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翻译：王帆；校对：刘欣 Oral glucocorticoid pulse therapy for induction of treatment of canine pemphigus foliaceus a comparative study Petra Bizikova and Thierry Olivry 摘要 背景-落叶型天疱疮(PF)常需要长期的免疫抑制治疗,这会导致不良反应。在人的天疱疮中,可以选择高剂量糖皮质激素脉冲疗法,在犬的落叶型天疱疮和寻常型天疱疮的治疗中,使用此方能使病患得到迅速的缓解。 目的-为了进一步确定脉冲疗法治疗犬PF的益处,在疾病管理的前三个月中,我们对口服糖皮质激素脉冲和传统治疗的效果进行比较。 动物-在PF管理的前12周,根据各自口服糖皮质激素的方案,将犬分为”传统(20只犬)”组和”脉冲(18只犬)”组。 结果-前12周达到痊愈的犬比例,”脉冲”组(61%)明显高于”传统”组(15%; P=0.0063)。犬口服糖皮质激素的最高剂量,”传统”组(中间值: 3.2 mg/kg)明显高于另一组(中间值: 1.1 mg/kg; P < 0.0001)。两组达到痊愈的时间,需要免疫抑制剂辅助治疗的比例,或者出现严重副作用的比例上都没有明显差异。 总结与临床意义-结果显示,口服糖皮质激素脉冲疗法有几个优点,如在前三周达到痊愈的比例更高,脉冲疗法的药物副反应少,而且糖皮质激素最高口服剂量的平均值更低。 介绍 Introduction 落叶型天疱疮（PF）是犬最常见的自体免疫性皮肤病，且在大多数情况下，需要长期治疗（通常是终生）。在有了长达30多年犬PF治疗经验后，糖皮质激素仍然是最常见的介入性治疗药。传统上，犬PF使用的泼尼松或泼尼松龙的诱导剂量范围是2.2到6.6mg/kg/天。一旦病情缓解，就会减少此药的剂量，通常需要几个月的时间。事实上，在最大的犬PF病例分析中，报道的犬皮肤病变痊愈（CR）的平均时间是9个月（范围是1-36个月）。令人惊讶的是，增加硫唑嘌呤作为辅助性治疗，并没有明显缩短这个时间。不幸的是，因为通常糖皮质激素的治疗时间会很长，通常会发生很多副作用，其中有许多会让主人无法接受，并导致安乐死。在两个病例分析中，有2-3%之间的被治疗的PF患犬被安乐死，因为不能接受治疗的副作用。因此，需要有一种替代治疗方案，能提供快速缓解，并且有可能减少高剂量通皮质激素所需的长期疗程。 Pemphigus foliaceus (PF) is the most common autoimmune skin disease of dogs, and, in most cases, it requires long-term (often life-long) treatment. After more than three decades of experience of treating dogs with PF, glucocorticoids remain the most common therapeutic intervention. Traditionally, the induction dose of prednisone or prednisolone used for canine PF ranges from 2.2 to 6.6 mg/kg/day. An attempt to reduce this dose is made as soon as the disease undergoes remission, which can often take several months. Indeed, the average time to complete remission (CR) of skin lesions in dogs reported in the largest canine PF case series was 9 months (range 1–36 months). Surprisingly, the addition of azathioprine as adjuvant therapy did not significantly shorten this time. Unfortunately, as the treatment with glucocorticoids is often prolonged, numerous adverse effects usually develop, many of which are intolerable for owners and lead to requests for euthanasia. In two series, between 2 and 3% of dogs treated for PF were euthanized because of unacceptable treatment adverse effects. Therefore, there is a need for alternative treatment protocols that would provide rapid remission and, potentially, reduce the need for prolonged courses of glucocorticoids at high dosages. 在三十多年前，人的寻常天疱疮（PV）采用高剂量糖皮质激素的脉冲疗法，作为一种能快速控制疾病的方法，使其能较早地减少糖皮质激素和/或辅助免疫治疗药物的剂量。最初，脉冲疗法被认为是在短时间内，使用很高剂量的糖皮质激素（10-20mg/kg甲基强的松龙或2-5mg/kg地塞米松）的间歇性静脉注射，联用或者不联用辅助性药物，像是环磷酰胺或硫唑嘌呤。虽然大多数开放性研究报道脉冲疗法的特殊好处，像是高效和快速痊愈表现，以及PV病患的低副作用，但是与传统PV疗法相比，随机双盲对照试验没有确定任何有优势的结果。 Pulse therapy with high-dose glucocorticoids for human pemphigus vulgaris (PV) was introduced more than three decades ago as a means to provide rapid disease control, which would then allow for earlier dose reduction of glucocorticoids and/or adjunctive immunosuppressive drugs. Originally, pulse therapy was defined as intermittent intravenous injections of very high doses of glucocorticoids (10–20 mg/kg of methylprednisolone or 2–5 mg/kg of dexamethasone) over a short period of time, with or without adjuvant drugs such as cyclophosphamide or azathioprine. While most open studies reported the exceptional benefits of pulse therapy, such as a high rate and a rapid onset of CR, as well as a low rate of adverse effects in patients with PV, a randomized double-blinded controlled trial did not identify any outcome benefits when compared to conventional PV therapy. 