗无效而实施安乐死(诊断后2.5-5个月)。两例患者在诊断后不久死亡或因不明原因被实施安乐死:一例患者在服用咪唑硫嘌呤三周后实施安乐死，另一例患者在诊断后一个月在家死亡。
End-point scores (1–6) were designated in 62 cases with greater than three months of follow-up or that were euthanized/died at any point. Higher end-point scores were indicative of better outcomes. The average end-point score was 3.35. Half of the cases (31 of 62) achieved an end-point that was considered “good” or better, whereas 21 of these cases (33.9%) were considered “fair” or worse, and remained on at least one immunosuppressive agent for control. Ten of 62 cases (16.1%) were euthanized for issues related to ischaemic disease and five of these were euthanized for severe systemic disease contemporaneous with skin lesion onset. Systemic diseases included aspiration pneumonia, lung lobe torsion and polyarthropathy, unspecified hepatopathy, protein losing enteropathy and unclassified central neurological disease, and protein losing nephropathy (euthanized one year later). Three of 10 cases were euthanized due to lack of response to therapy (2.5–5 months post diagnosis). Two cases died or were euthanized for unknown reasons shortly after diagnosis: one which was euthanized three weeks after starting azathioprine and one which died at home one month after diagnosis.
将终点评分与临床表现进行比较，体重<10 kg的患犬的终点评分(均分= 2.88)明显低于体重为>10 kg的患犬(均分= 4.14,P = 0.0045)。体重增加(P = 0.0128, r2 = 0.1)和较高的疫苗评分(P = 0.037, r2 = 0.07)与终点评分呈正相关。年龄增加(r2 = 0.13, P = 0.005),病变部位数量(r2 = 0.14, P = 0.003)和全身病变数量标志(r2 = 0.14, P = 0.0034)负相关端点(参见图3)。耳廓病变病例有显著更差的终点评分(平均分数= 2.97,P = 0.0033)和更高的治疗评分(分数= 95.04,P = 0.0049)。爪垫病变病例的终点评分明显较差(均值= 2.35,P = 0.0005)，但治疗评分无明显更高(P = 0.11)。只有单一疫苗注射部位的病灶倾向于较好的终点评分，但没有统计学意义(平均评分= 4.6,P = 0.073)。所有病例的终点评分均显著低于平均终点评分，所有见表S3。
When end-point scores were compared to clinical presentations, cases with a body weight <10 kg had significantly worse end-point score (mean score = 2.88) than those weighing >10 kg (mean score = 4.14, P = 0.0045). Increasing weight (P = 0.0128, r2 = 0.1) and higher vaccine scores (P = 0.037, r2 = 0.07) were positively correlated with end-point score. Increasing age (r2 = 0.13, P = 0.005), number of lesion sites (r2 = 0.14, P = 0.003) and number of systemic signs (r2 = 0.14, P = 0.0034) were negatively correlated with end-point (see Figure 3). Cases with pinnal lesions had significantly worse endpoint scores (mean score = 2.97, P = 0.0033) and higher treatment scores (mean score = 95.04, P = 0.0049). Cases with paw pad lesions had significantly worse endpoint scores (mean score = 2.35, P = 0.0005) but not significantly higher treatment scores (P = 0.11). Having only a single vaccine-site lesion trended toward a better endpoint score, but was not statistically significant (mean score = 4.6, P = 0.073). All lesions associated with endpoints significantly lower than the mean end-point for all cases are reported in Table S3)
使用己酮可可碱(平均终点评分= 3.27)与较高终点评分无显著相关性;然而，只有7例患者没有接受己酮可可碱治疗。此外，接受高剂量(>40 mg/kg/day)或低剂量(<40 mg/kg/day)己酮可可碱治疗的患者的终点评分没有显著差异。使用类固醇与明显较差的终点评分相关(平均得分= 2.72,P = 0.001)。
The use of pentoxifylline (mean end-point score = 3.27) was not significantly associated with greater end-point score; however, only seven cases were not treated with pentoxifylline. Additionally, there was no significant difference in end-point scores between cases treated with higher (>40 mg/kg/day) or lower (<40 mg/kg/day) doses of pentoxifylline. The use of steroids was associated with a significantly worse end-point score (mean score = 2.72, P = 0.001).
