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Long-term use of lokivetmab in dogs with atopic dermatits
洛基维特单抗在特应性皮炎犬的长期应用
Bettina Kasper | Yury Zablotski | Ralf S. Mueller
翻译：王帆
Abstract
摘要
Background: Lokivetmab, a caninised monoclonal antibody against interleukin (IL)-31, is an effective treatment for the pruritus associated with canine atopic dermatitis (cAD).
Objectives: To investigate the efficacy and safety of lokivetmab during longterm treatment defined as at least three consecutive lokivetmab injections in atopic dogs under field conditions. To assess individual factors influencing treatment outcome and adverse events.
Animals: 150 dogs with cAD.
Materials and Methods: Medical records of dogs treated with lokivetmab were reviewed, and owners and/or veterinarians were contacted as needed for follow-up. A decrease of the pruritus Visual Analog Scale (PVAS) score by ≥2 or a PVAS score≤2 after treatment was considered as treatment success. Logistic regression was used to investigate the influence of a variety of factors on outcome: type of cAD (food versus environment), age at first lokivetmab administration, disease chronicity, dosage and/or secondary infection. Any adverse event that occurred during the study period was recorded.
Results: Lokivetmab reduced the PVAS score with long-term use (p<0.01); the success rate was 53 of 69 total dogs (77%). The probability of treatment failure decreased with increasing treatment duration. None of the factors investigated influenced the treatment outcome. Twelve dogs of 150 (8%) showed adverse events such as gastrointestinal signs or lethargy.
Conclusion and Clinical Relevance: Lokivetmab appears to be an effective and safe long-term anti-itch therapy for dogs with cAD.
背景:洛基维特单抗是一种犬用抗白细胞介素(IL)-31的单克隆抗体，是治疗犬特应性皮炎(cAD)相关瘙痒的有效药物。
目的:探讨洛基维特单抗在长期治疗中的有效性和安全性，长期治疗定义为至少连续三次注射洛基维特单抗在野外条件下对特应性皮炎犬进行治疗。评估影响治疗结果和副作用事件的个体因素。
动物:150只cAD患犬。
材料和方法:回顾使用洛基维特单抗治疗犬的医疗记录，并根据需要联系宠主和/或兽医进行随访。治疗后瘙痒视觉模拟量表(PVAS)评分降低≥2分或PVAS评分≤2分视为治疗成功。使用Logistic回归来研究各种因素对结果的影响:cAD类型(食物与环境)、首次使用洛基维特单抗的年龄、疾病慢性性、剂量和/或继发感染。记录研究期间发生的任何副作用事件。
结果:洛基维特单抗长期使用降低PVAS评分(p<0.01);69只犬中成功率为53只(77%)。治疗失败的概率随治疗时间的延长而降低。所有调查的因素都不影响治疗结果。150只犬中有12只(8%)出现胃肠道症状或嗜睡等不良事件。
结论和临床意义:洛基维特单抗似乎是一种有效和安全的长期抗痒治疗犬cAD。
KEYWORDS
关键词
canine, cytopoint, IL-31, monoclonal antibody
犬，赛妥敏，IL-31，单克隆抗体
INTRODUCTION
介绍
Canine atopic dermatitis (cAD) is a common allergic skin disease, with a reported prevalence of 10%–15%.The chronic skin condition is characterised by pruritus, often associated with cutaneous inflammation, and typically requires life-long therapy.Although the pathogenesis of this multifactorial disease is still not fully understood,there are a number of symptomatic treatment options, which differ in their efficacy and associated adverse events.Broad-spectrum medications such as glucocorticoids and calcineurin inhibitors were the only therapies available in the past decades, yet newer therapeutic approaches provide more targeted treatment options with fewer adverse events.
犬特应性皮炎(cAD)是一种常见的过敏性皮肤病，据报道患病率为10%-15%。慢性皮肤病的特点是瘙痒，通常与皮肤炎症有关，通常需要终身治疗。虽然这种多因素疾病的发病机制尚不完全清楚，但有许多对症治疗方案，其疗效和相关副作用事件有所不同。在过去的几十年里，广谱药物如糖皮质激素和钙调磷酸酶抑制剂是唯一可用的治疗方法，但新的治疗方法提供了更有针对性的治疗选择和更少的副作用事件。
Lokivetmab (Cytopoint; Zoetis Belgium SA) is a caninised monoclonal antibody which selectively binds to circulating interleukin (IL)-31 in dogs. It was shown to effectively inhibit pruritus and related skin lesions in cAD for >1month, have a fast onset of action and minimal adverse events. In one study, the quality of life (QoL) of owners and their animals suffering from cAD increased as a consequence of the significant reduction of pruritus achieved through treatment with lokivetmab.In another study, the administration of lokivetmab significantly decreased both pruritus Visual Analog Scale (PVAS) scores and serum IL-31 levels in dogs with cAD.