糖皮质激素脉冲疗法有效的证据仅限于兽医皮肤病学。一项开放式研究显示，在以静脉注射甲基强的松龙单次冲击剂量11mg/kg，连用三天后，一只PV患犬和三只PF患犬的皮肤病变发生了明显且快速的改善（时间未说明）。四只犬中都没有观察到与这次脉冲治疗相关的副反应。虽然只报道了一种随机的，20只PF患犬没有进行对照试验，但与使用常规疗法得到的结果相比，没有显示出静脉注射甲基强的松龙的单次冲击剂量（10mg/kg连用三天）有任何额外优势。 The evidence of efficacy of glucocorticoid pulse therapy is limited in veterinary dermatology. An open study reported a dramatic and rapid improvement (time not specified) of skin lesions in one dog with PV and three with PF after a single pulse of intravenous methylprednisolone at 11 mg/kg for three consecutive days. Adverse effects associated with this pulse therapy were not observed in any of the four dogs. Although only reported in abstract form, a randomized, controlled trial of 20 dogs with PF did not suggest any additional benefits of a single intravenous pulse of methylprednisolone (10 mg/kg for three consecutive days) when compared to the outcomes achieved using conventional therapy. 我们的目标是对比口服糖皮质激素脉冲治疗和传统治疗，在疾病管理前3个月的治疗效果（即诱导期）。为了减少与任何回顾性研究相关的不精确性，只报道明显可见的结果。这些包括，每个治疗组中，获得痊愈的犬的数量、痊愈时间、需要辅助性免疫抑制治疗的犬的数量以及出现严重药物副作用的犬的数量。 Our objectives were to compare the therapeutic outcomes of oral glucocorticoid pulses and traditional therapy during the first 3 months of disease management (i.e. induction phase). To reduce the relative imprecision associated with any retrospective study, only outcomes that were clearly identifiable were reported. These included, for each treatment group, the number of dogs achieving CR, the time to CR, the number of dogs requiring adjuvant immunosuppressive therapy and the number of dogs experiencing severe adverse drug reactions. 材料和方法 Materials and methods 入选标准 Inclusion criteria 在这项研究中，我们检查了1994年10月至2013年12月在北卡罗莱纳州立大学（NCSU）兽医医院皮肤科就诊的所有权的医疗记录。对1994年到2003年的医疗记录数据进行了回顾性分析，而从2004年1月以后的PF患犬的数据则以一种前瞻性形式录入。 For this study we examined medical records of all dogs diagnosed with PF at North Carolina State University’s (NCSU) Veterinary Hospital’s Dermatology Service between October 1994 and December 2013. Medical record data from 1994 to 2003 were examined retrospectively, whereas data from dogs with PF seen after January 2004 were entered in a prospective fashion. 所有考虑列入定群研究的犬都被诊断为“典型的”PF表现型。犬表现为极少数的糜烂和结痂，伴有或不伴有脓疱，主要位于脸颊两侧和对称性病变模式；病变可能出现在身体其他部位（全身型），但是需要有“典型的”面部病变表现。在所有犬中，即无临床表现或有细微皮肤感染症状（例如：中性粒细胞内的球菌），或在病变活跃部位也没有交界处皮炎表现，显微镜下都可见棘层松懈角质细胞。结合临床表现，排除其他有皮肤棘层松懈组织学特性的疾病，例如由产生去角质毒素的葡萄球菌导致的脓皮病和脓疱性皮肤癣菌病。本研究中的病例，未进行组织和血液的抗角质细胞自体抗体和/或循环抗桥粒胶蛋白-1抗体增加的检测。 All dogs considered for inclusion in this cohort study had been diagnosed with a ‘classic’ phenotype of PF. The dogs exhibited – a minima – erosions and crusts, with or without pustules, located predominantly on the face in a bilateral and symmetrical fashion; lesions could be present on other body locations (generalized phenotype), but the presence of a ‘classic’ facial involvement was required. In all dogs there was microscopic demonstration of acantholytic keratinocytes with no clinical or microscopic signs of skin infection (i.e. intracellular cocci in neutrophils), nor interface dermatitis at the site of active lesions. Together with the clinical phenotype, the lack of these histological features permitted the exclusion of other acantholytic diseases such as pyoderma due to exfoliative toxin-producing staphylococci and pustular dermatophytosis. The demonstration of skin-fixed or circulating anti-keratinocyte autoantibodies and/or elevated circulating anti-desmocollin-1 antibodies was not required for inclusion of the cases herein. 