品种特异性结果
Breed-specific findings 约克夏㹴(n = 2)的终点评分显著低于其他所有病例(平均得分= 1,P = 0.036)，但与其他所有病例相比，治疗评分无显著差异(平均治疗得分= 80)。迷你杜宾 (n = 2)治疗评分显著高于对照组(平均治疗得分= 240,P = 0.0008)，但终点评分不显著低于对照组(平均得分= 2.5,P = 0.453)。
Yorkshire terriers (n = 2) had significantly worse endpoint scores (mean score = 1, P = 0.036) but not significantly different treatment scores (mean treatment score = 80) when compared to all other cases. Miniature pinschers (n = 2) had significantly higher treatment scores (mean treatment score = 240, P = 0.0008) but end-point scores were not significantly worse (mean score = 2.5, P = 0.453).
讨论
Discussion 虽然已经发表了一些病例分析研究疫苗相关的缺血性皮肤病和一些特发性缺血性疾病的病例报告，这里的数据代表了首次全面描述犬缺血性皮肤病。2 - 5,12,13本研究确定了一些品种倾向性和各种因素，当治疗缺血性皮肤病(不包括FDM)的病例时，可被作为预后参考。重要的是，本文提出半数以上病例不认为与疫苗有关，这表明有必要调查造成这种情况的其他潜在病因。
Although a few case series have been published examining vaccination-associated ischaemic dermatopathy and a few cases of idiopathic ischaemic disease have been reported, the data presented here represent the first comprehensive description of canine ischaemic dermatopathy.2–5,12,13 This study identified a number of breed predispositions and various factors that may be considered prognostic when dealing with cases of ischaemic dermatopathy (exclusive of FDM). Importantly, over half of the cases presented here were considered unlikely to be vaccine-associated, demonstrating the need to investigate other underlying causes for this condition.
1986年发表的最初的疫苗相关性缺血性皮肤病病例分析描述了13只犬(其中10只是贵宾犬，2只是比熊犬，1只是西施犬)，每只犬在最近接种狂犬疫苗的部位都有一个独立的病变。随后于1999年发表的病例分析包括3例喜乐蒂牧羊犬、西施犬和博美犬接种狂犬疫苗后出现的全身性缺血性病变。在进一步的研究中，回顾性分析了4例可能的疫苗引起的缺血性疾病，其临床病变一致。品种包括两只比熊犬，一只马尔济斯和一只迷你贵宾犬。总的来说，发表的数据和临床经验表明，小型犬的患病风险更高。
The original case series of vaccine-associated ischaemic dermatopathy published in 1986 described 13 dogs (10 of 13 were poodles, two were bichon frises and one was a shih tzu) each with a single lesion at the site of recent rabies vaccination.3 A subsequent case series published in 1999 included three cases of generalized ischaemic lesions following rabies vaccination in a Shetland sheepdog, shih tzu and Pomeranian.2 Four probable cases of vaccine-induced ischaemic disease, with consistent clinical lesions, were included in retrospective analysis of vasculitis in a further study; breeds included two bichon frises, one Maltese terrier and a miniature poodle.12 Altogether, published data, along with clinical experience, suggested that small breed dogs were at increased risk.