洛基维特单抗(赛妥敏)是一种犬用单克隆抗体，可选择性结合犬循环白细胞介素(IL)-31。研究表明，该药可有效抑制cAD患犬瘙痒和相关皮肤病变>1个月，起效快，副作用事件最少。在一项研究中，患有cAD的主人和他们的动物的生活质量(QoL)增加了，因为通过洛基维特单抗治疗可以显著减少瘙痒。在另一项研究中，给予洛基维特单抗可显著降低cAD犬的瘙痒视觉模拟量表(PVAS)评分和血清IL-31水平
A possible cause for the loss of efficacy during treatment with monoclonal antibodies is development of antidrug antibodies (ADAs). Three studies evaluated ADAs in dogs with cAD treated with lokivetmab.One study detected no treatment-induced immunogenicity after a single dose of lokivetmab,and in two other studies, antibodies were formed in 2.1%–2.5% of treated dogs.In another study, 2.6% of allergic dogs experienced a loss of efficacy after the second lokivetmab injection, yet no ADA levels were measured in those patients.
单克隆抗体治疗期间药效丧失的一个可能原因是抗药物抗体(ADA)的产生。三项研究评估了用洛基维特单抗治疗的cAD犬的ADA。一项研究发现，单剂量洛基维特单抗后未发现治疗诱导的免疫原性，另外两项研究显示，2.1%-2.5%的治疗犬产生了抗体。在另一项研究中，2.6%的过敏犬在第二次注射洛基维特单抗后药效丧失，但这些患犬没有检测到ADA水平。
To the best of the authors' knowledge, there is only one published study from North America that has investigated individual factors predictive of initial treatment success.This prompted us to explore whether similar factors, such as the type of cAD (food- or environmentally induced), the age at which lokivetmab was first administered, the disease chronicity, the dosage used and the presence of secondary infections on the day of the initial lokivetmab injection, have an impact not only on the initial treatment outcome but also on the long-term results in European dogs. The primary objective of the present study was to investigate the long-term use of lokivetmab in atopic dogs under field conditions in Germany. The secondary objective was to assess if concurrent factors affect treatment outcome initially in the long term. The tertiary objective was to report any adverse events observed over the study period.
据作者所知，北美只有一项已发表的研究调查了预测初始治疗成功的个体因素。这促使我们探索类似的因素，如cAD的类型(食物或环境诱导)，首次使用洛基维特单抗的年龄，疾病的慢性性，使用的剂量以及首次注射洛基维特单抗当天继发感染的存在，是否不仅对初始治疗结果有影响，而且对欧洲犬的长期结果也有影响。本研究的主要目的是调查洛基维特单抗在德国野外条件下对特应性皮炎犬的长期使用情况。次要目的是评估并发因素是否在长期内影响治疗结果。第三个目的是报告在研究期间观察到的任何副作用事件。
MATERIALS AND METHODS
材料和方法
This retrospective study was approved by the Ethics Committee of the Faculty of Veterinary Medicine/University of Munich under the number 232-26-08-2020.
本回顾性研究经慕尼黑大学兽医学院伦理委员会批准，编号为232-26-08-2020。
Study design
研究设计
Data were collected retrospectively from July 2017 to October 2021 by searching the database of the Centre for Clinical Veterinary Medicine at LMU Munich. In most cases, the available information was supplemented by telephone and mail contact with the pet owner and/or the primary veterinarian as needed.
通过检索慕尼黑大学临床兽医中心数据库，回顾性收集2017年7月至2021年10月的数据。在大多数情况下，根据需要通过与宠物主人和/或初级兽医的电话和邮件联系来补充现有信息
Inclusion/exclusion criteria
纳入/排除标准
All medical records of dogs with suspected cAD that received at least one lokivetmab injection at the Centre for Clinical Veterinary Medicine at LMU Munich during the study period were included. Patients whose treatment was initiated at the Centre, with some of the subsequent injections administered by the referring veterinarians, were intentionally also included. cAD was suspected based on the history and clinical presentation and confirmed by ruling out other differential diagnoses such as flea bite hypersensitivity and/or ectoparasite infestation. Food allergy was ruled out or confirmed by an elimination diet trial for 8weeks with either a commercially available fully hydrolysed protein, or a home-cooked diet consisting of a protein and carbohydrate source to which the animal had not previously been exposed.
纳入研究期间在慕尼黑大学临床兽医中心接受至少一次洛基维特单抗注射的疑似cAD犬的所有医疗记录。在该中心开始治疗的患犬，随后由转诊兽医进行一些注射，也有意包括在内。根据病史和临床表现怀疑cAD，并通过排除其他鉴别诊断(如跳蚤叮咬过敏和/或外寄生虫感染)来确诊。通过为期8周的食物排查试验，排除或证实了食物过敏，该试验要么使用市售超水解蛋白，要么使用由蛋白质和碳水化合物来源组成的家庭烹饪饮食，而动物以前从未接触过这种食物。
Study objects
研究对象
The following data were collected: signalment, body weight, date of birth, date of onset of cAD clinical signs, elimination diet trial status, previous medications (glucocorticoids, oclacitinib, ciclosporin), exact dates of lokivetmab injections, lokivetmab dosage and any observed adverse events.
收集以下数据:特征、体重、出生日期、cAD临床症状出现日期、食物排查试验状态、既往用药(糖皮质激素、奥拉替尼、环孢素)、注射洛基维特单抗的确切日期、洛基维特单抗剂量和观察到的任何副作用事件。
Pruritus was measured as a score on a PVAS scale19,20 documented at different time points and included in the data collection of the study: before the first lokivetmab administration and after the first and last lokivetmab injections, respectively.
瘙痒症以不同时间点记录的PVAS量表的评分来测量，并包括在研究的数据收集中:分别在第一次给药之前和第一次和最后一次注射洛基维特单抗之后。
Any other medication received in the 28day period before and after the first lokivetmab visit also was recorded, and a medication score was calculated using a previously published scoring system adapted to our study purposes (Table 1). Glucocorticoids were evaluated according to the potency of the respective active ingredient.
