赛妥敏改善犬皮肤趋上皮淋巴瘤的瘙痒

王帆

Lokivetmab improved pruritus in a dog with cutaneous epitheliotropic lymphoma

赛妥敏改善犬皮肤趋上皮淋巴瘤的瘙痒

作者：Kiyohiko Inai, Keita Kitagawa, Mami Murakami, Toshiroh Iwasaki

翻译：王帆

Abstract

A 13-year-old spayed female Cavalier King Charles Spaniel presented with chronic swelling and pruritus on the palmar aspect of the left forepaw and on the tail. Cutaneous epitheliotropic lymphoma (CEL) was diagnosed by histopathology and immunocytochemistry. Prednisolone was initially used alone as an alternative treatment for CEL. Despite long-term corticosteroid therapy, the patient’s physiological (pruritus) and dermatological signs (alopecia, erythema, erosion, and ulceration with crust) progressed and showed no evidence of improvement. To address the  worsening condition of pruritus, lokivetmab was started in combination with prednisolone. Once on lokivetmab, the pruritus steadily improved and was effective in resolving and maintaining remission. Further investigation on the critical role of IL-31 in the pruritus pathway of dogs with CEL is required.

摘要

一只13岁母犬已绝育的骑士查理王猎犬，左前爪掌部和尾部表现出慢性肿胀和瘙痒。经组织病理学检查及免疫组化确诊为皮肤趋上皮淋巴瘤(CEL)。最初单独使用泼尼松龙用于CEL的替代治疗。尽管长期使用皮质类固醇治疗，患犬的生理性(瘙痒)和皮肤症状(脱毛、红斑、糜烂、溃疡伴结痂)依旧存在，且症状没有改善。为了解决瘙痒恶化的情况，开始使用赛妥敏与泼尼松龙联合治疗。一旦使用赛妥敏，瘙痒持续得到改善，并有效地缓解且维持有效。需要进一步研究IL-31在CEL患犬的瘙痒途径中的关键作用。

Keyword: cutaneous epitheliotropic lymphoma, interleukin 31 (IL-31), lokivetmab, pruritus

关键词:皮肤趋上皮淋巴瘤、白介素31（IL-31）、赛妥敏、瘙痒

Cutaneous lymphoma in dogs accounts for approximately 3 to 8 % of all types of lymphomas. It occurs frequently in middle-aged and elderly dogs, and there is an unknown difference in morbidity depending on the breed or gender. Typically, canine cutaneous lymphoma represents the T-cell immunophenotype and is classified into cutaneous epitheliotropic lymphoma (CEL) and non-epitheliotropic lymphoma based on histopathology. Canine CEL can cause erythema, plaques, erosions, scales, nodules, hypopigmentation, crusts, alopecia and may cause mild to severe pruritus.

犬皮肤淋巴瘤约占所有淋巴瘤病例的3%至8%。常见于中老年犬，根据品种或性别不同，发病率差异未知。通常，犬皮肤淋巴瘤为T细胞免疫表型，根据组织病理学分为皮肤趋上皮淋巴瘤(CEL)和非趋上皮淋巴瘤。犬CEL可引起红斑、斑块、糜烂、皮屑、结节、色素减退、结痂、脱毛，并可引起轻度至重度瘙痒。

Interleukin 31 (IL-31) transmits pruritus signals to the brain via the janus kinase/signal transducer and activator of transcription pathway. Lokivetmab is a caninized anti-canine IL-31 monoclonal antibody (mAb) that interferes with the binding of IL-31 to its receptor by forming an antigen-antibody complex and neutralizing it. Thereby, it inhibits IL-31-mediated signal transduction and relieves pruritus associated with canine atopic dermatitis (CAD). In human medicine, some studies have reported a connection between pruritus in cutaneous lymphoma and IL-31. However, it has been controversial whether IL-31 is involved in the mechanism of pruritus in CEL in veterinary medicine.

白介素31 (IL-31)通过janus激酶/信号转换器和转录通路激活器将瘙痒信号传递到大脑。赛妥敏是一种犬化的抗犬IL-31单克隆抗体(mAb)，通过形成抗原-抗体复合物并中和IL-31与受体的结合，从而干扰IL-31与受体的结合。因此，赛妥敏可以抑制IL-31介导的信号转导，缓解与犬特应性皮炎(CAD)有关的瘙痒。在人医中，一些研究报道了皮肤淋巴瘤的瘙痒与IL-31之间的联系。然而，在兽医中IL-31是否参与CEL的瘙痒机制一直存在争议。

In this case report, we described a unique case of CEL in which pruritus was improved following treatment with lokivetmab. Lokivetmab was used after the patient failed on prednisolone. To the authors’ knowledge, this is the first case report in which an anti-IL-31 mAb played a possible role in reducing pruritus in a dog with CEL.