在本研究中，包括疫苗相关的和其他亚型的缺血性疾病，小型犬占大多数病例，其中63.6%小于10公斤。与之前的研究一致，吉娃娃犬、玩具贵宾犬、迷你贵宾犬和马尔济斯与普通犬种相比，在统计学上的比例过高。然而，包括约克夏㹴、中国冠毛犬、猎鼠㹴、舒伯齐犬和玩具猎狐㹴在内的其他一些小型犬种也在这一患病种群中占了过多的比例。拉布拉多寻回犬(n = 6)和拳击犬(n = 1)在本研究的背景人群中明显缺乏代表性。体重较轻与疫苗评分较低显著相关(P = 0.0029, r2 = 0.96)，这一发现似乎与以前发表的报告不一致，在以前的报告中，疫苗相关疾病几乎只在小型犬种中被描述。
In the present study, which included both vaccine-associated and other subtypes of ischaemic disease, small breed dogs represented the majority of cases, with 63.6% being <10 kg. Consistent with previous studies, Chihuahuas, toy and miniature poodles, and Maltese terriers were statistically over-represented compared to the general population. However, a number of other small breeds including Yorkshire terriers, Chinese crested dogs, rat terriers, schipperkes and toy fox terriers also were over-represented in this patient population. Labrador retrievers (n = 6) and boxers (n = 1) were significantly under-represented based on the background population. Smaller body weights were significantly correlated with lower vaccine scores (P = 0.0029, r2 = 0.96), a finding that appears to be at odds with previously published reports where vaccine-associated disease has been described almost exclusively in small breeds.2,3,12
品种间的差异很大。例如，玩具贵宾犬的疫苗评分(6只中的5只疫苗评分≥4)明显高于约克夏(4只均疫苗评分≤1)。此外，杰克罗素㹴(n = 5)的平均疫苗评分为1.33。之前的一份报告描述了5只杰克罗素㹴，它们的临床和组织学特征与本研究中描述的相同。在这个系列中，5只犬中有2只在首次发病时非常年轻(3个月和7个月大)。在这里报道的杰克罗素㹴中，皮肤活检的平均年龄(4.16岁)与整体组无显著差异;然而，这些病例中有几个在幼犬时期就有病变。这说明显然存在特殊品种易感幼犬发病型缺血性疾病/血管炎。考虑到这一点，与大型犬相比，较低的疫苗评分和较轻的体重之间的联系，可以解释小型犬的缺血性疾病类型具有较大的异质性。
Large differences between breeds were identified. As an example, toy poodles had significantly higher vaccine scores (five of six had a vaccine score of ≥4) when compared to Yorkshire terriers (where all four had a vaccine score of ≤1). Additionally, Jack Russell terriers (n = 5) had a low mean vaccine score of 1.33. A previous report described five Jack Russell terriers with identical clinical and histological characteristics to those described in this study. In that series, two of five dogs were very young (three and seven months of age) at initial presentation.13 In the Jack Russell terriers reported here, the mean age at skin biopsy (4.16 years) was not significantly different from the group as a whole; however, several of these cases had lesions described since puppyhood. This may represent a significant breed-specific predisposition to juvenile-onset ischaemic disease/vasculitis. Taking this into account, the association between lower vaccines scores and smaller body weights may be explained by greater heterogeneity in the types of ischaemic disease affecting small-breed dogs as compared to large-breed dogs.
根据这项研究的结果，以及之前发表的数据，很明显有一些品种具有或高或低的发生缺血性疾病的风险。通过对患有FDM的牧羊犬和喜乐蒂牧羊犬进行全基因组测序，已经确定了2个候选基因(PAN2和MAP3K7CL)。这两个基因的多态性，以及相应的风险MHC单倍型，增加了对疾病的易感性。这些发现也揭示了FDM犬发病年龄的差异;基因型属于中等风险的牧羊犬比基因型属于高风险的牧羊犬更有可能在以后的生活中患上这种疾病。值得注意的是，这些多态性在其他品种也有报道，其中一些在目前的研究中被过度代表。据报道，在两个新的候选基因或与FDM相关的MHC单倍型中存在一种或多种多态性的品种包括:吉娃娃、猎狐㹴、杰克罗素㹴、贵宾犬、拉布拉多寻回犬、约克夏㹴、腊肠犬、威尔士柯基犬和凯恩㹴。然而，只有两个品种的中危基因型被确定，杰克罗素㹴和威尔士柯基犬。这些发现似乎有力地表明，缺血性疾病的发生与遗传易感性有关。在北美和其他地区，需要进一步研究将这些遗传发现与高危品种的疾病联系起来，以确定发病机制和遗传力。
Based on the findings of this study, along with data published previously, there are clearly breeds at higher risk and lower risk of developing ischaemic disease.2,3,12Two candidate genes (PAN2 and MAP3K7CL) have been identified using whole-genome sequencing in collies and Shetland sheepdogs with FDM. Polymorphisms in these two genes, along with corresponding risk MHC haplotypes, conferred increased susceptibility to disease.14 These findings also shed some light on the differences in the age of onset in dogs with FDM; collies with a moderate-risk genotype were more likely to develop the disease later in life than individuals with a high-risk genotype. Notably, these polymorphisms were documented in other breeds, some of which were over-represented in the present study. Breeds reported to have of one or more polymorphisms, either in the two new candidate genes or MHC haplotypes associated with FDM, included the following: Chihuahuas, fox terriers, Jack Russell terriers, poodles, Labrador retrievers, Yorkshire terriers, Dachshunds, Cardigan Welsh corgis and cairn terriers. However, moderate-risk genotypes were identified in only two breeds, Jack Russell terriers and Cardigan Welsh corgis.14 These findings seem to strongly suggest a genetic susceptibility in the development of ischaemic disease. Further studies are needed to correlate these genetic findings with disease in at-risk breeds to ascertain pathogenesis and heritability, in North America and other regions.
