Comparison of various treatment options for canine atopic dermatitis: a blinded, randomized, controlled study in a colony of research atopic beagle dogs
犬异位性皮炎多种治疗方案对比:一项关于患异位性皮炎的比格犬盲法、随机、对照研究
作者：Rosanna Marsella , Kim Ahrens, Rachel Wilkes, Andrew Trujillo and Mackenzie Dorr
翻译：王帆 校对：刘欣
Background–No study has directly compared the various treatment options for canine atopic dermatitis and their effects on skin barrier.
Hypothesis/Objectives–To compare prednisone, oclacitinib, ciclosporin and lokivetmab treatment of atopic dermatitis.
Animals–Nineteen atopic beagle dogs.
Methods and materials–Controlled, blinded study. Dogs were challenged with allergen twice weekly and randomized to oclacitinib, ciclosporin, lokivetmab, prednisone or no treatment for four weeks. Dermatitis and pruritus were assessed at baseline and after each challenge. Transepidermal water loss (TEWL) and hydration were measured at baseline, Day (D)14 and D28 (pinnae, axilla, groin). Area under the curve (AUC) was calculated for Canine Atopic Dermatitis Extent and Severity Index, 3rd iteration (CADESI-03), pruritus, TEWL and hydration. For CADESI, the AUC of the first two weeks was compared to that of the last two weeks.
Results–For CADESI, restricted maximum-likelihood ANOVA showed effect of time (P = 0034) and group x time interaction (P = 0.0169). In the first two weeks, prednisone and oclacitinib were significantly lower than controls (P = 0.019 and P = 0.015, respectively). Lokivetmab prevented flares. Due to variability, no significance differences in pruritus were observed among groups. The TEWL increased with time in controls (P = 0.0237) and ciclosporin (P = 0.04, axilla, D28 versus D0) but not in the oclacitinib and lokivetmab groups. CADESI-03 correlated with TEWL (P = 0.0043) and pruritus (P = 0.0283). Hydration did not correlate with any parameters. Hydration decreased in controls and prednisone group (axilla, D14 versus D0, P = 0.004 and P = 0.027, respectively). AUC for hydration, over time, was higher for lokivetmab and oclacitinib than controls (P = 0.014 and P = 0.04, respectively).
Conclusions and clinical importance–Lokivetmab prevented flares when given before challenge. Oclacitinib and lokivetmab have some positive effects on skin barrier parameters.
摘要
背景–尚无研究直接比较异位性皮炎的各种治疗方案的效果,及其对皮肤屏障的影响。
假设/目的–比较泼尼松、奥拉替尼、环孢素和洛基维特单抗治疗异位性皮炎。
动物–19只患异位性皮炎比格犬。
方法和材料–对照、设盲研究。犬每周两次用过敏原激发,并随机分配至奥拉替尼、环孢素、洛基维特单抗、泼尼松组或不治疗组,持续4周。在基线和每次激发后评估皮炎和瘙痒。第14天(D)和D28(耳廓、腋窝、腹股沟)测量经表皮失水(TEWL)和水合能力基础值。计算第3版犬异位性皮炎严重程度指数(CADESI03)、瘙痒、TEWL和水合能力的曲线下面积 (AUC)。对于CADESI,将前两周的AUC与后两周的AUC进行比较。
结果–对于CADESI,限制性最大似然法ANOVA显示时间效应(P=0034),以及组x时间互作(P=0.0169)。在前两周,泼尼松和奥拉替尼显著低于对照组(分别为P=0.019和P=0.015)。洛基维特单抗可预防复发。由于不确定性,各组间未观察到瘙痒的显著差异。对照组(P=0.0237)和环孢素组(P=0.04,腋窝,28D vs. 0D)的TEWL随时间增加,但奥拉替尼组和洛基维特单抗组的TEWL未随时间增加。CADESI-03与TEWL(P=0.0043)和瘙痒 (P=0.0283)相关。水合能力与任何参数均不相关。对照组和泼尼松组水合能力下降(腋窝,D14与D0,分别为 P=0.004和P=0.027)。随着时间的推移,洛基维特单抗和奥拉替尼的水合能力AUC高于对照组(分别为P=0.014和P= 0.04)。
结论和临床重要性–过敏原激发前给予洛基维特单抗可预防复发。奥拉替尼和洛基维特单抗对皮肤屏障参数有一定积极影响。
Introduction 介绍
Several treatments are available for canine atopic dermatitis (cAD). A few studies have compared efficacy of treatments, typically comparing two options at a time, but never comparing multiple treatments concurrently in a controlled environment. Each option has strengths and weaknesses and it is useful to know how these treatments compare to each other, particularly in a controlled setting where allergen stimulation and diet are standardized.