在本报告中，我们描述了唯一一例CEL病例的瘙痒在使用赛妥敏治疗后得到改善。在患犬泼尼松龙治疗失败后使用赛妥敏。据作者所知，这是第一个抗IL-31单抗可能在缓解犬CEL瘙痒中发挥作用的病例报告。

A 13-year-old spayed female Cavalier King Charles Spaniel presented with chronic swelling and mild pruritus over the palmar aspect of the left forepaw and on the tail, defined as Day 1. The patient also sustained a superficial ulceration on the palmar aspect of the left forepaw. There was mild to moderate erythema on the tail. The patient’s degree of pruritus was quantitatively assessed using the pruritus visual analogue scale (PVAS) score (Fig. 1) . On skin cytology, impression smears of the ulcerated and erythematic lesion revealed mild to moderate suppurative granulomatous inflammation (i.e., small amounts of cocci, denatured neutrophils, and macrophages). On Day 14, the patient was started on cephalexin (Therios; DS Pharma Animal Health, Osaka, Japan) (20 mg/kg, PO, q12 hr, for 14 days). Despite antibacterial therapy, the lesion showed no marked improvement and additional nasal depigmentation had emerged overtime (Fig. 2). On Day 28 of follow-up, there were progressive ulcerations and worsened erythema on the left forepaw. Multiple biopsies from the muzzle and tail were submitted for histopathology to provide a definitive diagnosis. The erythema on the tail was resected as the lesion was only limited to the tip.

一只13岁的母犬已绝育的骑士查理王猎犬，左前爪掌部和尾部出现慢性肿胀和轻度瘙痒，视为第一天。患犬左前爪掌部也有浅表溃疡。尾部有轻度至中度红斑。使用瘙痒视觉评分(PVAS)定量评估患犬的瘙痒程度(图1)。在皮肤细胞学检查中，溃疡和红斑性病变的皮肤压片显示轻度到中度化脓性肉芽肿性炎症(即少量球菌、退行性中性粒细胞和巨噬细胞)。第14天，患犬开始使用头孢氨苄(20 mg/kg, PO，每12小时一次，连续14天)。尽管进行了抗生素治疗，但病变未见明显改善，随着时间的推移，出现了更多的鼻部色素减退(图2)。随访第28天，左前爪出现进行性溃疡，红斑加重。为了确诊，从口周和尾部的多处皮肤活检的组织病理学检查。由于尾部红斑病变仅限于尾尖，所以进行切除。

Skin biopsies were performed by an attending veterinarian (KI) and the samples were read by a board-certified pathologist. The diagnosis of CEL was made based on the histological findings and metastatic lesions. Histopathological findings from the skin biopsy of the muzzle revealed that the lymphoblastic-like tumor cells were infiltrating the epidermis, the hair follicle epithelium, and the sweat glands. The cytoplasm of the tumor cells was scant to moderate in amount. The nuclei were round but sometimes irregular with stippled chromatin and distinct nucleoli. These findings were also obtained in the tail lesion. These tumor cells were positive for CD3, but negative for CD79α and CD20 on immunohistochemistry (Fig. 3).

由主治兽医(KI)进行皮肤活检采样，样本由一名经委员会认证的病理学家进行判读。根据组织学表现及转移性病变诊断为CEL。口周皮肤活检的组织病理学结果显示，表皮层、毛囊上皮细胞和汗腺浸润了淋巴母细胞样肿瘤细胞。肿瘤细胞的细胞质少，中等数量。细胞核圆形，有时不规则，染色质点状，核仁明显。这些也在尾部病变中有发现。免疫组化结果显示肿瘤细胞CD3阳性，但CD79α和CD20阴性(图3)。