排除条件 Exclusion criteria 我们也排除了以下这些犬：(i)在进入NCSU之前已经接受免疫抑制治疗的；或(ii)NCSU兽医未给予口服糖皮质激素治疗的；或(iii)在PF治疗开始时，已给予一种辅助性免疫抑制治疗药的；或(iv)至少12周没有被一名NCSU的兽医随访过的；或(v)未按治疗建议完成的宠物主人。最后，我们排除了在治疗前三个月接受过“传统法”和“脉冲法”口服糖皮质激素治疗的犬。 We excluded from this series dogs that either: (i) had received immunosuppressive regimens prior to coming to NCSU; or (ii) had not been treated with oral glucocorticoids by a veterinarian at NCSU; or (iii) had been prescribed an adjuvant immunosuppressive drug at the onset of PF treatment induction; or (iv) had not been followed up for at least 12 weeks by one of the veterinarians from NCSU; or (v) had owners who had not been compliant with treatment recommendations. Finally, we excluded dogs that had received a combination of ‘traditional’ and ‘pulse’ protocols of oral glucocorticoids during the first trimester of treatment induction. 治疗组 Treatment groups 根据前12周口服糖皮质激素治疗PF的方法，把符合纳入标准的犬分为两组： Dogs that satisfied inclusion criteria were divided into two groups based on their oral glucocorticoid regimen during the first 12 weeks of PF treatment induction: “传统”组：传统法口服糖皮质激素治疗 ‘Traditional’ group: traditional oral glucocorticoid therapy 这些犬按照一种传统的治疗犬PF的标准管理法（即诱导治疗，目标剂量等于或大于2mg/kg/天，这个剂量一直持续到病变缓解为止；随后糖皮质激素的剂量需要降低，以保持症状完全缓解，并长期不间断的进行每日治疗）口服糖皮质激素（泼尼松或泼尼松龙）。 These dogs received oral glucocorticoids (prednisone or prednisolone) in a standard-of-care protocol traditionally employed for treatment of canine PF (i.e. inducing treatment with a targeted dosage equal or greater than 2 mg/kg/day, this dosage being continued until lesion remission; the doses of glucocorticoid being then reduced as needed to maintain the complete remission of signs, and aiming, in the long term, for intermittent daily therapy). “脉冲”组：口服糖皮质激素脉冲治疗 ‘Pulse’ group: oral glucocorticoid pulse therapy 在这组，患犬接受至少一次的口服糖皮质激素脉冲治疗，一次脉冲治疗是指泼尼松或泼尼松龙，10mg/kg，每日一次，连用三天，随后降低糖皮质激素剂量（目标：<2mg/kg/天）。尽管在三天的脉冲治疗里已经使用了更低剂量的糖皮质激素，但还是有新的病变出现，在兽医的判断下，仍可以重复进行脉冲治疗；脉冲治疗不能超过每周一次。每周都要评估一次每只犬的进展（每周复诊一次或相关兽医和/或主人进行直接交流）直到达到痊愈。 In this group, dogs received at least one pulse of oral glucocorticoids, each pulse consisting of prednisone or prednisolone at 10 mg/kg once daily for three consecutive days, followed by a reduced dosage of the glucocorticoid (target: <2 mg/kg/day). Pulses could be repeated, at the discretion of the veterinarian, if new lesions continued to appear in spite of the lower doses of glucocorticoids given between 3-day pulses; pulses were not to be repeated more than once weekly. The progress of each dog was evaluated on a weekly basis (weekly recheck visit or direct communication with the referring veterinarian and/or owner) until CR was achieved. 如果每组有犬在PF治疗前12周期间，也接受了烟酰胺（尼克酰胺）-四环素联合、外用治疗糖皮质激素或口服抗生素，这些干预措施都已被记录。 If dogs from either group were also treated with a nicotinamide (niacinamide)–tetracycline combination, topical glucocorticoids or oral antibiotics during the first 12 weeks of PF treatment induction, such interventions were recorded. 