犬异位性皮炎(cAD)有几种治疗方法。一些研究比较了治疗的效果，通常一次比较两种选方案，但从未在限制环境中同时比较多个治疗。每种方案都有优点和缺点，了解这些治疗方法之间的相互对比是很有用的，特别是在一个限制环境中，过敏原激发和日粮是标准化的。
A colony of atopic beagle dogs has been validated as model for spontaneously occurring cAD.These dogs are easily sensitized percutaneously to allergens possibly due to skin barrier abnormalities; they flare with dermatitis when exposed to allergen epicutaneously. These dogs are known to respond to commonly used treatments such as prednisone.
经证实一群患异位性皮炎比格犬为自发性cAD模型。由于皮肤屏障异常，这些犬很容易通过过敏原经由皮肤途径致敏。当过敏原暴露于皮肤表面时，会突发皮炎。众所周知，这些犬对常用的治疗如泼尼松有效果。
Several studies have described skin barrier dysfunction in cAD. Although it is still unclear whether primary skin barrier defects exist in atopic dogs, it is known that skin barrier is aggravated by inflammation. It is believed that skin barrier should improve when inflammation and/or pruritus are controlled although specific evidence is still lacking. Thus, it is helpful for clinicians to know if any of the available systemic treatments have beneficial effects on skin barrier parameters. We are still limited in making a reliable assessment of skin barrier parameters and no perfect methodology has been identified. The most commonly assessed parameters are transepidermal water loss (TEWL) and hydration. In human patients with AD, TEWL is increased and hydration is decreased. In atopic dogs, TEWL has been reported to be increased whereas decreased hydration has not, as yet, been confirmed. Despite the limitations of these methodologies and our incomplete knowledge of the relevance of hydration in cAD, it would be interesting to know if any of the available systemic treatments affects these parameters.
一些研究描述了cAD中的皮肤屏障功能障碍。虽然还不清楚异位性皮炎患犬中是否存在原发性皮肤屏障缺陷，但我们知道皮肤屏障功能会因炎症而加重。人们认为，当炎症和/或瘙痒得到控制时，皮肤屏障功能应得到改善，但仍缺乏具体的证据。因此，这有助于临床医生了解，是否任何可使用的全身治疗对皮肤屏障功能参数也有效。我们仍然局限于对皮肤屏障参数的可靠评估，还没有找到完美的方法。最常被评估的参数是皮肤经皮失水率(TEWL)和水合能力。在人AD病例中，TEWL升高，水合能力降低。在异位性皮炎患犬中，已报道TEWL升高，而水合能力降低尚未得到证实。尽管这些方法有局限性，而且我们对cAD中水合能力的相关知识也不完整，但我们很想知道是否有任何可用的全身治疗方法会影响这些参数。
Thus, the aims of this prospective, blinded, controlled study were two-fold. The first aim was to concurrently evaluate the clinical efficacy of oral prednisone, oclacitinib, ciclosporin and injectable lokivetmab on severity of dermatitis and pruritus using a colony of atopic beagle dogs. In this colony, flares can be triggered by allergen exposure and camera recording of pruritus is possible. The second aim was to evaluate if any of these systemic treatments had measurable effects on TEWL and hydration.
因此，本篇前瞻性、盲法、对照研究的目的有两点。第一个目的是同时评价口服泼尼松、奥拉替尼、环孢素和注射用洛基维特单抗对一群患异位性皮炎比格犬皮肤病和瘙痒严重程度的临床疗效。在这群研究动物中，过敏原激发会触发突然发病，可能会通过摄像头记录瘙痒情况。第二个目的是评估这些全身治疗是否对TEWL和水合能力有可测量的影响。
Methods and materials 方法和材料
Animals and treatments 研究动物和治疗方法
All procedures were approved by the Institutional Animal Care and Use Committee, College of Veterinary Medicine, University of Florida. Nineteen 8-year-old atopic beagle dogs (nine intact females, nine intact males, one neutered male) maintained in a research facility, which are sensitized to Dermatophagoides farinae were challenged with allergen twice weekly and allocated to receive either oclacitinib (Apoquel, Zoetis; Kalamazoo, MI, USA) orally at a dose of 0.5 mg/ kg twice daily for two weeks then once daily for two weeks, or ciclosporin (Atopica, Elanco; Greenfield, IN, USA) p.o. at 5 mg/kg once daily for 28 days, lokivetmab (Cytopoint, Zoetis) given once subcutaneously at 2 mg/kg on the first day of allergen challenge, or prednisone (Teva Pharmaceuticals; Shawnee, KS, USA) p.o. at a dose of 0.5 mg/kg twice daily for two weeks, then 0.5 mg/kg once daily for one week, then 0.5 mg/kg once every 48 h for one week. A control group received no treatment. Allergen challenge was achieved by application of 1.6 mL of a 16.5 mg/mL D. farinae solution(Stallergenes Greer; Lenoir, NC, USA) epicutaneously to the inguinal area twice weekly (see Figure 1 for timeline) for a total of eight challenges without any prior shaving or tape stripping.