在首次使用洛基维特单抗之前和之后的28天内接受的任何其他药物也被记录下来，并使用先前发布的适合我们研究目的的评分系统计算药物评分(表1)。糖皮质激素根据各自活性成分的效力进行评估。
Secondary infections on the day of the first lokivetmab administration and within 1month after injection were recorded if a cytological sample was available and had been assessed using a previously validated cytological score scale ranging from 0 to 4.26 If the cytological score indicated infection (score≥1), the cytological results were considered positive. If the dog had a negative cytological sample or the clinician decided not to take a cytological sample based on clinical presentation, typically because of the absence of both pruritus and clinical lesions, the dog was considered negative for secondary infection.
记录第一次给药当天和注射后1个月内的继发感染，如果有细胞学样本，并使用先前验证的细胞学评分量表进行评估，评分范围从0到4.26。如果细胞学评分表明感染(评分≥1)，则认为细胞学结果为阳性。如果犬的细胞学样本呈阴性，或者临床医生根据临床表现决定不采取细胞学样本，通常是因为没有瘙痒和临床病变，则认为犬为继发感染阴性。
Evaluation of treatment efficacy
疗效评估
Long-term treatment was defined as receiving at least three lokivetmab injections. The corresponding longterm efficacy was evaluated after the last injection administered at the time of data collection, and the initial response was assessed after the first lokivetmab administration. Efficacy was measured primarily by improvement in the PVAS score by ≥2 following the lokivetmab injection by comparing the PVAS score recorded immediately before the first lokivetmab injection with the PVAS score after the first and last lokivetmab treatments, respectively. If the dog's pruritus was low before the first injection of lokivetmab owing to prior treatment with other medications, a PVAS score of ≤2 following the corresponding lokivetmab administration was likewise considered a success. All dogs with a PVAS score ＜2 after lokivetmab treatment were recorded separately, as this was regarded as the normal range. As recommended by the International Committee for Allergic Diseases in Animals, the number of dogs in which the PVAS score was reduced by ≥50% also was calculated.
长期治疗的定义为接受至少3次洛基维特单抗注射。相应的长期疗效在数据收集时的最后一次注射后进行评估，初始缓解在第一次洛基维特单抗给药后进行评估。疗效主要通过比较第1次洛基维特单抗注射前即刻记录的PVAS评分与第1次和最后1次洛基维特单抗治疗后的PVAS评分，判断洛基维特单抗注射后PVAS评分改善≥2分。如果犬在第一次注射洛基维特单抗前瘙痒程度较低(因为之前接受过其他药物治疗)，则在相应的洛基维特单抗给药后PVAS评分≤2分也被视为成功。所有在洛基维特单抗治疗后PVAS评分<2分的犬分别记录，这被视为正常范围。根据国际动物过敏性疾病委员会的建议，我们还计算了PVAS评分降低≥50%的犬的数量。
In addition to pruritus, changes in medication score and the development of secondary infection under the effect of the first lokivetmab dose were assessed.
除瘙痒外，还评估第一次洛基维特单抗剂量作用下用药评分的变化和继发感染的发生情况。
Loss of treatment effectiveness associated with long-term use
Loss of efficacy was considered when the initial success which had been recorded after the first lokivetmab administration was no longer observed after the last administered lokivetmab injection. The extent of the effect reduction of the treatment was estimated using the following formula:
当在最后一次注射洛基维特单抗后不再观察到第一次洛基维特单抗给药后记录的初始成功时，则认为无效。使用以下公式估计治疗效果降低的程度:
The calculated percentages of effect reduction of lokivetmab treatment were classified ≤20%, no loss; >20% and ≤40%, low effect reduction; >40% and≤60%, moderate effect reduction; and>60%, severe effect reduction.
洛基维特单抗治疗效果降低的计算百分比分类为≤20%，有效;>20%≤40%，效果降低低;>40%≤60%，效果降低适中;且>60%，效果降低严重
Statistical analysis
The normality assumption was assessed by the Shapiro–Wilk normality test. For non-normally distributed data, nonparametric tests were used.
采用Shapiro-Wilk正态性检验评估正态性假设。非正态分布数据采用非参数检验。
A Friedman test followed by a Durbin–Conover test was conducted to show the PVAS change over the course of treatment in all included long-term patients with three or more administered lokivetmab injections.
Friedman试验和Durbin-Conover试验显示所有长期接受三次或更多洛基维特单抗注射的患犬在治疗过程中PVAS的变化。
Long-term success was measured by means of a survival analysis. For the analysis, long-term patients with an average interval of injections ≤100days were included.
通过生存分析来衡量长期的成功。纳入平均注射间隔≤100d的长期患犬进行分析。
In order to determine whether the outcome of longterm and initial lokivetmab therapy was affected by individual factors (such as food versus environmentally induced cAD, disease chronicity, dosage and secondary infection on day of first lokivetmab administration for the initial success; and age during first lokivetmab administration and dosage for the long-term success), a logistic regression with both univariate and multivariate analysis was performed with all included dogs receiving initial or long-term treatment, respectively. As the results of both analyses were identical, only the results of the multivariate analysis are presented.