如果，在至少4周的口服糖皮质激素治疗后（使用“传统法”或“脉冲法”），还持续有新的脓疱或糜烂病变出现，相关兽医可以选择添加一种辅助性免疫抑制药物，如硫唑嘌呤或环孢素，按这类疾病的常规使用剂量。使用这种辅助性治疗也被记录下来。 If, after at least 4 weeks of oral glucocorticoid therapy (using either ‘traditional’ or ‘pulse’ protocols), new pustules or erosive lesions continued to appear, the attending veterinarian had the option of adding an adjuvant immunosuppressive drug, such as azathioprine or ciclosporin at dosages normally used for this disease. This use of adjuvant therapy was also recorded. 主要观测指标 Main outcome measures 最初，为了确保两组犬的相似度，在治疗组中对比了疾病的发生年龄以及只有面部病变表现和有一般性表现的病患百分比。由于回顾性记录的相对不精确性，每组中我们选择了从临床访问总结和每只犬的客户沟通记录中明显可见的结果进行测试： Initially, to ensure that both groups of dogs were similar, the age of disease onset and the percentage of subjects with exclusively facial versus generalized phenotype were compared among treatment groups. Due to the relative imprecision of reviewing records retrospectively, we then selected outcome measures that were clearly identifiable from the clinical visit summaries and client communication records of each dog included in either group: 1 在PF治疗的前12周中，达到痊愈的犬的数量（%）。完全缓解是指所有直接由PF导致的病变完全消失。（例如：脓疱、糜烂和糜烂上的结痂） 1 Number (percentage) of dogs achieving CR during the first 12 weeks of PF treatment induction. Complete remission was defined as a complete disappearance of all lesions directly attributed to PF (e.g. pustules, erosions and crusts covering erosions). 2 痊愈时间，指如果在PF治疗的前12周中达到痊愈的话，达到痊愈所需时间（周）。 2 Time to CR, defined as the time (in weeks) needed to achieve CR, if so attained, during the first 12 weeks of PF treatment induction. 3 需要辅助性免疫抑制治疗的犬的数量（%），后者是指增加了硫唑嘌呤或环磷酰胺（或其他具有类似免疫抑制特性的药物）。 3 Number (percentage) of dogs needing adjuvant immunosuppressive therapy, the latter being defined as the addition of azathioprine or ciclosporin (or any other drug with similar immunosuppressive properties). 4使用抗生素、外用糖皮质激素或烟酰胺联合四环素治疗的犬的数量（%），因为这些干预已经显示或被认为对结果有影响。 4 Number (percentage) of dogs treated with antibiotics, topical glucocorticoids or niacinamide with tetracycline, as these interventions have been shown, or are perceived, to have an influence on outcome. 5有严重药物副反应（ADEs）的犬的数量（%），指死亡或需要医疗管理/治疗的ADEs。糖皮质激素治疗的药物副反应（如：多饮多尿等）不属于这一类。 5 Number (percentage) of dogs experiencing severe adverse drug effects (ADEs), defined as death or ADEs requiring medical attention/treatment. Adverse drug events that are expected with glucocorticoid therapy (e.g. polyuria, polydipsia, etc.) were not included in this category. 统计分析 Statistical analyses 利用双面的确切概率测试，对组间的分类参数进行了比较；用一种Mann–Whitney紫外线测试法测的连续值。显著性阈值设定为P=0.05。用Prism 5（Graphpad software, San Diego, CA, USA）进行统计分析。 The comparison of categorical parameters between groups was done using two-sided Fisher’s exact tests; that of continuous values was made with a Mann–Whitney U-test. The threshold of significance was set at P = 0.05. Statistical analyses were done using Prism 5 (Graphpad software, San Diego, CA, USA). 结果 Results 研究对象 Study subjects 在图1所示的流程图中可以找到与“传统组”和“脉冲组”有关的犬的分组细节。这两组的犬的发病年龄，或者一般性病变表现和局限于面部的病变的犬的比例无明显差异（数据未显示）。 Details on the allocation of dogs with PF to the ‘traditional’ and the ‘pulse’ groups can be found in the flow chart presented as Figure 1. These groups were not significantly different in regards to age of the dogs at the time of disease onset, or the proportion of dogs with a generalized rather than facially restricted disease (data not shown). 