所有方法都得到了佛罗里达大学兽医学院动物护理和使用委员会的批准。19只饲养在一个研究机构的8岁异位性皮炎比格犬(9只未绝育母犬、9只未去势公犬、1只已去势公犬),使用粉尘螨过敏原每周两次激发致敏，并接受口服奥拉替尼剂量为0.5mg/kg连续两周每天两次，然后改为每天一次连用两周，或5mg/kg口服环孢素，每日一次连用28天，在过敏原激发的第一天，皮下注射洛基维特单抗2 mg/kg或口服泼尼松剂量为0.5 mg/kg，每日两次，连续两周，然后每天一次，连续一周，然后每48小时一次，连续一周。对照组未接受任何治疗。过敏原激发是通过每周两次将1.6 mL的浓度为16.5 mg/mL的粉尘螨溶液涂到腹股沟区域的皮肤表面(时间线见图1)，共进行了8次激发，无需事先剃毛或用胶带粘。
Dogs were housed in pairs in a research facility where runs were cleaned daily and no toys that could trap dust were allowed. Dogs were fed the same diet (Hill’s Science Diet, Chicken, small bites, Hill’s Pet Nutrition, Inc.; Topeka, KS, USA with no change for six months before the study. Dogs were monitored throughout the study for evidence of adverse effects.
所有犬被两两关在一个研究机构里，那里每天都要明确犬的奔跑路线，而且不允许携带任何能够携带灰尘的玩具。在研究开始前的六个月里，所有犬被喂食同样的食物，没有任何变化。在整个研究过程中，对犬进行了监测，以寻找不良反应的证据。
Clinical assessment of dermatitis 临床皮肤评估
All clinical assessments were done by the same investigator who was unaware of treatment allocation. Dermatitis was evaluated using as validated scoring system the Canine Atopic Dermatitis and Extent Severity Index, 3rd iteration (CADESI-03).Dogs were scored at various time points (Figure 1). These times were baseline [before any allergen exposure, Day (D)0], twice daily on the days of challenge (in the morning before allergen exposure and 6 h after) and the day following challenge (24 h post-challenge).
所有的临床评估都是由同一名不知道治疗方案的研究者完成的。以第三版犬异位性皮炎严重程度指数(CADESI-03)作为验证的评分系统进行评估。在不同的时间点分别对12只犬进行了评分(图1)。这些时间分别为基线[在接触过敏原之前为第(D)0天，在过敏原激发当天、一天、两次(在接触过敏原之前的早上和接触过敏原6小时之后)，以及接触过敏原后的第二天(接触过敏原24小时之后)。
Clinical assessment of pruritus 临床瘙痒评估
Camera recordings were taken at baseline (D0) and on the first allergen challenge of each week of the study (D2, D9, D16 and D23), 4 h after allergen exposure). Pruritus was assessed by two people who were unaware of treatment allocation. Two scoring systems for pruritus were based on 30-min video recording using GoPro cameras (GoPro; San Mateo, CA, USA).
在基线(D0)和每周第一次过敏原挑战(D2、D9、D16和D23)、过敏原暴露后4小时，均通过摄像进行记录。瘙痒由两名不知道治疗方案的人进行评估。有两种瘙痒评分系统是基于使用GoPro相机进行30分钟的视频记录(GoPro;(美国加州圣马特奥)。
The first scoring was quantitative using the BORIS (Behavioral Observation Research Interactive Software) software (http://www.b oris.unito.it/). This program allows computer-based review of recorded videos. BORIS was used to score the duration (s) of licking, biting and scratching. Videos were played in the software and when the dog performed an action of interest (e.g. licking, biting or scratching) a key was pressed by the observer. For biting or scratching, the observer pressed a key which indicated the start of the behaviour and pressed again to indicate the stop. For licking, each lick was indicated by a key press. These data were exported into an excel spreadsheet.
第一个评分是使用BORIS(行为观察研究交互软件)软件(http://www.b oris.unitoit /)进行定量。这个程序允许计算机审查录制的视频。鲍里斯被用来记录舔、咬和抓的持续时间。软件会播放视频，当犬做出相关动作(如舔、咬或抓)时，观察者会按下一个键。对于咬或抓挠，观察者按一下按钮表示行为开始，然后再按一下表示行为停止。舔的时候，每舔一次都是按一次按钮。这些数据被导出到excel电子表格中。
The second scoring was a subjective global score called Pruritus Global Score using the Pruritus Visual Analog Scale (PVAS). This validated scoring system assigned a number ranging from 0 to 10 where higher numbers mean the most severe pruritus.13 The number 0 was described as “no itching is observed” whereas 10 was described as “severe itching, manifested as interruption of eating, playing or resting in order to itch”. Using this system, the same evaluators that reviewed the recordings placed a mark on a 10 cm scale as a subjective overall global assessment of their perception of the severity of the pruritus for each dog.