为了确定长期治疗和初始洛基维特单抗治疗的结局是否受个体因素的影响(如食物和环境诱导的cAD，疾病慢性化，首次洛基维特单抗给药日的剂量和继发感染;以及首次使用洛基维特单抗时的年龄和长期成功的剂量)，分别对所有纳入的初始或长期治疗犬进行单因素和多因素分析。由于两种分析结果相同，故仅给出多因素分析的结果。
The significance level of all analyses conducted was set at p<0.01.
所有分析的显著性水平设为p<0.01。
RESULTS
结果
Study objects
研究对象
A total of 150 medical records were included in the study of which 69 could be evaluated for long-term analysis. Of these 69 long-term patients, 50 dogs received injections at an average interval of ≤100days. The signalment of included dogs is given in Table 2.
该研究共纳入了150份医疗记录，其中69份可以进行评估以进行长期分析。在69例长期患者中，50只犬接受注射，平均间隔≤100天。所包括的犬的特征列于表2。
The study included 44 of 150 dogs (29%) diagnosed with cAD sensu lato (no elimination diet performed), 72 of 150 dogs (48%) with cAD sensu stricto (pruritus failed to respond to an elimination diet) and 34 of 150 dogs (23%) presenting with a concurrent food allergy. Before the first treatment with lokivetmab, of 150 dogs, 103 (69%) had received glucocorticoids, 101 (67%) oclacitinib and 15 (10%) ciclosporin. Further data on the course of the disease are presented in Table S1 in the Supporting information, and the total number of lokivetmab injections is listed in Table S2. The dog with the highest number of injections received 35 treatments in total over 36.5months. The lokivetmab dosage administered ranged from 0.8 to 2.5mg/kg (mean 1.3mg/kg). The average injection interval of each dog ranged from 19 to 409days (median 48days). Therapy duration varied from 1 to 48months (average 9.4months).
研究包括150只犬中的44只(29%)被诊断为广义cAD(没有进行食物排查)，72只(48%)被诊断为狭义cAD(瘙痒对食物排查没有反应)，34只(23%)同时有食物过敏。在首次使用洛基维特单抗治疗前，150只犬中有103只(69%)接受过糖皮质激素治疗，101只(67%)接受过奥拉替尼治疗，15只(10%)接受过环孢素治疗。有关病程的进一步数据见支持信息表S1, 洛基维特单抗注射总次数见表S2。注射次数最多的那只犬在36.5个月的时间里总共接受了35次治疗。洛基维特单抗给药剂量为0.8 ~ 2.5mg/kg(平均1.3mg/kg)。每只犬平均注射时间为19 ~ 409d，中位数为48d。治疗时间1 ~ 48个月，平均9.4个月。
Evaluation of treatment efficacy
疗效评估
The PVAS score over the course of lokivetmab therapy is illustrated in Figure 1. While the median PVAS score was 6 before the first lokivetmab administration, it decreased to 1 after that first injection and to 2 after the last. Pruritus decreased significantly from before in comparison with after therapy with lokivetmab. This was observed both after initial injection (p<0.01) and in association with long-term use (p<0.01). There also was a significant difference between the PVAS score after the first and after the last lokivetmab injections (p<0.01).
洛基维特单抗治疗期间的PVAS评分见图1。第一次给予洛基维特单抗前，中位PVAS评分为6分，第一次给药后下降至1分，最后一次给药后下降至2分。与洛基维特单抗治疗前相比，瘙痒症状显著减轻。在初次注射(p<0.01)和长期使用(p<0.01)后均观察到这一现象。第1次和最后1次注射洛基维特单抗后PVAS评分也有显著性差异(p<0.01)。
Eighty-nine dogs of 150 (59%) had a PVAS score＜2 after the first lokivetmab injection; a PVAS score reduction by ≥50% was observed in 119 of 150 dogs (79%) after the first administration of lokivetmab. Thirty-two of 69 dogs (46%) receiving long-term therapy obtained a PVAS score the reduction of ≥50% was seen when comparing the PVAS score before the first with that after the last lokivetmab application.
150只犬中有89只(59%)在第一次注射洛基维特单抗后PVAS评分<2分;在首次给予洛基维特单抗后，观察到150只犬中的119只(79%)PVAS评分降低了≥50%。在69只接受长期治疗的犬中，有32只(46%)获得了PVAS评分，与首次应用洛基维特单抗前相比，PVAS评分降低≥50%。
The efficacy rate after the first lokivetmab injection was 90% (135 of 150 dogs). Comparing the assessed medication score before and after the first lokivetmab injection, it decreased in 67 of 150 dogs (45%). A decrease of the medication score by ≥50% was observed in 34 of 150 dogs (23%). Forty-eight dogs of 150 (32%) were assessed to show no clinical or cytological signs of secondary infections at the first visit: 35 of 48 dogs (73%) maintained this status, while 13 of 48 (27%) developed infections within 4weeks of therapy. Fifty-one of 150 dogs (34%) were identified with an infection at the first visit: 30 of the 51 (59%) responded to concurrent, appropriate antimicrobial therapy and 21 (41%) maintained cytological positivity. Aural haematomas formed in 2 of 150 dogs (1%) and acute moist dermatitis in 4 of 150 (3%) during treatment with lokivetmab.