每组的主要测量结果见表1。在PF治疗的前12周中，“脉冲组”达到痊愈的犬的比例（61%）明显高于“传统组”（15%）（P=0.0063）。在脉冲治疗和传统治疗对比期间，为了痊愈所需的治疗（NNT）的数量（例如：痊愈比例之间的差倒数，向上的圆形）预测是三只，一个低位数（例如：如传统治疗相比，为了增加痊愈有3只犬将接受脉冲治疗）。在图2中，每周达到痊愈的犬的比例被绘成累积图，如图3所示，在第一个口服糖皮质激素脉冲后有两例快速得到改善。在治疗的前12周内，接受糖皮质激素脉冲治疗的犬的痊愈时间和需要辅助性免疫抑制治疗的犬的比例更低，但是两组间没有显著差异（表1）。 The main outcome measures for each group can be found in Table 1. The proportion of dogs achieving CR during the first 12 weeks of PF treatment induction was significantly (P = 0.0063) higher in dogs from the ‘pulse’ group (61%) compared to those from the ‘traditional’ group (15%). The number needed to treat (NNT) for CR during pulse compared to traditional therapy (i.e. the inverse of the difference between percentages of CR, rounded upward) was calculated at three, a low number (i.e. three dogs would need to be treated with pulse therapy to get an additional CR compared to traditional protocols). The proportion of dogs reaching CR every week is depicted in a cumulative graph in Figure 2, and two examples of rapid improvement following the first oral glucocorticoid pulse are shown in Figure 3. The time to CR and the proportion of dogs needing adjuvant immunosuppression during the first 12 weeks of treatment induction were lower in dogs receiving glucocorticoid pulses, but they were not significantly different between groups (Table 1). 脉冲组的平均时间和/中间值是2（范围：1-4）。治疗期间，“传统组”的犬口服糖皮质激素[中间值3.2; 95%可信区间(CI): 2.5–3.9 mg/kg]最大剂量明显高于第二组的犬的脉冲剂量(中间值1.1; 95% CI: 1.1–1.7 mg/kg; P < 0.0001)。 The mean and/median number of pulses was two (range: 1–4). The maximal oral glucocorticoid dosage given to dogs from the ‘traditional’ group during treatment induction was significantly higher [median 3.2; 95% confidence interval (CI): 2.5–3.9 mg/kg] than that given between pulses to dogs from the second group (median 1.1; 95% CI: 1.1–1.7 mg/kg; P < 0.0001). 在“传统组”和“脉冲组”之间，使用外用糖皮质激素治疗的犬的比例没有显著差异（40% 比67%; P = 0.119）。同样，除糖皮质激素治疗外，接受烟酰胺联合四环素治疗的犬的比例，“传统组”和“脉冲组”间没有明显差异(20% 比50%; P = 0.087)。在前12周治疗期间，接受抗生素治疗的犬，“传统组”（40%）和“脉冲组”（44%）无明显差异（P=1.000）。 The percentage of dogs treated with topical glucocorticoids was not significantly different between ‘traditional’ and ‘pulse’ groups (40% versus 67%; P = 0.119). Similarly the percentage of dogs receiving niacinamide and tetracycline in addition to their glucocorticoids was not significantly different between ‘traditional’ and ‘pulse’ groups (20% versus 50%; P = 0.087). There was no significant difference in the prescription of antibiotics during the first 12 weeks of treatment induction in dogs from the ‘traditional’ (40%) and those from the ‘pulse’ group (44%) (P = 1.000). 在两组中，有严重ADEs的犬的数量是相同的（各两只犬）。在“传统组”中，有一只犬突然死亡，另一只出现了硫唑嘌呤诱导的骨髓抑制。在“脉冲组”中，一只犬出现了医源性库兴氏综合征的症状，因主人要求而被安乐死，另一只犬在第四次脉冲治疗时出现了黑便。在“传统组”中，在糖皮质激素治疗中，除了预期的药物副反应以外（例如：多饮多尿、食欲增加、体重增加），没有发生其他的ADEs发生。但是在“脉冲组”中，有两只犬（11%）出现一过性腹泻，两只（11%）表现出短暂的攻击行为；这些ADEs在脉冲治疗结束时自行恢复。 The number of dogs with severe ADEs was identical in both groups (two dogs each). In the ‘traditional’ group, one dog died suddenly and one developed azathioprine-induced myelosuppression. In the ‘pulse’ group, one dog was euthanized at his owner’s request due to the appearance of signs of iatrogenic Cushing’s syndrome and one dog developed melena on its fourth pulse. In the ‘traditional’ group, there were no ADEs other that those expected to occur with glucocorticoid therapy (e.g. polyuria/polydipsia, polyphagia, weight gain). In the ‘pulse’ group, however, two dogs (11%) developed transient diarrhoea and two (11%) exhibited transient aggressive behaviour; these ADEs regressed spontaneously at the end of the pulses. 