第二个评分是使用瘙痒视觉模拟评分(PVAS)的一种整体的主观评分，称为瘙痒整体评分。这个有效的评分系统指定了一个从0到10的数字，数字越大，瘙痒越严重。数字0被描述为“没有瘙痒”，而10被描述为严重瘙痒，表现“因为瘙痒而中断进食、玩耍或休息”。使用这个系统，相同的评估者在10厘米的量表内进行标记，作为对每只犬瘙痒程度的主观整体评估。
Assessment of skin barrier function 皮肤屏障功能评估
Skin barrier parameters were assessed every two weeks, on D0 (baseline, before allergen exposure), D14 and D28 (24 h post-allergen exposure). Parameters measured included TEWL and hydration.
皮肤屏障参数每两周评估一次，分别为D0(基线，过敏原暴露前)、D14和D28(过敏原暴露后24小时)。测量的参数包括TEWL和水分作用。
TEWL. TEWL was measured using a closed chamer device (VapoMeter, Delfin Technologies Ltd; Kuopio, Finland) at ambient temperature (20–26°C). Dogs were acclimatized for 30 min before TEWL measurements. All readings were collected in triplicate and means were used for statistical analysis. Three unclipped areas were evaluated: concave surface of pinnae, axilla and inguinal areas. These sites were selected because they are commonly affected in cAD, and a significant difference in TEWL between atopic and normal beagles had been reported for these areas. Measurements were expressed as evaporation rate (g/m2/h). Area under the curve (AUC) for TEWL was calculated and used for statistical analysis.
TEWL。TEWL是在环境温度(20-26℃)下使用封闭的chamer设备进行测量的。犬适应环境30分钟后测量TEWL。所有阅读数据收集一式三份，并使用平均值进行统计分析。评估三个未剪毛区域:耳廓凹面、腋窝和腹股沟。之所以选择这些地点，是因为它们是cAD常发病部位，异位性皮炎比格犬和正常比格犬在这些部位的TEWL有显著差异。测量值用蒸发速率(g/m2/h)表示。计算了TEWL曲线下面积(AUC)，并进行了统计分析
Hydration. Hydration was measured using a Corneometer, CM825 (Courage + Khazaka electronic GmbH; Cologne, Germany). Measurements were obtained by placing the probes perpendicular to the skin for 10 s with measurements obtained once per second. Values were expressed in micro siemens (lS), as conductance units.
水合能力。水合能力测量使用 Corneometer, CM825。测量方法是将探头垂直于皮肤放置10秒，每秒测量一次。数值用微西门子(lS)表示，表示电导单位。
Statistical analysis 统计学分析
The AUC was calculated for each dog and adjusted to baseline. For CADESI-03 scores, the four week period was divided into two periods of two weeks. This was done because treatment administration included a loading period (first two weeks) and a maintenance period (last two weeks) for some drugs (e.g. prednisone and oclacitinib). The first two weeks were referred as “T1 or Acute phase” and the final two weeks were referred to as “T2 or Chronic phase”.
计算每只犬的AUC，并调整到基线。对于CADESI-03的分数，四周的时间被分成两个两周。之所以这样做是因为治疗给药包括一些药物的加载期(前两周)和维持期(后两周)(如泼尼松和奥拉替尼)。前两周称为“T1或急性期”，最后两周称为“T2或慢性期”。
We used a mixed-model restricted maximum-likelihood 5-Group x 2-Time ANOVA (REML-ANOVA) with a between-subjects factor of Group (Control, Ciclosporin, Lokivetmab, Oclacitinib, Prednisone) and within-subject factor of Time (T1-Acute, T2-Chronic). AUC was calculated for TEWL and hydration for each site. The Kruskal–Wallis test was used to determine any difference between groups. Friedman’s test was used to investigate an effect of time. The statistical software used was SAS SYSTEM FOR WINDOWS v9.0 (SAS Institute; Cary, NC USA). Statistical comparisons were considered to be significant when P < 0.05.
我们使用一个混合模型，最大可能性限制5组x 2倍方差分析(REML-ANOVA)，组间因素(对照组、环孢素、洛基维特单抗、奥拉替尼、泼尼松)和组内时间因素(t1 -急性，t2 -慢性)。AUC计算了每个位点的TEWL和水合能力。使用Kruskal Wallis检验来确定各组之间的差异。弗里德曼检验被用来研究时间的影响。统计软件为WINDOWS v9.0版SAS系统(SAS研究所;卡里,美国NC)。当P <0.05。
Results 结果
CADESI Means and standard deviations (SD) of the CADESI scores for all time points and all groups are presented in Figure 2. Large variability was observed with a typical increase of scores after allergen exposure.
