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Cutaneous lesions and clinical outcomes in five cats after frunevetmab injections
5只猫注射夫卢维单抗后的皮肤病变和临床结果
Anjie Storrer , John T Mackie , Marcus N Gunew and Jeylan Aslan
翻译：王帆
Abstract
摘要
Case series summary This case series describes five cats with cutaneous adverse events after subcutaneous administration of frunevetmab, a felinised anti-nerve growth factor monoclonal antibody, including histopathological findings in one case. All cats displayed moderate to severe pruritus resulting in self-trauma to the neck and/or head, causing lesions ranging from superficial dermatitis to alopecia and ulcerations. There were no reactions at the injection sites. In one cat, clinical signs developed after the second frunevetmab dose the cat received, with no reaction noted after the first dose. For the remaining cats, clinical signs were observed after their first dose of frunevetmab. The onset of the first episode of pruritus and self-trauma was 3–18 days after the most recent frunevetmab injection. Three cats had one or more additional frunevetmab injections after the original adverse event and all had subsequent reactions. Subsequent reactions were either similar in time frame or occurred more rapidly, with similar or more severe pruritus compared with the original reactions. Treatments and outcomes varied between cases.
病例系列研究 描述了5只猫在皮下注射夫卢维单抗(一种猫的抗神经生长因子单克隆抗体)后出现皮肤不良事件，包括其中一例的组织病理学发现。所有猫都表现出中度至重度瘙痒，导致颈部和(或)头部自损，引起从浅表性皮肤病到脱毛和溃疡的皮肤病变。注射部位无反应。一只猫在接受第二次夫卢维单抗注射后出现了临床症状，在第一次注射后未观察到反应。对于剩余的猫，我们在它们注射第一次夫卢维单抗后有临床症状表现。首次瘙痒和自损发生在最近一次夫卢维单抗注射后3-18日。3只猫在最初的不良事件后注射1次或多次夫卢维单抗再注射，所有猫都有后续反应。与初始反应相比，后续反应要么在时间范围上相似，要么发生得更快，瘙痒程度相似或更严重。不同病例的治疗和结果不同。
Relevance and novel information Frunevetmab is a novel, monthly injectable monoclonal antibody for the management of pain associated with osteoarthritis in cats. This is the first published report detailing the nature of cutaneous adverse events associated with this treatment, and the first report of the histopathological findings.
相关性和新信息 夫卢维单抗是一种新的、可每月注射的单克隆抗体，用于治疗猫骨关节炎相关疼痛。这是首次发表的报告，详细介绍了与这种治疗相关的皮肤不良事件的性质，以及组织病理学结果的第一份报告。
Keywords: Adverse event; frunevetmab; Solensia; dermatology; skin; idiopathic ulcerative dermatitis
关键词:不良事件;夫卢维单抗;索伦西亚;皮肤病;皮肤;特发性溃疡性皮肤病
Introduction
介绍
Degenerative joint disease (DJD) is highly prevalent in senior cats, with one study reporting radiographic evidence of DJD in 90% of cats aged over 12 years. While chronic pain can be difficult to assess in cats, prospective studies have demonstrated improvements in mobility with analgesia. Most pharmacological analgesics require daily or multiple-times-per-day oral administration, which can be challenging for both cats and their owners, and has the potential for injury to the owner. Non-steroidal anti-inflammatory drugs (NSAIDs) have traditionally been considered the mainstay for the management of chronic pain owing to osteoarthritis (OA) in dogs and cats. However, as OA and chronic kidney disease (CKD) can occur concurrently in up to 70% of feline cases, there is often a reluctance to prescribe longterm NSAIDs in older cats. While a recent review has indicated that this reluctance may not be fully justified, alternative medications may be sought due to the concern about renal toxicity.