After consultation with the owners, they did not wish to accept chemotherapy such as the CHOP protocol or L-asparaginase, due to concern about the side effects. Instead, treatment with prednisolone alone was chosen (PREDNISOLONE Tablets 5 mg “Mita”; KYORIN Rimedio, Kanazawa, Japan) (2 mg/kg, PO, q24 hr on Day 42). At this point, the pruritus was mild and the PVAS score was 3. On Day 56, in addition to the lesion previously monitored on the palmar aspect of the left forepaw, similar lesions had emerged on the other paws. Moreover, the pruritus worsened, and the patient had a PVAS score of 4. The prednisolone dose was tapered to 1.5 mg/kg, PO, q24 hr. On Day 63, exacerbation of the erythema on the muzzle was found, whereas the ulcer on the palmar aspect of all four paws did not significantly worsen. The patient’s PVAS score of 5 showed worsening conditions. On Day 77, the patient was continued on the same dose of prednisolone. There was a progressive worsening ulcer on the paws and alopecia with crusting was found on the face and upper back. The patient had a PVAS score of 7, in line with exacerbation of pruritus. On Day 91, the patient continued to develop multifocal areas of facial alopecia with crusting, along with concurrent pruritus. On Day 105, as the dose of prednisolone remained the same, the patient’s clinical signs, including facial alopecia and ulcerative lesions continued to progress despite treatment. By then, the patient had a PVAS score of 8.

在与宠主协商后，他们不希望接受CHOP方案或L-天冬酰胺酶等化疗，因为担心副作用。相反，选择单独使用泼尼松龙治疗(2 mg/kg, PO, 24小时，第42天)。此时瘙痒较轻，PVAS评分为3分。第56天，除之前监测到的左前爪掌侧病变外，其他爪子也出现了类似的病变。瘙痒加重，PVAS评分4分。泼尼松龙剂量逐渐减少至1.5 mg/kg, PO, q24小时。第63天，口周红斑加重，四足掌部溃疡无明显加重。PVAS评分为5分，病情进一步恶化。在第77天，患犬继续使用相同剂量的泼尼松龙。爪部溃疡逐渐恶化，面部及上背部出现脱毛及结痂。患犬PVAS评分为7分，瘙痒加重。第91天，患犬继续出现多灶性面部脱毛，伴结痂，同时伴有瘙痒。第105天，由于泼尼松龙的剂量不变，尽管进行了治疗，但患犬的面部脱毛、溃疡等临床症状仍在发展。此时，患者PVAS评分为8分。

In the hope of mitigating this ongoing pruritus, lokivetmab (Cytopoint; Zoetis, Tokyo, Japan) (1.25 mg/kg, SC, once) was initiated in combination with prednisolone (1.5 mg/kg, PO, q24 hr). On Day 112, facial alopecia with crusting was still present. The ulcerative lesions remained  unchanged with no remarkable improvement. Despite the patient’s minimal clinical response, the PVAS score was found to be 7. A decision was made to further taper the dose of prednisolone to 1 mg/kg, PO, q24 hr. The PVAS score fell from 5 to 3 in two weeks. On Day 132, one month after starting lokivetmab, the pruritus subsided. To prevent the possibility of relapse, lokivetmab (1.25 mg/kg, SC, once) was re-administered. On Day 153, despite the persistence of the facial alopecia with crusting, the PVAS score had dropped to 2, suggesting the pruritus was now well-controlled. On Day 160, the pruritus was controlled with a PVAS score of 1. Since the pruritus was negligible, active monitoring was initiated without further treatment of lokivetmab. Hair started to regrow on the face where alopecia was previously reported. On Day 167, the pruritus remained stable with a PVAS score of 1. Since the last visit, the patient sustained an excellent quality of life and eventually passed away due to progressive lymphoma on Day 183.

为了缓解持续的瘙痒，使用赛妥敏(1.25 mg/kg, SC，使用1次)与泼尼松龙(1.5 mg/kg, PO, q24小时)联合治疗。第112天，仍有面部脱毛伴结痂。溃疡病变未见明显改善。虽然患犬临床效果改善很小，但PVAS评分为7分。决定进一步减少泼尼松龙的剂量至1 mg/kg, PO, q24小时。PVAS评分在两周内从5降至3。第132天，使用赛妥敏后一个月，瘙痒消退。为了防止复发的可能性，再次给予赛妥敏(1.25 mg/kg, SC, 使用1次)。第153天，尽管面部脱毛和结痂持续存在，但PVAS评分下降到2，表明瘙痒现在得到了很好的控制。第160天，瘙痒得到控制，PVAS评分为1。由于瘙痒很轻微，停用赛妥敏进行进一步观察。之前脱毛部位，面部毛发开始重新生长。第167天，瘙痒控制维持稳定，PVAS评分为1。自上次就诊以来，患犬一直维持着良好的生活质量，最终于第183天因淋巴瘤进一步发展进行安乐。