讨论 Discussion 人天疱疮的糖皮质激素脉冲治疗的主要目的是疾病缓解效率高、速度快，以及有可能建立一个长期痊愈。在这种回顾性研究中，口服糖皮质激素脉冲治疗与使用传统治疗方法相比，在治疗的前3个月犬达到痊愈的比例明显增高（脉冲组：61%，传统组：15%）。尽管一篇大型案例分析中，报道的91只达到痊愈的P F患犬中，有52%的犬使用的常规治疗方案，但是这不能与我们的痊愈率直接进行比较，因为在我们的研究中，报道的痊愈的时间范围并不仅限于前三个月的治疗。一项评估静脉注射甲基强的松龙10mg/kg/天的单次脉冲治疗（连用3天）的有效性的随机对照试验，表明组间反应无差异（脉冲组67%；传统组75%）。再次表明，报告的痊愈时间范围并不局限于前三个月的治疗。此外，在我们的研究中，患犬只接受了重复的脉冲治疗，而随机对照试验中的患犬在开始治疗时只用了一次脉冲治疗。 The main goal of glucocorticoid pulse therapy in human pemphigus is to achieve a higher rate and speed of disease remission and, potentially, to establish a long-term CR. In this retrospective study, oral glucocorticoid pulse therapy resulted in a significantly higher proportion of dogs achieving CR during the first 3 months than in those using traditional protocols (pulse: 61%, traditional: 15%). Although a large case series of 91 PF-affected dogs reported CR in about 52% of dogs using conventional treatment approaches, a direct comparison with our CR data could not be made because the time frame of the reported CRs was not limited to the first 3 months of treatment, as in our study. Results of a randomized controlled trial evaluating the efficacy of a single pulse (three consecutive days) of intravenous methylprednisolone dosed at 10 mg/kg/day, showed no difference in response between groups (pulse dose 67% CR; traditional dose 75% CR). Again, the time frame of the reported CR was not limited to the first 3 months of treatment.Moreover, dogs in our study received repeated pulses, whereas dogs in the randomized control trial received only a single pulse at the beginning of their treatment. 在本研究中，脉冲治疗组痊愈的中间时间是6.9周。在随机对照试验中，报道的痊愈平均时间是8.2周。在两项研究中，脉冲组和传统组之间的痊愈时间无明显差异。此外，我们研究中的两个治疗组的痊愈中间时间，比前篇报道6.5个月的痊愈中间时间明显更短。这种差异的原因尚不明确。 In the present study, the median time to CR in the pulse therapy group was 6.9 weeks. The mean time to CR reported in a randomized control trial was 8.2 weeks. In both studies, the time to CR was not significantly different between the pulse and the traditional groups. Furthermore, the median time toCRin both treatment groups in our study was markedly shorter than the median time to CR of 6.5 months previously reported. The reason for such differences remains unknown. 在管理犬PF时常使用辅助性免疫抑制药物，尽管其附加效益尚未得到充分证实。事实上，至今为止所报道的最大病例分析中的治疗结果分析显示，对单一使用糖皮质激素治疗有反应的犬的数量，与糖皮质激素联合硫唑嘌呤治疗有反应的犬的数量之间无明显差异。在我们的研究中，允许犬接受辅助性免疫调节治疗，在至少4周的口服糖皮质激素治疗后（使用传统法或脉冲法），还有新的脓疱或糜烂病变出现。与“传统组”（60%）相比，“脉冲组”（39%）中需要接受辅助性免疫调节的犬的比例更低，但差异不显著。 Adjuvant immunosuppressive drugs are commonly used for management of canine PF, even though their additional benefit has not been fully confirmed. Indeed, the analysis of treatment outcomes in the largest case series reported to date did not show a statistically significant difference between the numbers of dogs responding to glucocorticoid monotherapy and dogs treated with combination of glucocorticoids and azathioprine. In our study, adjuvant immunoregulatory therapy was allowed in dogs in which, after at least 4 weeks of oral glucocorticoid therapy (using either traditional or pulse therapy), new pustules or erosive lesions continued to appear. While the proportion of dogs needing adjuvant immunoregulation was lower in the ‘pulse’ (39%) compared to the ‘traditional’ (60%) group, the differencewasnotsignificantlydifferent. 