退行性关节疾病(DJD)在老年猫中非常普遍，一项研究报告，12岁以上的猫中90%有DJD的影像学证据。虽然猫的慢性疼痛很难评估，但前瞻性研究表明，镇痛可改善活动能力。大多数药物镇痛药需要每天或每天多次口服给药，这对猫和它们的宠主都是一个挑战，并且有可能对宠主造成伤害。传统上，非甾体抗炎药(NSAID)被认为是治疗犬猫骨关节炎(OA)引起的慢性疼痛的主要药物。然而，由于多达70%的猫的OA和慢性肾脏病(CKD)可同时发生，因此通常不愿为老年猫开出长期非甾体抗炎药。虽然最近的一项综述表明，这种不情愿可能没有充分的理由，但由于担心肾毒性，可以寻求替代药物。
A recent advance in the management of chronic pain in cats has been the development of a felinised anti-nerve growth factor (NGF) monoclonal antibody (mAb), frunevetmab (Solensia; Zoetis). NGF is a cytokine expressed at sites of inflammation, such as joints affected by DJD, and has been recognised as a major contributor to the generation, propagation and sensation of pain. NGF is also involved in nociceptor sensitisation, potentially resulting in hyperalgesia and/or allodynia. Frunevetmab blocks the activity of feline NGF and has been shown to be effective in reducing pain in cats diagnosed with DJD. Frunevetmab is the only anti-NGF mAb approved for use in cats in the USA and has recently been recommended as a first-tier medication for the treatment of OA pain in cats.
治疗猫慢性疼痛的最新进展是一种经猫的抗神经生长因子(NGF)单克隆抗体(mAb) 夫卢维单抗(索伦西亚)。NGF是一种细胞因子，在炎症部位表达，如DJD影响的关节，并被认为是疼痛产生、传播和感觉的主要贡献者。NGF也参与伤害感受器敏化，可能导致痛觉过敏和/或痛觉超敏。夫卢维单抗阻断猫NGF的活性，已被证明可有效减轻被诊断为DJD患猫的疼痛。夫卢维单抗是美国唯一批准用于猫的抗NGF的mAb，最近被推荐作为治疗猫OA疼痛的一线药物。
There is limited literature regarding the adverse events of frunevetmab administration. In two studies assessing efficacy, cutaneous adverse events were reported with significantly greater frequency in cats receiving frunevetmab vs placebo, and these findings are presented in the manufacturer’s prescribing information. In one study, 32/182 (18%) cats receiving frunevetmab developed skinrelated adverse events compared with 8/93 (9%) cats receiving placebo. Of the cats receiving frunevetmab, 11/182 (6%) had dermatitis and eczema, 10/182 (5.5%) had alopecia and 7/182 (3.8%) had pruritus, although it is unclear whether the cats had these conditions simultaneously and lesion distribution was not described. In another study, 16/85 (19%) cats receiving frunevetmab developed dermatitis/eczema, 4/85 (5%) had alopecia (distribution not stated) and pruritus was not reported. Again, it is unclear whether pruritus, alopecia and dermatitis occurred simultaneously. This latter study concluded that the adverse events were likely related to wearing an activity-monitoring collar. However, only 1/41 (2%) cats receiving placebo (also wearing collars) developed dermatitis/eczema and none had alopecia.
关于给予夫卢维单抗的不良事件的文献有限。在两项评估疗效的研究中，在注射夫卢维单抗的猫中，皮肤不良事件的发生率显著高于接受安慰剂的猫，这些结果在制造商的处方信息中显示。在一项研究中，182只接受夫卢维单抗的猫中有32只(18%)发生了皮肤相关不良事件，而93只接受安慰剂的猫中有8只(9%)发生了皮肤相关不良事件。在接受夫卢维单抗治疗的猫中，11/182(6%)有皮肤病和湿疹，10/182(5.5%)有脱毛，7/182(3.8%)有瘙痒，但尚不清楚这些猫是否同时有这些情况，皮肤病变分布也未被描述。在另一项研究中，16/85(19%)接受夫卢维单抗的猫出现了皮肤病/湿疹，4/85(5%)出现了脱毛(分布未说明)，瘙痒未被报告。同样，目前尚不清楚瘙痒、脱毛和皮肤病是否同时发生。后一项研究得出的结论是，不良事件可能与佩戴活动监测项圈相关。然而，只有1/41(2%)接受安慰剂的猫(也戴项圈)发生了皮肤病/湿疹，没有发生脱毛。
The current case series describes cutaneous adverse events after the administration of frunevetmab in one cat, including histopathological findings. It also describes four additional cats with cutaneous adverse events after the administration of frunevetmab, including the temporal course, distribution, severity, treatments and outcome.