所有时间点和各组CADESI得分的均值和标准差(SD)如图2所示。过敏原激发后评分的典型增加可观察到较大差异。
REML-ANOVA yielded a significant main effect of time (F1,14 = 12.41, P = 0.0034), showing that AUC was greater at T2 than T1, and a significant group x time interaction (F4,14 = 4.36, P = 0.0169). Group x time interaction was driven largely by prednisone and oclacitinib groups, in which AUC/CADESI-03 increased in T2 compared to T1. The effect of group approached significance (F4, 14 = 2.754, P = 0.0616). Prednisone and oclacitinib groups were significantly lower than controls during T1 (P = 0.019 and P = 0.015, respectively). Figure S1 shows CADESI/AUC for the various groups.
REML-ANOVA分析主要受时间影响显著(F1,14 = 12.41, P = 0.0034)，说明AUC在T2时大于T1, x组时间交互作用显著(F4,14 = 4.36, P = 0.0169)。x组时间交互作用主要受泼尼松组和奥拉替尼组驱动，其中T2时AUC/CADESI-03较T1增加。组间比较差异有统计学意义(F4, 14 = 2.754, P = 0.0616)。T1时泼尼松组和奥拉替尼组明显低于对照组(P = 0.019和P = 0.015)。图S1显示了不同组别的CADESI/AUC。
At D28, control dogs had evidence of severe dermatitis with erythema, excoriations and papules, whereas the lokivetmab and oclacitinib dogs had mild to no erythema. Ciclosporin-treated dogs showed evidence of dermatitis (Figure 3).
在第28天，对照组的犬有皮肤红斑、抓痕和丘疹的严重皮肤炎症表现，而使用洛基维特单抗和奥拉替尼的犬有轻微到没有红斑。经环孢素治疗的犬显示出皮肤炎症表现(图3)。
Pruritus 瘙痒
Large variability in pruritus was seen. The mean global score for pruritus (PVAS) and SD for the various groups are presented in Figure S2. Means and SD of pruritus [duration (s) of scratching during a 30-min recording] are presented in Figure S3. When AUC for pruritic seconds was calculated for T1 and T2 (Figure S4), due to the large variability, no statistically significant difference was detectable.
瘙痒的变化很大。各组瘙痒症(PVAS)和SD的平均整体评分(mean global score for pruritus, PVAS)见图S2。瘙痒的平均值和SD(在30分钟的记录中抓挠的持续时间)见图S3。在计算T1和T2的痒秒AUC时(图S4)，由于变化较大，未检测到有统计学意义的差异。
Skin barrier parameters 皮肤屏障参数
TEWL. On D0 there was no difference between groups for any site (Figure 4). On D14, Kruskal–Wallis comparison found significant difference between groups (P = 0.03) for the inguinal site and Dunn’s Multiple Comparison test found that the ciclosporin group had significantly higher TEWL than prednisone-treated dogs (P = 0.0283). On D28, Kruskal–Wallis comparison revealed significant differences between groups (P = 0.03), with controls having higher TEWL than prednisone and lokivetmab in pinnae and axillary areas (P = 0.02 and P = 0.031, respectively). An effect of time for TEWL was noted in the prednisone-treated dogs (Friedman’s test, P = 0.004), with an increase from D14 to D28, in axillary and inguinal areas (P = 0.0400 and P = 0.014, respectively).
TEWL。D0任何部位之间没有组间差异(图4)。D14, Kruskal沃利斯比较发现腹股沟部位组间差异显著(P = 0.03)，邓恩年代多重比较检验发现环孢素治疗组TEWL显著高于泼尼松治疗组犬(P = 0.0283)。D28时，Kruskal Wallis比较组间差异有统计学意义(P = 0.03)，对照组在耳廓凹面和腋窝部位的TEWL高于泼尼松和洛基维特单抗治疗组 (分别为P = 0.02和P = 0.031)。泼尼松治疗组的犬腋窝区和腹股沟区的TEWL有效时间(Friedman s检验，P = 0.004)，从D14增加到D28 (分别为P = 0.0400和P = 0.014)。
An effect of time for TEWL was detected in ciclosporin-treated dogs for the axillae (Friedman’s test, P = 0.041) with a significant increase from baseline (Dunn’s Multiple Comparison test D0 versus D28, P = 0.04). No effect of time was seen for TEWL in lokivetmab- and oclacitinib treated dogs for any of the sites. An effect of time was seen on TEWL in the controls, with increased TEWL in the axillae (D0 versus D28, P = 0.0237).