首次注射洛基维特单抗后有效率为90%(150只犬中135只)。比较第一次注射洛基维特单抗前后的评估药物评分，150只犬中有67只(45%)降低。150只犬中有34只(23%)的用药评分下降≥50%。150只犬中的48只(32%)在第一次就诊时没有显示继发性感染的临床或细胞学体征:48只犬中的35只(73%)保持这种状态，而48只犬中的13只(27%)在治疗4周内发生感染。150只犬中有51只(34%)在第一次就诊时被发现有感染:51只犬中有30只(59%)对当前适当的抗菌治疗有反应，21只(41%)保持细胞学阳性。在洛基维特单抗治疗期间，150只犬中的2只(1%)形成了耳血肿，150只犬中的4只(3%)形成了脓性创伤性皮炎。
Long-term efficacy in PVAS reduction was achieved in 77% (53 of 69 dogs). The outcome of long-term use of lokivetmab based on a survival analysis is visualised in Figure 2. Treatment failure was observed in 13 of 50 dogs by Day (D) 740. The last treatment failure was on D749. The longer treatment with lokivetmab was continued, the lower the likelihood of treatment failure.
在PVAS复位中，77%(69只犬中的53只)达到了长期疗效。基于生存分析的长期使用洛基维特单抗的结局见图2。到第740天，50只犬中有13只治疗失败。末次治疗失败发生在D749。洛基维特单抗治疗持续时间越长，治疗失败的可能性越低。
Loss of treatment effectiveness with long-term use
长期使用治疗效果下降
Overall, 12 of 69 dogs (17%) treated long-term experienced a loss of efficacy; in all 12, the level of effect reduction was severe. The remaining 57 dogs (83%) did not develop any loss of effect over the treatment period.
总体而言，69只接受长期治疗的犬中有12只(17%)失去了疗效;12例患犬的疗效降低程度均为重度。其余57只犬(83%)在治疗期间没有出现任何效果丧失。
Influencing factors of the treatment outcome
影响治疗结果的因素
There was no significant association between the treatment outcome and any of the tested factors in the regression analysis. The initial efficacy was not significantly influenced by the diagnosis of food-induced versus environmentally induced cAD (p=0.88), nor by the disease chronicity (p=0.53), the dosage administered (p=0.079) or the presence of a secondary infection on the day of the first lokivetmab administration (p=0.92). The outcome of long-term efficacy also was not significantly affected by the age during the first lokivetmab administration (p=0.67) or the administered dosage (p=0.061).
在回归分析中，治疗结果与任何检验因素之间均无显著相关性。初始疗效不受食物诱发与环境诱发cAD的诊断(p=0.88)、疾病慢性化(p=0.53)、给药剂量(p=0.079)或首次给药当天是否有继发性感染(p=0.92)的显著影响。长期疗效的结果也不受第一次洛基维特单抗给药时的年龄(p=0.67)或给药剂量(p=0.061)的显著影响。
Adverse events
副作用
A total of 12 of 150 dogs (8%) experienced adverse events during treatment with lokivetmab. Gastrointestinal signs such as diarrhoea, vomiting or nausea were observed in two of these (1.33%), unspecified skin rashes occurred in two others (1.33%), anorexia in two (1.33%) and lethargy in six (4%). More detailed information about the reported adverse events is provided in Table 3. Of particular note is dog 129. This dog developed a multifocal crusting dermatitis following the first lokivetmab injection. Several biopsy samples were obtained 1month after lokivetmab was administered. The histological examination revealed epidermal hyperplasia, multifocal epidermal necrosis, serocellular crusts, moderate parakeratosis with serum lakes and occasional bacteria. Intracorneal and subcorneal neutrophilic as well as mononuclear pustules were observed. Additionally, a chronic, superficial, moderate, perivascular-to-interstitial, mixed mononuclear dermatitis with oedema and mucin, along with some fibroblastic changes, was identified. Small vessel leucocytoclastic vasculitis with haemorrhage and dilated lymphatic vessels also was noted. The morphological diagnosis was hyperplastic, mixed dermatitis characterised by the presence of serocellular crusts, intra- and subcorneal pustules and leucocytoclastic vasculitis withi small vessels. The lesions resolved with oclacitinib. Further injections of lokivetmab were not administered and as such an adverse drug reaction remains a possibility. This dog was included in our analysis. All other listed adverse events were reversible and resolved either spontaneously or with mild symptomatic therapy.
150只犬中有12只(8%)在接受洛基维特单抗治疗期间发生副作用事件。其中2例(1.33%)出现腹泻、呕吐或恶心等胃肠道症状，2例(1.33%)出现皮疹，2例(1.33%)出现厌食，6例(4%)出现嗜睡。关于报告的副作用事件的更详细信息见表3。特别值得注意的是129号犬。这只犬在第一次注射洛基维特单抗后发生了多灶性结痂性皮炎。洛基维特单抗给药后1个月采集了若干活检样本。组织学检查:表皮增生，多灶性表皮坏死，浆细胞结痂，中度角化不全伴血清区，偶见细菌。观察角质层内和角质层下脓疱的中性粒细胞和单个核细胞。此外，还发现了一种慢性浅表、中度、血管周围-间质混合性单个核细胞皮炎，伴水肿和黏蛋白，以及一些成纤维细胞改变。小血管破白细胞性血管炎伴出血和淋巴管扩张。形态学逻辑诊断为增生性混合性皮炎，表现为浆液细胞结痂、角质层内和角质层下脓疱和伴有小血管的白细胞碎裂性血管炎。奥拉替尼治疗后，病变消退。没有进一步注射洛基维特单抗，因此仍有可能发生此类药物不良反应。这只犬被纳入了我们的分析。所有列出的其他不副作用事件都是可逆的，并且在自发或轻度对症治疗后消退。
DISCUSSION
讨论
Pruritus of dogs with cAD was effectively reduced by single and long-term administration of lokivetmab.