目前的病例系列描述了1只猫注射夫卢维单抗后皮肤不良事件，包括组织病理学结果。它还描述了另外4只猫在注射夫卢维单抗后出现皮肤不良事件，包括时间过程、分布、严重程度、治疗和结果。
Case series description
案例系列描述
The principal case in this report (case 1), a 6.0 kg, 14-yearold, female spayed domestic shorthair, received a frunevetmab injection (7 mg) subcutaneously between the shoulder blades in September 2022 in Queensland, Australia. It was an indoor-only cat without access to other cats. Four weeks previously, the cat had received its first dose of frunevetmab, with no adverse reaction observed. The cat had no history of pruritic skin disease, although it had experienced a mild, transient, localised reaction to transdermal methimazole over 1 year before receiving frunevetmab. Nine days after the second frunevetmab injection, an area of ulceration was noted on the right ventrolateral neck. There was no reaction at the injection site. Concurrently, the cat was noted to be moderately pruritic, using its hindlimbs to scratch its neck and the right side of its face. Twelve days after the second frunevetmab injection (40 days after the cat’s first dose), the cat presented for investigation of the neck lesion. At this time, the neck lesion appeared ulcerated and moist with suspected secondary bacterial infection. No ectoparasites were macroscopically identified. Cytology from the right ear revealed cocci and occasional Malassezia organisms. Over the next 11 weeks after presentation, the cat was treated with multiple different medications, including multiple doses of long-acting parenteral antibiotics, oral and parenteral corticosteroids, topical antiseptic application and Elizabethan collars (Table 1). The pruritus and the severity of the lesion (area affected and extent of ulceration) appeared to wax and wane, with some temporary, moderate improvement in pruritus noted after the administration of corticosteroids. However, the lesion did not resolve, and the cat continued to periodically traumatise its right ventrolateral neck, causing the lesion to enlarge and worsen in appearance (Figure 1). Thirteen weeks after the second frunevetmab injection, a surface swab for bacterial culture and an incisional biopsy for histopathology were performed. Bacterial culture yielded a moderate growth of Staphylococcus felis (susceptible to all antimicrobials tested) and a light growth of the environmental organism Stenotrophomonas maltophilia (antimicrobial susceptibility testing was not performed).
本文的主要病例(病例1)是一只体重6.0 kg、14岁、已绝育雌性家养短毛猫，于2022年9月在澳大利亚昆士兰州肩胛骨之间注射夫卢维单抗皮下注射(7 mg)。猫只在室内活动，不能接触其他猫。4周前，这只猫注射第一次夫卢维单抗，未观察到不良反应。这只猫没有瘙痒性皮肤病的病史，但在接受夫卢维单抗治疗前1年多，它对透皮甲巯咪唑有过轻度、短暂、局部反应。第2次注射夫卢维单抗后9日，在右侧腹外侧颈部观察到溃疡区域。注射部位无反应。同时，观察到猫有中度瘙痒，用后肢搔抓颈部和右侧面部。第二次注射夫卢维单抗后12天(猫第一次注射后40天)，猫来检查颈部病变。此时颈部病变出现溃疡，潮湿，疑似继发细菌感染。肉眼未见体外寄生虫。右耳细胞学检查显示球菌，偶见马拉色菌。在就诊后的11周内，我们对这只猫进行了多种不同的药物治疗，包括多剂量的长效肠外抗生素、口服和肠外糖皮质激素、外用抗菌药和伊丽莎白项圈(表1)。瘙痒和病变的严重程度(患病面积和溃疡程度)似乎有增有减，使用糖皮质激素后，瘙痒有一些暂时的中度改善。然而，病变未消退，猫右颈部腹外侧继续有周期性病变，导致病变增大，外观恶化(图1)。在第二次注射夫卢维单抗后13周，我们进行了表面拭子细菌培养和切开活检，以进行组织病理学检查。细菌培养显示猫葡萄球菌中度生长(对检测的所有抗菌药物敏感)，而环境微生物嗜麦芽窄食单胞菌轻度生长(未进行抗菌药物敏感试验)。
Histopathology revealed epidermal ulceration overlain by a serocellular crust (Figure 2). Necrosis extended to the superficial dermis. Beneath the ulceration, the superficial dermis contained a relatively mild perivascular inflammatory infiltrate consisting of mainly neutrophils with low numbers of mononuclear cells and mast cells. There was minimal extension of inflammation into hair follicles at the junction of ulcerated and intact epidermis, and in one follicle, luminal keratin contained coccoid bacteria. Additional changes included minor superficial dermal fibroplasia. Deeper levels in the tissue block revealed a subcorneal pustule at the junction of ulcerated and intact epidermis. A periodic acid-schiff (PAS) stain did not reveal fungi.