检测到在环孢素治疗组犬的腋窝的TEWL有效时间(Friedman s检验，P = 0.041)，与基线相比显著增加(Dunn s多重比较试验D0与D28, P = 0.04)。在洛基维特单抗和奥拉替尼治疗组中，没有观察到TEWL对时间的影响。对照组的TEWL受时间影响，轴突的TEWL增加(D0比D28, P = 0.0237)。
When AUC was calculated by body site, for all groups, Kruskal–Wallis detected a difference between groups only for axillae (P = 0.040), with ciclosporin-treated dogs having higher values than prednisone-treated dogs (P = 0.035). When AUC was compared specifically between active treatments and controls, prednisone-treated dogs had significantly lower AUC (P = 0.022) in the axillae and ciclosporin-treated dogs had lower AUC in the pinnae (P = 0.044) than the control group.
Kruskal Wallis通过体位计算AUC时，发现所有组间差异仅在腋窝(P = 0.040)，环孢素治疗组的AUC值高于泼尼松治疗组(P = 0.035)。当比较主动治疗组和对照组的AUC时，泼尼松治疗组犬腋窝的AUC显著低于对照组(P = 0.022)，环孢素治疗组犬的耳廓 AUC显著低于对照组(P = 0.044)。
Hydration. Compared to D0, controls and prednisone had decreased hydration in the axillae on D14 (P = 0.004 and P = 0.027, respectively); lokivetmab decreased hydration on D28 (pinnae, P = 0.027). When AUC for hydration values was calculated for all sites over time, values for lokivetmab- and oclacitinib-treated dogs were significantly greater and presumed to be more hydrated than controls (P = 0.014 and P = 0.04, respectively).
水合能力。与D0相比，对照组和泼尼松组在D14时腋窝水合能力降低(P = 0.004和P = 0.027);D28时洛基维特单抗水合能力下降(耳廓, P = 0.027)。当计算所有位点随时间的AUC补水值时，洛基维特单抗和奥拉替尼治疗组的犬的补水值显著大于对照组(分别为P = 0.014和P = 0.04)。
Correlations between skin barrier parameters and clinical parameters 皮肤屏障参数和临床参数相关性
CADESI correlated with TEWL (r = 0.21; P = 0.0043) and Pruritus Global Score or PVAS (r = 0.22; P = 0.028) (Figure 5). Pruritus Global Score correlated with objective measurement of seconds spent itching based on camera recordings (r = 0.81; P < 0.0001). PVAS and TEWL also were correlated (r = 0.277; P = 0.0071). Hydration did not correlate with any parameters.
CADESI与TEWL相关(r = 0.21;P = 0.0043)和瘙痒评分或PVAS (r = 0.22;(P = 0.028)(图5)。瘙痒评分与基于摄像机记录的瘙痒持续时间客时观测量相关(r = 0.81;P & lt;0.0001)。PVAS与TEWL也有相关性(r = 0.277;P = 0.0071)。水合能力与任何参数无关。
Discussion 讨论
In this blinded, randomized, controlled study we found that lokivetmab was able to abolish flares and pruritus when given on the very first day of allergen challenge. We found that, in the first two weeks of the study, oclacitinib, lokivetmab and prednisone had lower dermatitis scores then ciclosporin. We also found that, when all sites were considered, oclacitinib and lokivetmab increased hydration compared to the controls. The effects on TEWL were varied and no definitive conclusions could be made.
在这项盲法、随机、对照的研究中，我们发现洛基维特单抗在过敏原激发的第一天就能消除急性发病和瘙痒。我们发现，在研究的前两周，奥拉替尼、洛基维特单抗和泼尼松的皮肤炎症评分低于环孢素。我们还发现，在考虑所有部位时，与对照组相比，奥拉替尼和洛基维特单抗会增加水合能力。对TEWL的影响各种各样，没有明确的结论。
Many of the findings on the clinical efficacy are consistent with other previous studies. For example, the speed of action of oclacitinib, prednisone and lokivetmab on pruritus was faster than for ciclosporin. This had been reported in separate clinical trials with privately owned animals.It is important to note how, in our study, the effect of prednisone decreased once it was given once daily and every other day, compared to the efficacy of the induction period of twice daily administration. The efficacy of lokivetmab seen in our study was consistent with a report of the ability of lokivetmab to prevent pruritus and flares of dermatitis when used in a proactive fashion.In our study, the injection was given on the day of the first allergen challenge, 1 h before allergen challenge, and thus it was consistent with a proactive protocol. Clinical flare of AD was largely prevented in the lokivetmab group, highlighting the importance of interleukin (IL)-31 in the early stages of the allergic cascade.