目前对缺血性皮肤病的发病机制知之甚少。研究最充分的缺血性疾病，FDM，被认为是由一个遗传易感个体加上一个环境触发的免疫介导机制，。环境诱因，如感染、疫苗、药物、紫外线照射和应激事件，单个病例都曾有轶事性报道。在最初的一系列局灶性疫苗相关缺血性疾病中，曾怀疑疫苗物质在疾病发展中有直接作用。在这项研究中，所有患犬都只在接种狂犬病疫苗的部位有病变。有趣的是,发表的文章反映了流行率,目前的研究发现,只有疫苗注射部位病变的九只犬,三是玩具贵宾犬,一只比熊犬和一只西施犬,表明可能为这些品种有易感性,但没有全身性症状。此外，本研究中仅发生局灶性病变的病例，虽然没有统计学上的显著性差异，但治疗评分较整体组低，终点评分较高，表明局部病变整体预后较好。随后的一项研究疫苗引起的多灶性疾病患犬进行了检查，该研究描述了微血管系统周围的血供不足和补体沉积，表明先天免疫反应在疾病发展中发挥了作用。尽管其发病机制仍是个谜，但人类对幼年皮肌炎的研究表明，补体确实在患犬皮肤和肌肉中的小血管损伤中发挥作用。
Currently, little is known about the pathogenesis of ischaemic dermatopathy. The most well-studied of ischaemic diseases, FDM, is thought to be driven by an immune-mediated mechanism in genetically susceptible individuals following an environmental trigger. Environmental triggers such as infections, vaccines, drugs, UV exposure and stressful events have been described anecdotally in connection with individual cases.15 In the original series of focal vaccine-associated ischaemic disease, a direct role of the vaccine substance in the development of disease was suspected. Dogs in that study all had lesions located only at the site of rabies vaccination.3 Interestingly, mirroring the population in that publication, the current study found that of nine dogs with a vaccinesite-only lesion, three were toy poodles, one was a bichon frise and one a shih tzu, indicating a possible propensity for these breeds to develop local, but not generalized disease. Additionally, although not statistically significant, cases in this study with focal lesions only, had lower treatment scores and higher end-point scores than the group as a whole, indicating that localized disease may have a better overall prognosis. A subsequent study examining dogs with vaccine-associated multifocal disease described hypovascularity and complement deposition around microvasculature, suggesting a role for the innate immune response in development of disease.2 Although the pathogenesis remains enigmatic, human research on juvenile dermatomyositis suggests that complement does play a role in damage to small blood vessels in the skin and muscles of affected patients.16–18
虽然疫苗似乎在某些病例中发挥了作用，但全身性特发性缺血性皮肤病更可能包括一系列不同的疾病，其严重程度各不相同，引发原因不明，但范围广泛。由于本数据集中所代表的大多数病例(93例中的48例)可能与疫苗接种无关，因此很明显，疫苗只是这个谜题的一部分。这项研究没有发现任何与潜在疾病的显著关联，也没有发现其他诱因。因此，还需要进行更多的研究来检查这种疾病的特定亚型，以确定病因和了解缺血性病变的发病机制。
Although vaccines appear to play a role in some cases, generalized idiopathic ischaemic dermatopathy more likely encompasses a diverse group of diseases with variations in severity and unidentified but wide-ranging triggers. Because the majority of cases (48 of 93) represented in this dataset were likely to be unrelated to vaccination, it is clear that vaccines are only part of the puzzle. This study did not find any significant association with underlying disease, nor did it identify other triggers. Consequently, additional studies will be needed to examine specific subsets of the disease with the goal of identifying triggers and understanding the pathogenesis of ischaemic lesions.