组织病理学显示表皮溃疡覆盖一层血清性结痂(图2)。坏死延伸至真皮浅层。溃疡下方真皮浅层血管周炎性细胞浸润相对较轻，以中性粒细胞为主，单核细胞和肥大细胞数量较少。在溃疡的表皮和完整的表皮交界处，炎症轻微扩展到毛囊，在一个毛囊中，毛囊腔角蛋白含有球菌。其他改变包括轻微的皮肤浅表纤维增生。在组织块的更深层次显示在溃疡和完整的表皮交界处有一个角质下脓疱。过碘酸-希夫(PAS)染色未发现真菌。
After the incisional biopsy, further medications were trialled, including oral antibiotics and multiple doses of parenteral corticosteroids (Table 1). Again, pruritus improved only temporarily after corticosteroid doses and the skin lesion did not resolve. A total of 18.5 weeks after the second frunevetmab injection, owing to a lack of response to medical treatment, the neck lesion was surgically resected. Histopathology of the excised specimen revealed epidermal ulceration, superficial bacterial infection (cocci consistent with Staphylococcus species) and superficial dermal fibrosis and fibrovascular hyperplasia accompanied by relatively mild inflammation (Figures 3 and 4). Additional changes included patchy subcorneal pustules, and atrophy and loss of hair follicles. After excision of the lesion, the pruritus improved dramatically and the skin healed completely. The cat continued to demonstrate occasional, very mild pruritus, which was managed with subcutaneous dexamethasone injections for the first 2 months postoperatively. While the pruritus occurred spontaneously, the owner also described pruritus/muscle twitching being triggered by touch around the cat’s face/neck. At the time of submission of this manuscript (6 months after the excisional biopsy), no further skin lesions have developed. Furthermore, pruritus has now completely resolved and the cat has not required any medications for the past 4 months.
切开活检后，我们试验了其他药物治疗，包括口服抗生素和多剂量皮质类固醇肠外给药(表1)。同样，使用皮质类固醇后，瘙痒仅短暂改善，皮肤病变未消退。在第二次注射夫卢维单抗后共18.5周，由于药物治疗无效，我们手术切除了颈部病变。切除样本的组织病理学显示表皮溃疡、浅表细菌感染(球菌与葡萄球菌属一致)、真皮浅表纤维化和纤维血管增生伴相对轻微的炎症(图3和图4)。其他变化包括斑片状角质层下脓疱以及毛囊萎缩和缺失。皮肤病变切除后，瘙痒明显改善，皮肤完全愈合。这只猫继续表现出偶尔的、非常轻微的瘙痒，在术后的前2个月通过皮下注射地塞米松进行治疗。虽然瘙痒是自发的，但宠主还描述说，触摸猫的脸/脖子会引发瘙痒/肌肉抽搐。在提交本文时(切除活检后6个月)，没有出现进一步的皮肤病变。此外，瘙痒现在已经完全缓解，猫在过去4个月里不需要任何药物治疗。
Additional cases of cutaneous adverse reactions to frunevetmab were identified by searching for reports on Veterinary Information Network message boards and via online veterinary dermatology forums. Three veterinarians contributed four additional cases (cases 2–5), with a total of nine adverse events documented between August 2022 and January 2023. The contributing veterinarians provided information via a questionnaire regarding signalment, clinical signs, cutaneous lesions, previous dermatological disease, treatments and outcome (Table 2). Two cats had three adverse reactions each, one cat had two reactions and one cat had one reaction. None of these additional cases had received a dose of frunevetmab without experiencing a cutaneous reaction. A previous history of skin disease was reported in case 3 (transient facial pruritus after administration of a behavioural supplement containing l-theanine, magnolia/phellodendron and whey protein concentrate) and case 5 (seasonal pruritus).