关于临床疗效的许多发现与以前的其他研究是一致的。例如，奥拉替尼、泼尼松和洛基维特单抗对瘙痒的作用速度快于环孢素。这已经在宠主动物临床试验中报道过。值得注意的是，在我们的研究中，泼尼松在每日一次和隔天一次时，与诱导期每日两次的效果对比有所下降。在我们的研究中发现洛基维特单抗的疗效与其预防瘙痒和皮肤炎症的作用报告是一致的。在我们的研究中，在首次过敏原激发的当天进行注射，比过敏原激发早1小时注射，因此这与前瞻性方案是一致的。在洛基维特单抗组，AD的临床急性发病基本上得到了预防，这突出了在过敏级联的早期阶段白细胞介素(IL)-31的重要性。
A few points worth addressing are the choices of scoring system. Although newer scoring systems are available, CADESI-03 was selected for this study for the sake of consistency and comparison with other studies that had been done using this colony. In hindsight, the authors also could have used new scoring systems besides CADESI-03 to comply with more current recommendations for clinical trials. For the assessment of pruritus, we were able to do camera recordings and this provides a more objective assessment of pruritus. In the past we have documented cases in which CADESI scores and pruritus did not correlate, whereas in the present study, CADESI-03 and pruritus scores were significantly correlated. Yet, it is important not to overlook the fact that some individual dogs can be very pruritic and have minimal dermatitis, and vice versa.
值得注意的几点是评分系统的选择。虽然有更新的评分系统，但为了与其他使用该类研究保持一致和进行比较，本次研究选择了CADESI-03。事后看来，作者也可以使用除CADESI-03之外的新评分系统来遵守更多当前临床试验的建议。对于瘙痒症的评估，我们可以进行摄像记录，这提供了一个更客观的瘙痒评估。在过去，我们有文献记载的案例中，CADESI评分和瘙痒不相关，而在目前的研究中，CADESI-03和瘙痒评分显著相关。然而，重要的是不要忽视一个事实，有些个体可能会非常瘙痒，而皮炎很轻微，反之也存在。
This study has important limitations including the very small number of dogs in each group and the consequent impact of variability on statistical analysis. Despite the small sample size, valuable information is provided by examining treatments in a controlled setting with no confounding factors due to environment or dietary differences. The number of dogs was determined by the size of the colony. A more ideal design would have been a cross-over such that each dog was exposed to all treatments, thereby serving as its own control and undergoing each treatment. Although this approach helps to decrease variability and to increase the number of dogs per treatment group, it does require wash-out periods between treatments and significantly increases the cost (due to research facility per diem rates per dog) and duration of the trial. These factors prevented the investigators from conducting this trial in a cross-over design.
这项研究有重要的局限性，包括每组犬只数量非常少，以及由此产生的差异对统计分析的影响。尽管样本量小，但在没有环境或日粮差异造成的混杂因素参与的限制环境中，对检查治疗提供了有价值的信息。犬的数量是由群体的大小决定的。一个更理想的设计应该是让每只犬都接受所有的治疗方案，从而作为自己的控制管理方案，并接受每一种治疗。虽然这种方法有助于减少可变性和增加每个治疗组的犬的数量，但它确实需要有治疗之间的洗脱期，并会显著增加试验的成本(由于研究机构每天每只犬的发病率)和试验时间。这些因素阻止了研究者进行交叉设计的试验。
Studies on skin barrier function and the effect of medications on it are challenging and difficult to interpret due to the limited ways we have to assess skin barrier function, the variability of the methodologies used and the unknown significance for some of them.9,17 For example, measurement of TEWL is controversial due to variability and the meaning of hydration in atopic dogs is still under discussion. Bearing this in mind, a few studies have evaluated the effects of treatments and skin barrier function. In a previously published study on oclacitinib and TEWL, the effects were varied and increased TEWL was found in the inguinal area in the oclacitinib-treated dogs compared to the placebo group. In the present study, although the dogs on placebo and ciclosporin challenged with allergen had increased TEWL (e.g. in the axilla), no increase was seen in the oclacitinib and lokivetmab groups despite the allergen challenges. That can be considered a positive effect. One published study evaluated TEWL during lokivetmab therapy.19 This study was longer than ours (it lasted 12 weeks and involved three injections versus four weeks and one injection in our study) and was done on privately owned dogs. The authors reported that TEWL decreased in the majority of body sites examined. The authors calculated a mean TEWL score for each dog/day because the TEWL did not decrease in all body sites. In our study, we did not calculate the average TEWL for each dog combining all body sites and we examined fewer body sites.