In this dog, there was no history of CAD or cutaneous adverse food reactions before the age of 8, and the patient's pruritus worsened as skin lesions progressed over time despite the use of prednisolone. Therefore, in this case the pruritus was considered to be related to CEL. IL-31 is produced mainly by activated T cells, and it is a critical pruritogenic cytokine associated with atopic dermatitis in humans and dogs. It has been reported that the serum concentrations of IL-31 were not statistically different between non-pruritic dogs with CEL and healthy controls. However, the contribution of IL-31 to pruritus in dogs with cutaneous lymphoma has not been fully understood in veterinary medicine. In human medicine, it has been reported that the expression of serum IL-31 in cutaneous T-cell lymphoma (CTCL) patients is upregulated.Decreasing serum IL-31 levels are correlated with the resolution of pruritus in CTCL patients. Lokivetmab, a monoclonal antibody used to treat CAD, is reported to neutralize IL-31 and mitigate canine pruritus. Although lokivetmab is not indicated for the treatment of CEL, it was used in the hope of reducing pruritus. In this case of CEL, lokivetmab decreased pruritus. Thus, anti-IL-31 therapy appears to be a potential treatment option in controlling pruritus associated with CEL in dogs.

本文患犬8岁前无CAD病史及皮肤食物不良反应病史，尽管使用泼尼松龙，但患犬瘙痒随时间推移皮肤病变加重而加重。因此，本例中瘙痒被认为与CEL有关。IL-31主要由活化的T细胞产生，是一种与人类和犬的特应性皮炎相关的致痒细胞因子。据报道，IL-31的血清浓度在患CEL的非瘙痒患犬中和健康对照组之间没有统计学差异。然而，在兽医中，IL-31对皮肤淋巴瘤患犬瘙痒的作用尚未完全了解。在人医中，有报道皮肤T细胞淋巴瘤(CTCL)患者血清IL-31表达上调。CTCL患者血清IL-31水平降低与瘙痒缓解有相关性。赛妥敏是一种用于治疗CAD的单克隆抗体，据报道可以中和IL-31并减轻犬瘙痒。虽然赛妥敏不是用于CEL的治疗，但使用赛妥敏希望能减轻瘙痒。在这个CEL病例中，赛妥敏可以减轻瘙痒。因此，抗IL-31治疗似乎是控制与CEL相关的犬瘙痒的潜在治疗选择。

In this case, the IL-31 concentration before and after lokivetmab treatment was not quantified, and the correlation between the clinical improvement of pruritus in CEL and the IL-31 concentration was not specifically reported. Further studies are needed to determine whether IL-31 plays a critical role in the pruritus pathway in dogs diagnosed with CEL.

本病例中，没有量化赛妥敏治疗前后的IL-31浓度，CEL瘙痒的临床改善与IL-31浓度之间的相关性也没有特异性报道。还需要进一步的研究来确定IL-31是否在被诊断为CEL的犬的瘙痒通路中发挥关键作用。

Fig. 1 The change in the pruritus visual analogue scale (PVAS) score over time. The change of PVAS score is drawn in a black line, decreasing at the time when lokivetmab was administered. Lokivetmab was administered on Day 105 and Day 132 (black arrow). The blue bar below the graph shows the dosage of prednisolone prescribed.

图1瘙痒视觉评分表(PVAS)随时间的变化。PVAS评分的变化用黑线表示，当使用赛妥敏时，PVAS评分下降。赛妥敏在第105天和第132天使用(黑箭头)。图下方的蓝色条形图显示了泼尼松龙的使用剂量。

Fig. 2 (A) On Day 14, nasal depigmentation had emerged. (B) On Day 105, progression of facial alopecia with crusting was found. (C) On Day 132, facial alopecia with crusting was still present. (D) On Day 160, hair regrew on the face where alopecia was present.

图2 (A)第14天，鼻部出现色素减退。(B)第105天，面部脱毛伴结痂加重。(C)第132天，面部脱毛伴结痂仍然存在。(D)第160天，脱毛部位的毛发再生长。

Fig. 3 Histopathological and immunohistochemical images of the muzzle sample. The epithelium was thickened and markedly infiltrated by the tumor cells (A, B). The tumor cells in the epithelium were strongly positive for CD3 (C), but negative for CD20 (D). Bar=200 μm (A), Bar=50 μm (B, C, D).

图3 口周样本的组织病理及免疫组化图像。表皮细胞增厚，肿瘤细胞浸润明显(A、B)， 表皮细胞的肿瘤细胞的CD3强阳性(C)， 但CD20阴性(D)， 标尺=200 μm (A)， 标尺=50 μm (B、C、D)。

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