除了快速建立缓解以外，脉冲治疗的目的是减少糖皮质激素的整体用量。虽然在我们的研究中，由于其回顾性研究的性质，糖皮质激素的累积剂量无法计算，但“传统组”患犬的最大口服糖皮质激素的平均剂量明显高于“脉冲组”的犬。与传统疗法相比，最近在人PV和犬PF中进行的糖皮质激素脉冲治疗的随机对照试验中，未能证明脉冲疗法对每日平均糖皮质激素和/或糖皮质激素积累剂量之间的有效性有任何影响。尽管如此，研究人PV的作者报道了一个明确的，但没有统计学意义的趋势，在“脉冲组”中使用泼尼松龙达到痊愈的平均剂量更低。最后我们推测，之前报道的犬PF脉冲治疗缺乏附加效应（痊愈时间更短、糖皮质激素使用总剂量更低）这一点，可能与试验开始时使用了一次糖皮质激素脉冲治疗有关，这与我们研究中通常给犬使用多次脉冲治疗形成了对比。同样地，有报道称，人天疱疮的糖皮质激素脉冲治疗方案需要重复进行脉冲治疗，直到达到疾病的痊愈。 In addition to rapid establishment of remission, a goal of pulse therapy is to reduce the overall amount of glucocorticoids received. While the cumulative dose of glucocorticoids could not be calculated in our study due to its retrospective nature, the average maximal oral glucocorticoid dosage given to dogs from the ‘traditional’ group was significantly higher than that given between pulses to dogs from the ‘pulse’ group. In contrast, recent randomized control trials of glucocorticoid pulse therapy in human PV and canine PF failed to demonstrate any beneficial effect of pulse therapy on the average daily dose of glucocorticoids and/or the cumulative dose of glucocorticoids when compared to traditional therapy. Nevertheless, authors of the human PV study reported a positive, but not statistically significant, trend with a lower mean prednisolone dose used to achieve CR in the ‘pulse’ group.Finally, we speculate that the lack of added benefit (shorter time to CR, lower total dose of glucocorticoids used) for pulse therapy reported previously for canine PF could be related to the single glucocorticoid pulse given at the beginning of the trial, which is in contrast to the often multiple pulses given to the dogs in our study.Similarly, reported protocols for glucocorticoid pulse therapy in humans with pemphigus involve repeated pulses until disease CR is reached. 因为犬PF的抗生素治疗效果有矛盾的结果，所以在我们的研究中，每组犬都记录了接受抗生素同时也接受免疫抑制药物的犬的数量。在开始治疗的前12周，各组接受抗生素治疗的犬的比例没有显著差异。 Because of the contradictory results regarding the effect of antibiotic therapy on the outcome of canine PF, the number of dogs receiving antibiotics concurrently with the immunosuppressive drugs was recorded for each group of dogs in our study. There was no significant difference between groups in the percentage of dogs having received antibiotics during the first 12 weeks of treatment. 与PF患犬治疗相关的药物副反应是安乐死的最常见原因。因为大多数ADEs与长期使用中到高剂量的糖皮质激素有关，所以在我们的研究中，经过3天脉冲治疗以及低维持剂量后，长期治疗导致的ADEs有可能更少。在本研究中，各组患严重ADEs的犬的数量相同，这与其他两项研究结果相似。 Adverse drug effects related to the treatment of dogs with PF are the most common reason for euthanasia. Because most ADEs are associated with the long-term use of medium to high dosages of glucocorticoids, the 3-day courses of pulse therapy in our study followed by low maintenance dosages could, potentially, result in fewer ADEs in the long term. In this study, severe ADEs were documented in an equal number of dogs from each group, which was similar to findings reported intheothertwopulsestudies. 与前两篇报道相比，我们的研究中使用的糖皮质激素脉冲治疗的途径不是静脉注射，而是口服。与人的方法相似。在犬中，泼尼松龙口服吸收率高，能快速提供充足的血药浓度（血浆浓度峰值约1.5h内），充分证明这种动物的口服脉冲治疗是合理的。