通过搜索兽医信息网络留告板和在线兽医皮肤病论坛上的报告，确定了其他对夫卢维单抗发生皮肤不良反应的病例。3名兽医报告了另外4例病例(病例2-5)，在2022年8月至2023年1月期间共记录了9起不良事件。参与调查的兽医通过问卷提供了有关特征、临床症状、皮肤病变、既往皮肤病、治疗和结果的信息(表2)。两只猫各有3种不良反应，一只猫有2种反应，一只猫有1种反应。这些其他病例都是在注射一次夫卢维单抗后发生皮肤反应。病例3(注射含有l-茶氨酸、木兰/黄柏和乳清蛋白浓缩物的行为补充剂后出现短暂的面部瘙痒)和病例5(季节性瘙痒)既往有皮肤疾病史。
For these additional cases (cases 2–5), the cats were aged 8.5–14 years. Frunevetmab (7 mg) was administered subcutaneously, either between the shoulder blades or over the hip region for the management of OA pain. The adverse reactions began 3–18 days after the cats’ first frunevetmab injections. Clinical signs in all cases consisted of mild to severe pruritus of the neck and/or head, distant from the site of injection. Signs of self-trauma, including excoriation with crusting, occurred in all cases. Of the four cats, three (cases 2, 4 and 5) also developed alopecia in the regions of pruritus. Cases 2, 3 and 4 received subsequent doses of frunevetmab, which elicited further cutaneous reactions with similar or more severe pruritus occurring in the same time frame or more rapidly compared with prior reactions. Treatments varied among cases (Table 2). In the principal case (case 1), although corticosteroids were found to improve pruritus, surgical resection was the only treatment that resolved the skin lesion. In case 2, amoxicillin/clavulanic acid, oral antihistamine and topical hydrocortisone did not appear to improve the clinical signs. After the third episode, pruritus resolved after oral prednisolone at a dose of 1 mg/kg q24h. In this case, prednisolone was continued in the long term at 1 mg/kg every second day as it improved the cat’s mobility. In case 3, severe pruritus after the second frunevetmab injection improved rapidly after the administration of oclacitinib (Apoquel; Zoetis) for 10 days. Specifically, pruritus resolved in less than 24 h, which compared favourably with the 26 days for resolution of pruritus after the cat’s first adverse reaction was treated with topical fatty acids and ceramide. After 10 days of treatment with oclacitinib, the medication was discontinued for 3 days before starting again due to the relapse of pruritus. Four days later, it was possible to discontinue the medication without any further pruritus. Case 4 did not receive any specific treatment and clinical signs resolved 4 weeks after the third adverse reaction. In case 5, prednisolone administered at 2.5 mg every third day for three doses did not improve pruritus. Nail trimming was believed to limit the damage caused by scratching, resulting in clinical resolution. In cases 2–5, resolution of clinical signs occurred within 2–6 weeks after the final dose of frunevetmab.