单次和长期给予洛基维特单抗可有效减轻cAD犬的瘙痒。
To the best of the authors' knowledge, no previous study has investigated the efficacy and safety of lokivetmab over a relatively long period of time. In one study, lokivetmab was administered three times in three consecutive months, with a significant decrease in pruritus and Canine Atopic Dermatitis Extent and Severity Index (CADESI)-04 score. In another study, the first part of the trial demonstrated that lokivetmab was noninferior to ciclosporin in terms of pruritus reduction in atopic dogs after 3months of treatment. In the second part of the study, some of the dogs from the lokivetmab group were treated with lokivetmab for an additional 6months, allowing efficacy to be monitored for up to 9months, and 76.3% of the dogs were classified as normal at the end of the study. In another publication, a total of 21 dogs were treated with lokivetmab monotherapy according to manufacturer's instructions and followed for up to 1year. One quarter of the dogs did not experience a disease flare during monotherapy with lokivetmab for at least 1year, and half of the treated dogs developed a flare within 2months after discontinuing other anti-allergic medications.
据作者所知，之前没有研究调查过洛基维特单抗在相对较长时间内的疗效和安全性。在一项研究中，连续3个月给予洛基维特单抗3次，瘙痒和犬特应性皮炎范围和严重程度指数(CADESI)-04评分显著降低。在另一项研究中，试验的第一部分证明，在特应性皮炎犬中，治疗3个月后，在减轻瘙痒方面，洛基维特单抗不劣于环孢素。在研究的第二部分中，洛基维特单抗组的一些犬接受了另外6个月的洛基维特单抗治疗，允许长达9个月的疗效监测，在研究结束时，76.3%的犬被归类为正常。在另一篇文章中，共有21只犬按照制造商的说明接受了洛基维特单抗单抗治疗，并随访了长达1年。1/4的犬在接受洛基维特单抗单药治疗至少1年期间没有疾病发作，一半接受治疗的犬在停止其他抗过敏药物治疗后2个月内出现疾病发作。
Compared with the initial lokivetmab success rate, a decrease in treatment efficacy was observed. One potential cause for the decrease in efficacy may be the formation of ADAs directed against lokivetmab, even though lokivetmab is a caninised monoclonal antibody. ADAs may bind to the administered monoclonal antibodies and lead to their neutralisation, and consequently result in a reduction of treatment efficacy. ADAs directed against lokivetmab have been measured in two veterinary studies and identified in 2.1%–2.5% of atopic dogs treated with this monoclonal antibody.In a 9-month field study, treatment efficacy was reduced in one of a total of three dogs with ADA levels present against lokivetmab. ADAs were formed only in the first 3 months of treatment, not thereafter. One study did not detect any treatment-induced immunogenicity after a single injection of lokivetmab. The results of the presents study support those findings. The Kaplan–Meier curve illustrates that the probability of treatment failure decreased with treatment duration. In another study, a loss of efficacy was noted in 2.6% of allergic dogs after the second dose of lokivetmab, yet ADA levels were not measured in that study. Interestingly, one of the affected dogs was reported to exhibit lethargy in association with its third injection. We observed this phenomenon in one of our study participants. Dog 102 showed lethargy and loss of efficacy after the twelfth lokivetmab administration. In a laboratory safety evaluation of lokivetmab, in which healthy laboratory beagle dogs received seven consecutive monthly doses of lokivetmab, no evidence of immunogenicity was observed; unfortunately, ADA levels were not measured. Further prospective long-term studies are needed as the clinical relevance of ADAs in dogs treated with lokivetmab is not clear. It would be extremely interesting to measure ADA concentrations not only in treatment failures but also in long-term patients receiving >10 injections.
与初始洛基维特单抗成功率相比，治疗有效率降低。疗效下降的一个潜在原因可能是针对洛基维特单抗的ADA形成，但洛基维特单抗是一种犬化单克隆抗体。ADAs可能与给药的单克隆抗体结合并导致其被中和，从而导致疗效降低。针对洛基维特单抗的ADA已在两项兽医研究中测定，并在2.1%-2.5%的特应性皮炎犬中鉴定出该单克隆抗体。在一项为期9个月的现场研究中，共有3只犬出现抗洛基维特单抗的ADA水平，其中1只的疗效降低。ADA仅在治疗的前3个月形成，此后未形成。一项研究在单次注射洛基维特单抗后未检测到任何治疗诱导的免疫原性。本研究的结果支持这些发现。Kaplan-Meier曲线显示，随着治疗时间的延长，治疗失败的概率降低。在另一项研究中，在第二剂洛基维特单抗给药后，有2.6%的过敏犬出现疗效丧失，但该研究未测定ADA水平。有趣的是，据报道，其中一只患犬在第三次注射时表现出嗜睡。我们在我们的一项研究中观察到这种现象的参与者。犬102在第12次注射洛基维特单抗后表现出嗜睡和无效。在一项洛基维特单抗的实验室安全性评估中，健康的实验室比格犬连续7个月接受洛基维特单抗，未观察到免疫原性证据;遗憾的是，本试验未测定ADA水平。由于使用洛基维特单抗治疗的犬中ADA的临床相关性尚不明确，因此需要进一步的前瞻性长期研究。不仅在治疗失败的患犬中测定ADA浓度，而且在长期接受>10次注射的患犬测定ADA浓度将是非常有趣的。
Pruritus as a result of secondary infections could be another possible cause of treatment failure with long-term use. In previous studies, treatment with lokivetmab was more effective in controlling pruritus than inflammatory skin lesions. In our study, owners were often late for the recommended 4-week follow-up visits for continued treatment with lokivetmab. The average injection intervals of the individual dogs in our study showed a wide range. In addition, skin cytological investigation and subsequent topical therapy was only infrequently conducted at the primary care veterinarian during the course of lokivetmab therapy. Consequently, skin lesions and secondary infections possibly occurred during allergy flares. Nevertheless, this delay in treatment is not necessarily detrimental. The duration of action of lokivetmab varies slightly by patient and time of year, and in one study, an injection of lokivetmab at 2 mg/ kg inhibited pruritus for ≤42 days.