本文报道的结果数据揭示了一些趋势，这些趋势可能被用作预后因素，并有助于指导患犬的治疗。一般来说，半数病例的终点评分较高，这表明大量病例的预后较好或更好，可以长期使用相对安全的药物维持。然而，另一半患犬要么死亡，要么被安乐死，要么继续接受长期免疫抑制治疗。与较低(较差)终点评分相关的因素包括体重<10公斤、年龄增长、病变部位较多、存在全身病变以及包括耳廓和爪垫在内的特定病变部位。可能因为耳廓出血和/或跛行，这些部位的病变被宠主认为是更严重。这种认知可能导致主人习惯性地对患有这些病变的犬进行长期治疗，而其他部位的脱毛或萎缩病变可能被忽略。年龄较大的犬可能因为存在其他疾病而有更糟的预后，或者可能没有被积极地治疗，因为它们对药物副反应的风险增加，并且担心比年轻的犬情况更糟。有趣的是，由于较低的疫苗评分与较年长的年龄相关，这可能表明这一亚群的发病机制存在不同。
The outcome data reported here reveal a number of trends that may be used as prognostic factors and help to guide therapy for patients. In general, half of the cases had high end-point scores, indicating that a large number of cases had a good or better outcome and could be maintained on relatively safe medications long-term. However, the other half of the cases either died, were euthanized, or continued long-term immunosuppressive therapies. Factors associated with lower (worse) end-point scores included weights <10 kg, increasing age, greater number of lesion sites, presence of systemic signs and specific lesion sites including the pinna and paw pad. It is possible that lesions at these sites were perceived as more severe by owners due to pinnal bleeding and/or lameness. This perception may have resulted in increased propensity for owners to continue long-term treatment in dogs with these lesions, whereas alopecic or atrophic lesions at other sites may have been ignored. Older dogs may have had worse outcomes due to the presence of comorbidities or may not have been treated as aggressively due a perception of increased risk for adverse effects and fear that they may have fared worse than younger dogs. Interestingly, because lower vaccine scores were correlated with older ages, this is likely to indicate a difference in pathogenesis for this subgroup.
总体治疗评分相对较低(中位治疗评分= 60)的只有少数异常值。这一发现表明，在没有显著改变药物或联合治疗的情况下，缓解或稳定的疾病可能已经实现。在治疗皮肌炎的基础上，己酮可可碱因其可能的流变学和免疫调节作用，历来被用作治疗的主要药物;然而，很少有报道评估其在犬的作用机制，特别当它被用于缺血性疾病时。一项对犬的药代动力学的研究没有发现任何可测量的血液学变化，这表明免疫效应可能在其中发挥更大的作用。这项研究并没有发现接受己酮可可碱治疗的犬和没有接受己酮可可碱治疗的犬在结果上的差异。然而，这一发现的解释是困难的，因为大多数病例(93例中的86例)和所有有终点评分的病例(62例中的62例)都用此药物治疗。此外，使用的己酮可可碱的剂量有很大的差异，使推广困难。因此，需要进一步评价该药物在犬体内的作用机制及其在前瞻性、对照研究中的应用，以更密切地研究己酮可可碱对疾病预后的影响。
Treatment scores were relatively low overall (median treatment score = 60) with just a few outliers. This finding indicates that remission or stable disease may have been achieved without significant changes in medications or combination therapy. Based on treatment of dermatomyositis, pentoxifylline historically has been used as the mainstay of therapy for its presumed rheological and immunomodulatory effects; however, few reports have evaluated its mechanism of action in dogs, especially as it pertains to use for ischaemic disease. One study examining pharmacokinetics in dogs did not find any measurable haematological changes, indicating that the immunological effects may play a larger role in its effect.19 This study did not identify differences in outcome between dogs treated with pentoxifylline and those that were not. However, interpretation of this finding is difficult because the majority of cases (86 of 93) and all cases with an endpoint calculation (62 of 62) were treated with this medication. Additionally, there was a large variation in the dose of pentoxifylline that was employed, making generalizations difficult. Thus, further evaluation of the mechanism of action of this drug in dogs and its use in prospective, controlled studies, are needed to more closely investigate the effect of pentoxifylline on disease outcome.