其他的病例(病例2-5)的猫年龄为8.5-14岁。肩胛骨之间或臀部上方皮下注射夫卢维单抗 (7 mg)，用于治疗OA疼痛。猫首次注射夫卢维单抗后3-18 d开始出现不良反应。所有病例的临床症状均为远离注射部位的颈部和(或)头部轻度至重度瘙痒。所有病例均有自损性症状，包括抓痕和结痂。4只猫中，3只(病例2、4和5)也在瘙痒部位出现脱毛。病例2、3和4再次注射夫卢维单抗，引起了进一步的皮肤反应，瘙痒程度相似或更严重，与之前的反应发生的时间相同或更快。治疗方法因病例而异(表2)。在主要病例(病例1)中，虽然发现皮质类固醇可改善瘙痒，但手术切除是解决皮肤病变的唯一治疗方法。例2给予阿莫西林/克拉维酸、口服抗组胺药及外用氢化可的松治疗后，临床症状未见明显改善。第3次发作后，瘙痒在口服泼尼松龙(1 mg/kg，每24小时1次)后缓解。在这个病例中，由于泼尼松龙改善了猫的活动能力，因此以每次注射第二天1 mg/kg的剂量长期持续用药。病例3第2次注射夫卢维单抗后的重度瘙痒在使用奥拉替尼10天后得到改善。具体来说，瘙痒在24小时内消退，这与外用脂肪酸和神经酰胺治疗猫的第一次不良反应后的26天瘙痒消退相比，具有优势。奥拉替尼治疗10 天后，因瘙痒复发，停药3 d后再次开始用药。4天后可停药，无进一步瘙痒。病例4未做特殊处理，发生第3次不良反应后4周临床症状消失。在病例5中，每3日给药1次，每次2.5 mg，共给药3次的泼尼松龙未能改善瘙痒。修剪指甲被认为可以限制抓痕造成的损伤，从而达到临床缓解。在病例2-5中，临床症状在最后一剂夫卢维单抗给药后2-6周内消退。
Discussion
讨论
This case series describes cutaneous adverse events in five cats after the administration of frunevetmab, including the histopathological findings in one cat. Pruritus/ self-trauma was a consistent feature, and it is suspected that skin lesions or alopecia were a consequence of selftrauma in all cases. Histopathology in case 1 demonstrated ulceration with superficial dermal fibrosis and neutrophilic inflammation. These findings could also be caused entirely by self-trauma with secondary superficial bacterial infection. There was no eosinophilic inflammation to specifically indicate a hypersensitivity reaction. The histological lesion had similarities to feline idiopathic ulcerative dermatitis (FIUD), a poorly understood condition associated with self-trauma. FIUD is characterised by a demarcated, crusted, non-healing ulcer that occurs most commonly on the dorsal neck or between the scapulae. Lesions have also been reported on the lateral neck and temporal areas. While some cases of FIUD have been shown to respond to glucocorticoids, topiramate, oclacitinib, surgical resection, bandaging/prevention of self-trauma or environmental enrichment, some authors regard the prognosis as guarded, as lesions may be refractory to medical treatment or may recur despite surgical resection. In the present case series, a range of responses was noted, from spontaneous resolution in case 4, to the principal case (case 1) in which the skin lesion was refractory to medical treatment and required surgical resection.
本病例系列描述了5只猫在注射夫卢维单抗后发生的皮肤不良事件，包括其中一只猫的组织病理学发现。瘙痒/自损是一致的特征，所有病例的皮肤病变或脱毛均怀疑是自损的结果。病例1组织病理显示溃疡伴真皮浅层纤维化和中性粒细胞性炎症。这些发现也可能完全由自损继发浅表细菌感染引起。没有特异性提示超敏反应的嗜酸性炎症。组织学病变与猫特发性溃疡性皮肤病(FIUD)有相似之处，而FIUD是一种与自损相关的疾病，我们对此知之甚少。FIUD的特征是边界清楚、结痂、不愈合的溃疡，最常发生在颈背部或肩胛骨之间。颈侧和颞区也有病变报告。尽管糖皮质激素、托吡酯、奥拉替尼、手术切除、包扎/预防自损或丰富环境等治疗对部分FIUD有效，但也有部分作者认为，FIUD的预后需要谨慎，因为FIUD可能对药物治疗无效或手术切除后仍可能复发。在本病例系列中，我们观察到一系列的缓解，从病例4的自发缓解到主要病例(病例1)，在该病例中，皮肤病变药物治疗无效，需要手术切除。
In FIUD, it has been speculated that cats self-traumatise due to hyperstimulation of nerve endings (neuropathic itch syndrome). It is believed that the face, interscapular and neck regions are predisposed to neuropathic itch, as they contain dense aggregates of sensory nerves and are also easily accessible for cats to scratch.As NGF acts on sensory afferent nerves, it is conceivable that some cats receiving frunevetmab could develop altered nerve sensation, leading them to self-traumatise. This would explain why the lesion distribution and histopathology are similar to FIUD. The human literature reports cases of paraesthesia, hyperaesthesia and a burning sensation in 5–10% of patients receiving anti-NGF mAbs. In these studies, most of the sensory abnormalities resolved within 1 month, although reports of persistent symptoms lasting up to 5 months have also been documented. The relatively transient nature of these symptoms has been speculated to be due to a temporary change in the sensitivity, or ‘tone’, of afferent nerve fibre populations. A temporary change in sensitivity could also explain why the clinical signs resolved without treatment in one case in the present report (case 4).