继发性感染引起的瘙痒可能是长期用药治疗失败的另一个可能原因。在之前的研究中，洛基维特单抗治疗在控制瘙痒方面比炎症性皮肤病变更有效。在我们的研究中，宠主经常迟到，未能按照建议的4周随访访视，以继续接受洛基维特单抗治疗。在我们的研究中，每只犬的平均注射间隔时间范围很广。此外，在洛基维特单抗治疗期间，在初级保健兽医处进行皮肤细胞学检查和后续外部治疗的情况很少。因此，过敏发作时可能出现皮肤病变和继发感染。然而，这种治疗延迟并不一定是有害的。洛基维特单抗的作用持续时间因患犬和季节而略有变化，在一项研究中，2 mg/kg的洛基维特单抗注射可抑制瘙痒≤42日。
Our criteria defining treatment success were chosen to be comparable to the results of previous studies with similar study designs investigating the initial success of lokivetmab. Based on these criteria, our observed initial success rate of 90% is consistent with both of the previous studies, in which initial success rates of 87.8% and 98% were reported in dogs with allergic dermatitis after 1month of treatment. A PVAS score reduction by ≥50% after initial treatment with lokivetmab occurred in 79% of our patients, which is in line with other reports in other studies of 73%–77%.
选择我们定义治疗成功的标准是为了与之前研究的结果相比较，之前的研究设计类似，研究的是洛基维特单抗的初始成功。基于这些标准，我们观察到的90%的初始成功率与之前的两项研究一致，在之前的研究中，在患过敏性皮炎的犬中，治疗1个月后的初始成功率分别为87.8%和98%。在我们的患犬中，接受洛基维特单抗初始治疗后，PVAS评分降低≥50%的发生率为79%，这与其他研究中73%~77%的报告一致。
Treatment failure in the small proportion of dogs not responding to lokivetmab could result from the fact that these dogs may have less circulating IL-31 and/or other cytokines more prominently involved in the pruritus cascade. cAD is a complex, multifactorial disease and accordingly demands a multifaceted treatment spectrum. Breed-associated variations in the clinical phenotypes of cAD have been detected, suggesting differences in the underlying pathomechanisms. Likewise, study results from human medicine on the use of monoclonal antibodies confirmed that some patients did not respond to these specifically targeted treatment options.
在一小部分对洛基维特单抗无效的犬中，治疗失败的原因可能是这些犬的循环中IL-31和/或其他与瘙痒级联反应密切相关的细胞因子较少。cAD是一种复杂的多因素疾病，因此需要多方面的治疗。在cAD的临床表型中已检测到与品种相关的亚型，提示潜在的病理机制存在差异。同样，人类医学中使用单克隆抗体的研究结果证实，一些患者对这些特异性靶向治疗方案无应答。
No significant association was found in our study between treatment outcome and any of the factors tested, including the type of cAD, age at first administration of lokivetmab, disease chronicity, dosage and the presence of secondary infections on the day of the first lokivetmab injection. Those results are consistent with a previous study that also reported no significant association between treatment success and similar parameters. There appeared to be a subtle and not statistically significant association between dosage of lokivetmab and treatment efficacy: the higher the dose of lokivetmab, the lower the treatment success. In a previous study, the administration of higher doses of lokivetmab also did not increase the likelihood of treatment success.Therefore, administration of higher doses of lokivetmab does not seem to offer any additional benefit for atopic patients. Additional and larger prospective studies are needed to verify this.
在我们的研究中，没有发现治疗结果与测试的任何因素之间的显著关联，包括cAD类型，首次使用洛基维特单抗的年龄，疾病的慢性，剂量和第一次注射洛基维特单抗当天是否有继发性感染。这些结果与之前的一项研究一致，该研究也报告了治疗成功与类似参数之间没有显著关联。洛基维特单抗剂量与治疗效果之间存在微妙的无统计学意义的关联:洛基维特单抗剂量越高，治疗成功率越低。在之前的一项研究中，较大剂量的洛基维特单抗也未增加治疗成功的可能性。因此，给予较高剂量的洛基维特单抗似乎并没有为特应性皮炎患犬提供任何额外的益处。需要更多更大规模的前瞻性研究来验证这一点。
The absence of a statistically significant impact of secondary infections on the day of the initial lokivetmab injection on treatment outcome may be a consequence of the strong antipruritic action of the antibody. Alternatively or additionally, the topical antimicrobial therapy prescribed in those dogs may have sufficiently treated the infection to render it insignificant.