皮肤屏障功能的研究和药物对皮肤屏障功能的影响是具有挑战性和难以解释的，因为我们必须通过有限的方法来评估皮肤屏障功能、使用的方法多样以及其中一些方法的意义未知。例如，TEWL的测量由于可变性而存在争议，而异位性皮炎患犬水合能力的意义仍在讨论中。考虑到这一点，一些研究已经评估了治疗和皮肤屏障功能的效果。在先前发表的关于奥拉替尼和TEWL的研究中，与安慰剂组相比，奥拉替尼治疗的犬的作用是不同的，在腹股沟区发现了TEWL的增加。在本研究中，虽然使用安慰剂和环孢素组过敏原激发的犬的TEWL增加(例如在腋窝)，但奥拉替尼和洛基维特单抗组没有增加，尽管有过敏原激发。这可以被认为是一种主动治疗的作用。一项发表的研究在洛基维特单抗治疗期间评估了TEWL。这项研究比我们的更长(它持续了12周，包括三次注射，而我们的研究是四周一次注射)，而且是在家养犬身上进行的。作者报告说，TEWL在大多数身体部位都有所下降。作者计算了每只犬/天的平均TEWL分数，因为TEWL并没有在所有的身体部位都减少。在我们的研究中，我们没有计算每只犬所有身体部位的平均TEWL，我们检查了较少的身体部位。
When using AUC for analysis, in our study ciclosporin and prednisone also had a decreased AUC for TEWL compared to the controls, which can be consistent with decreased inflammation because severity of dermatitis (CADESI-03 scores) and TEWL positively correlated in our study. In a study published on the effects of ciclosporin on TEWL, a decrease was reported in privately owned dogs for inguinal area and antebrachial fossa;whereas in our study a worsening of TEWL was seen in the axillae at the end of the study compared to the baseline. It is important to note that the study on privately owned dogs had a larger number of subjects and that likely increased the ability to detect a positive effect.
在使用AUC分析时，在我们的研究中，环孢素组和泼尼松组与对照组相比，TEWL的AUC也降低了，这与炎症反应的降低是一致的，因为在我们的研究中，皮炎的严重程度(CADESI-03评分)与TEWL呈正相关。在一项发表的关于环孢素对TEWL影响的研究中，据报道，在家养犬的腹股沟区和前肢内侧中，TEWL下降了;而在我们的研究中，在研究结束时，与基线相比，在腋窝中发现了TEWL的加重。值得注意的是，这项针对家养犬的研究有大量的研究对象，这可能增加了检测主动治疗的能力。
To the best of the authors’ knowledge, no previous study has investigated the effects of various treatments for cAD on hydration. The positive effect on hydration observed for lokivetmab- and oclacitinib-treated dogs has unclear clinical significance because hydration did not correlate with other clinical parameters in our study and it is still unclear whether decreased hydration is a feature of atopic dogs, as it is in people.9 Clearly, more studies are needed to investigate this topic further.
据作者所知，目前还没有研究探讨各种cAD治疗对水合能力的影响。洛基维特单抗和奥拉替尼对水合能力的主动治疗效果尚不清楚，因为在我们的研究中水合能力与其他临床参数不相关，而且还不清楚水合能力的减少是否是异位性皮炎患犬的一个特征，就像在人身上一样。显然，需要更多的研究来进一步研究这个问题。
In summary, prednisone, oclacitinib and lokivetmab had positive clinical effects on dermatitis in the first two weeks of the treatment. Importantly, in our colony, prednisone did not control clinical signs well when given on alternate day regimen. A clinically relevant outcome of our study was the ability of a single injection of lokivetmab immediately before first allergen challenge to prevent development of pruritus and dermatitis despite allergen challenges. This emphasizes the relevance of IL-31 and the benefit of blocking this cytokine early on in the inflammatory cascade triggered by allergen exposure. This approach appeared superior to other strategies, including use of broad-spectrum drugs such as oral glucocorticoids and ciclosporin. The effects of these treatments on skin barrier parameters were varied and the relevance of hydration in cAD remains unclear at this point. It is concluded that we need reliable, sensitive, noninvasive methodologies to expand our knowledge of the effects of cAD therapies on skin barrier function.
综上所述，泼尼松、奥拉替尼和洛基维特单抗在治疗的前两周对皮炎有积极的临床效果。重要的是，在我们的研究群体中，泼尼松在隔天给药时没有很好地控制临床症状。我们的研究的一个临床相关的结果是在第一次过敏原激发之前注射一次洛基维特单抗有防止瘙痒和皮炎发展的作用，尽管有过敏原激发。这强调了IL-31的相关性和在过敏原激发引发的炎症级联时，早期阻断这种细胞因子的好处。这种方法似乎优于其他方法，包括使用广谱的药物，如口服糖皮质激素和环孢素。这些治疗对皮肤屏障参数的影响各不相同，在这一点上，水合能力在CAD中的相关性仍不清楚。因此，我们需要可靠、敏感、非侵入性的方法来扩展我们对cAD治疗对皮肤屏障功能影响的认识。
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发表于 2020-5-5 17:41:03
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，洛基维特单抗现在有在卖吗？