在FIUD中，人们推测猫由于神经末梢的过度刺激而产生自损(神经性瘙痒综合征)。人们认为，面部、肩胛间和颈部容易发生神经性瘙痒，因为它们含有密集的感觉神经聚集，也很容易被猫抓。由于NGF作用于感觉传入神经，可以想象一些接受夫卢维单抗的猫可能会发生神经感觉的改变，导致它们自损。这可以解释为什么病灶分布和组织病理学与FIUD相似。人类文献报道，在接受抗NGF单抗的患者中，有5-10%的患者出现感觉异常、感觉过敏和烧灼感。在这些研究中，大多数感觉异常在1个月内消退，但也有持续长达5个月的症状的报告。这些症状相对短暂的性质被推测是由于传入神经纤维群的敏感性或“基值”的暂时变化。敏感性的暂时性变化也可以解释本文中1例患猫(病例4)的临床症状未经治疗即可缓解的原因。
The pruritus exhibited by one cat (case 3) after its second reaction to frunevetmab resolved rapidly (within 12 h) after off-label treatment with oclacitinib, compared with its previous (first) reaction when only topical treatments were used. Oclacitinib is a Janus kinase inhibitor, which blocks JAK1-dependent cytokines involved in inflammation and pruritus. This medication is used in the treatment of canine atopic dermatitis and has experimentally been shown to reduce pruritus in 63% of cats if administered 1 h before an injection of IL-31, a pruritogenic cytokine. Oclacitinib has also been reported to be successful in the treatment of one case of refractory FIUD.
一只猫(病例3)在第二次注射夫卢维单抗出现瘙痒反应后，接受奥拉替尼标签外治疗后(12小时内)出现瘙痒迅速消退，而之前(第一次)仅使用外用治疗。奥拉替尼是Janus激酶抑制剂，可阻断参与炎症和瘙痒的JAK1依赖性细胞因子。该药物用于治疗犬特应性皮炎，实验表明，如果在注射IL-31(一种致痒细胞因子)前1小时给药，可减轻63%的猫的瘙痒。据报道，奥拉替尼也成功治疗了1例难治性FIUD。
In the present case series, other treatments considered by veterinarians to improve the clinical course were surgical resection (1 case), subcutaneous dexamethasone (1 case), oral prednisolone (2 cases) and trimming the nails on the hindfeet to prevent further self-trauma (1 case). In case 1, other medical treatments were not trialled as the cat was not amenable to oral medications. Surgery resolved the lesion, although ongoing, very mild episodic pruritus continued for a further 2 months. Ongoing self-trauma and/or lesion recurrence has previously been documented in cases of FIUD treated with surgical resection.