首次注射洛基维特单抗当日的继发性感染对治疗结局无统计学显著影响，这可能是抗体的强止痒作用的结果。另外，在这些犬中 外部用抗生素治疗可能已经充分治疗了感染，使其变得无关紧要。
The type of cAD did not seem to influence treatment outcome. Lokivetmab may be a viable long-term treatment option for any dog with suspected cAD whose owners are hesitant to pursue a comprehensive work-up. Likewise, neither age at the time of first administration of lokivetmab nor chronicity of disease affected treatment outcome. Additional prospective studies are necessary to elucidate this.
cAD的类型似乎不影响治疗结果。洛基维特单抗可能是一种可行的长期治疗选择，任何怀疑患有CAD的犬的主人不愿进行全面的检查。同样，首次给予洛基维特单抗时的年龄和疾病的慢性程度均不影响治疗结局。需要更多的前瞻性研究来阐明这一点。
Lokivetmab appears to be a safe and effective pruritus treatment for long-term use in cAD. Most of the adverse events that we recorded throughout the entire study period, including gastrointestinal signs, anorexia and lethargy, were very mild and consistent with previous publications. Lokivetmab proved safe not only when administered once within 28days but also in a clinical trial with monthly injections for up to 9months. In a laboratory study of the safety of lokivetmab, in which a dose of ≤10mg/kg was administered to 24 healthy laboratory beagle dogs for 7 consecutive months, lokivetmab also was observed to be well-tolerated. Two of our study patients developed unspecified skin rashes that had not been previously reported. In the dog with multifocal crusting dermatitis resulting from a suspected drug reaction, treatment with lokivetmab resulted in a significant decrease in PVAS score from 9 to 2, yet the owners still chose to discontinue the therapy. Instead, oclacitinib was administered, resulting not only in the disappearance of the multifocal crusts but also in the continued reduction of pruritus. A second dog exhibited a pustular rash within 30min of receiving lokivetmab from the primary care veterinarian. Whether this was an acute medication reaction or detection of a previously unobserved bacterial infection is unclear, as unfortunately no cytological samples were obtained. Peracute development would be atypical for bacterial pyoderma. As the primary veterinarian successfully treated the pustular rash with prednisolone, a drug reaction seems possible. More studies are needed to further evaluate rare adverse events with lokivetmab.
长期使用洛基维特单抗治疗cAD是一种安全有效的瘙痒治疗方法。我们在整个研究期间记录的大多数不良事件(包括胃肠道症状、厌食和嗜睡)均非常轻微，与之前发表的结果一致。洛基维特单抗不仅在28日内给药1次，而且在长达9个月的每月1次注射的临床试验中也被证明是安全的。在一项关于洛基维特单抗安全性的实验室研究中，24只健康的实验室比格犬连续7个月接受≤10mg/kg的剂量，观察到洛基维特单抗的耐受性良好。我们的研究中有2例患犬出现了以前从未报道过的不明皮疹。在疑似药物反应导致的多灶性结痂性皮炎的犬中，洛基维特单抗治疗使PVAS评分从9分显著下降到2分，但主人仍然选择停止治疗。我们给予了奥拉替尼作为替代治疗，结果不仅多灶性结痂消失，而且瘙痒持续减轻。另一只犬在从初级保健兽医处接受洛基维特单抗后30分钟内出现脓疱性皮疹。目前尚不清楚这是急性药物反应还是检测到之前未观察到的细菌感染，因为遗憾的是，本试验未采集细胞学样本。对于细菌性脓皮病来说，过急性发展不典型。由于初级兽医成功地用泼尼松龙治疗了脓疱性皮疹，药物反应似乎是可能的。我们需要开展更多研究来进一步评估洛基维特单抗的罕见不良事件。
The major limitation of this study is its retrospective nature. Owners and primary veterinarians were actively contacted, yet information was recalled from medication records and owner statements related to the past, which limits reliability compared to prospectively collected and standardised data. For the same reason, injection intervals and medication intake were not standardised, complicating the comparability of the data.
本研究的主要局限性是回顾性研究。研究人员积极联系了犬主和初级兽医，但从用药记录和犬主过去的陈述中召回了相关信息，与前瞻性收集和标准化的数据相比，这限制了可靠性。出于同样的原因，注射间隔和药物摄入没有标准化，这使数据的可比性变得复杂。
In conclusion, the current study demonstrates that lokivetmab is an effective and safe pruritus treatment option for long-term use in cAD under field conditions. Additional prospective studies conducted under standardised settings are necessary to validate our findings. Regular follow-up visits conducted by specialists utilising validated scoring systems can corroborate owners' statements and facilitate sample collection for cytological investigation and the measurement of ADAs.
综上所述，目前的研究表明，洛基维特单抗是一种在野外条件下长期使用的有效和安全的瘙痒治疗方案。有必要在标准化条件下进行更多的前瞻性研究来验证我们的发现。利用经过验证的评分系统，由专家进行定期随访，可以证实业主的声明，并便于进行细胞学调查和ADA测量的样本采集。
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发表于 2024-8-17 01:57:09
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