当考虑到单一糖皮质激素治疗和人医报到的给药途径之间剂量等价时（500mg甲基强的松龙等同于625mg泼尼松），可以假设我们研究中使用的泼尼松/泼尼松龙的口服剂量可能会略高一些。有趣的是，在不同剂量的甲基强的松龙的短期诱导结果中，人们没有发现明显的差异(1000mg对250mg，5mg/kg对10mg/kg等)，这表明我们剂量的微小差异可能与临床无相关性。最后，一项研究表明，11-b-羟基脱氢酶，一种负责将泼尼松转化为活性成分泼尼松龙的酶，可能会因高剂量的泼尼松而达到饱和。这一观察结果提出了一个问题，像泼尼松龙或地塞米松这样的糖皮质激素是否比泼尼松更适合脉冲治疗。 In contrast to these previous two reports, the route of administration of glucocorticoid pulses in our study was not intravenous but oral. A similar approach has been used in people. In dogs, the high oral absorption of prednisolone that very rapidly provides an adequate drug concentration (peak plasma concentration within about 1.5 h) fully justifies an oral route for pulse therapy in this species. When considering the dose equivalency between individual glucocorticoids and their route of administration reported in people (500 mg of methylprednisolone equals 625 mg of prednisone), it could be hypothesized that the oral dose of prednisone/prednisolone used in our study could have been slightly higher. Interestingly, several controlled comparative dose studies in people did not find significant differences in short-term outcomes induced by different doses of methylprednisolone (1000 mg versus 250 mg, 5 mg/kg versus 10 mg/kg, etc.), suggesting that the small difference in our dose might have been clinically irrelevant. Finally, one study suggested that 11-b-hydroxydehydrogenases, an enzyme family responsible for the conversion of prednisone to its active form prednisolone, might get saturated with higher dosages of prednisone. This observation raises the question whether glucocorticoids such as prednisolone or dexamethasone might be more suitable for pulse therapy rather than prednisone itself. 本研究结果的可行性在一定程度上因其局限性而受到限制，像是患者数量较少，以及回顾性的性质。尽管如此，我们的研究结果表明，使用本文报道的治疗方案进行口服糖皮质激素脉冲治疗有以下几点好处，比如(i)在前三个月达到痊愈的犬的比例较高；(ii)在脉冲治疗间，给予的口服糖皮质激素的平均最大剂量更低；(iii)最小ADEs。 The translatability of the results of this study is, to some extent, restricted by its limitations, such as the relatively small number of patients and its retrospective nature. Nonetheless, our results suggest several benefits that could be associated with oral glucocorticoid pulse therapy using the protocol reported herein, such as (i) a higher percentage of dogs achieving CR during the first three months, (ii) a lower average maximal oral glucocorticoid dosage given between pulses, and (iii) minimal ADEs. 对未来研究的设计，包括更多的病例数和使用泼尼松龙而不是泼尼松，可提供更多有关口服糖皮质激素脉冲治疗犬PF的疗效信息。 Future studies of a prospective design, including more patients and the use of prednisolone rather than prednisone, could provide additional information on the benefit(s) of oral glucocorticoid pulse therapy for management of canine PF. 图1：“传统组”和“脉冲组”犬的分配流程图。TOGT：传统法口服糖皮质激素治疗；OGPT：口服糖皮质激素脉冲治疗。“非典型”落叶型天疱疮（PF）:没有典型面部病变表现的PF。 Figure 1. A flow chart demonstrating the allocation of dogs into ‘traditional’ versus ‘pulse’ groups. TOGT, traditional oral glucocorticoid therapy; OGPT, oral glucocorticoid pulse therapy. ‘Atypical’ pemphigus foliaceus (PF), PF in which the typical facial lesion distribution is missing. 表1：在前12周的治疗期间，“传统组”和“脉冲组”的测试结果 图2：一个累积表，描述每周达到痊愈的犬的比例。 图3：落叶型天疱疮的临床案例（左）和首次口服糖皮质激素脉冲治疗后的快速治疗反应（右）
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发表于 2018-10-15 11:56:03
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