由于其回顾性，本研究存在一些固有的局限性，包括病历报告的差异、完整性和缺乏复诊。最重要的是，基于历史报道和品种倾向FDM被排除在外，所以可能有些病例可能与FDM更一致，但在非典型或未报道的品种中，被包括在内。此外，尽管在大多数纳入病例中都对记录进行了审查，但由于医疗记录质量和在疾病开始时可能遗漏了微小的病变，与疾病开始(例如从接种疫苗到病变开始)和进展相关的时间线很难解释。临床结果也很难建立在记录的基础上，因为病变可能进展缓慢，而其他可能导致疤痕，可能永远无法完全解决。此外，许多记录在描述病变的进展或恢复方面并不完整。由于这些原因，设立终点评分是为了提供更客观的终点评价，但它可能不反映“最终”预后。应该注意的是，采用的治疗评分系统并不反映一个静态的时间段。因此，复诊时间较长的犬有可能获得更高的治疗评分。然而，这个评分报告的治疗困难的病例并未反应出最终的结果。尽管就作者所知，这份报告包含了迄今为止最多的缺血性疾病患犬，但代表各种犬种的个体仍然相对较少。这使得对特殊品种敏感性的解释更加复杂。最后，这项研究，以及之前的大多数出版物，是基于美国/北美的犬种，因此研究结果可能不适用于世界其他地区。
Due to its retrospective nature, this study has a number of inherent limitations which include variations in medical record reporting, completeness and lack of follow-up. Foremost, because FDM was excluded based on reported histories and breed, it is possible that some cases that could be more consistent with FDM, but in atypical or unreported breeds, were included.Furthermore, although records were reviewed in most included cases, timelines associated with disease onset (e.g. time between vaccination and onset of lesions) and progression were difficult to interpret due to medical record quality and the possibility of subtle lesions being missed at disease onset. Clinical outcomes also were difficult to establish based on records because lesions may be slow to progress and others result in scarring that may never fully resolve. Additionally, many records were not complete in their description of progression or resolution of lesions. For these reasons, the end-point score was created to provide more objective end-point evaluation but it may not reflect a “final” outcome. It should be noted that the treatment scoring system employed does not reflect a static time period. Thus, dogs with a longer follow-up have the potential to have a greater treatment score. However, this score depicts difficulty in achieving remission in cases that may not have been reflected in the final outcome. Although this report, to the best of the authors’ knowledge, contains the largest number of dogs with ischaemic disease to date, there are still relatively few individuals representing various breeds. This complicates interpretation of breed-specific susceptibilities. Lastly, this study, along with the majority of previous publications, was based on canine populations in the USA/ North America, and thus findings may not be transferrable to other areas of the world.2,3,12–14
未来的研究需要帮助确定特发性疾病的诱因，并进一步阐明疾病的发病机制，包括特定疫苗成分的作用。考虑到FDM病例中新发现的与疾病严重程度相关的基因型，对遗传因素的检查可能有助于理解某些品种风险增加的原因。
Future studies are needed to help identify triggers of idiopathic disease and further elucidate disease pathogenesis, including the role of specific vaccine components. Given the newly identified genotypes associated with disease severity in cases of FDM, examination of genetic factors may help to understand why certain breeds are at increased risk.
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发表于 2019-8-7 21:50:28
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