在本病例系列中，兽医考虑改善临床病程的其他治疗包括手术切除(1例)、皮下注射地塞米松(1例)、口服泼尼松龙(2例)和修剪后足指甲以防止进一步的自损(1例)。在病例1中，其他药物治疗没有进行试验，因为猫不适合口服药物。手术缓解了病变，但非常轻微的发作性瘙痒持续了2个月。既往有文献报道外科切除治疗的FIUD病例存在持续的自损和/或病变复发。
Topiramate, an anticonvulsant medication, was administered in a reported case of refractory FIUD, leading to improvement within 2 weeks and resulting in longterm remission. While it is difficult to draw conclusions on potential therapeutic options in cats, treatments that are effective for FIUD may also prove effective for cutaneous reactions secondary to frunevetmab. Gabapentin or topiramate could be considered due to their inhibitory effects on neuronal excitability.Whether these medications could be administered concurrently with frunevetmab to reduce the severity of a cutaneous reaction in cats that have experienced prior episodes warrants further investigation.
托吡酯是一种抗惊厥药，用于报道的1例难治性FIUD病例，结果在2周内改善，并达到长期缓解。虽然很难就猫的潜在治疗方案得出结论，但对FIUD有效的治疗方法可能也对夫卢维单抗继发的皮肤反应有效。加巴喷丁或托吡酯对神经元兴奋性有抑制作用，可考虑使用。这些药物是否可以与夫卢维单抗同时使用，以减轻既往发生过皮肤反应的猫的皮肤反应严重程度，需要进一步研究。
As previously mentioned, an early study of the efficacy and safety of frunevetmab suggested that activitymonitoring collars were the cause of observed skin disorders, including dermatitis/eczema and alopecia. This assumption is also repeated in the manufacturer’s prescribing information. However, a significantly greater number of cats receiving frunevetmab were affected compared with those receiving placebo, despite all cats wearing the collars. In addition, none of the cats in the present case series had collars in place at the time of their frunevetmab administration or their subsequent cutaneous reactions. These findings suggest that the administration of frunevetmab results in an abnormal sensation around the neck, which collars may or may not exacerbate.
如前所述，对夫卢维单抗的疗效和安全性进行的一项早期研究提示，活动监测项圈是观察到的皮肤疾病(包括皮肤病/湿疹和脱毛)的原因。这一假设也重复出现在制造商的处方信息中。然而，与接受安慰剂的猫相比，接受夫卢维单抗的猫患病的数量显著增加，但所有猫都戴着项圈。此外，在本病例系列中，所有猫在使用夫卢维单抗或发生随后的皮肤反应时都没有颈圈。这些发现提示，注射夫卢维单抗会导致颈部异常感觉，这种感觉可能会加重，也可能不会加重。
In the present case series, of the cats that received multiple frunevetmab injections, cutaneous adverse reactions were often evident more rapidly at subsequent injections. This could indicate a sensitisation component or a cumulative pharmacological effect. To determine whether this is a true pattern, larger, prospective studies are required.
在本病例系列中，接受多次夫卢维单抗注射的猫，皮肤不良反应往往在随后的注射中更迅速地显现出来。这可能表明一种致敏成分或累积的药理作用。为了确定这是否是一个真正的模式，需要更大规模的前瞻性研究。
It should be noted that all four of the veterinarians who contributed cases to this series continue to recommend frunevetmab for cats diagnosed with reduced mobility due to OA. They do, however, warn owners of possible cutaneous adverse events. For cats with a single episode of pruritus and traumatic skin lesions after frunevetmab, owners should be warned that subsequent injections may lead to repeat cutaneous reactions. For each cat, the risk of recurrent adverse events must be weighed against the clinical benefits of the drug.
值得注意的是，本系列病例的所有四位兽医都继续推荐对被诊断为OA导致的活动能力降低的猫使用夫卢维单抗。然而，他们确实警告宠主可能的皮肤不良事件。如果猫在注射夫卢维单抗后出现一次瘙痒和自损性皮肤病变，应警告猫主，后续注射可能会导致重复的皮肤反应。对于每只猫，必须权衡复发不良事件的风险与药物的临床益处。
Conclusions
结论
This case series further characterises cutaneous adverse events that may occur after the administration of frunevetmab. We postulate that the mechanism is primarily hyperaesthesia/paraesthesia with neuropathic itch resulting in self-trauma, causing alopecia, ulceration and possible secondary bacterial infection. There is clinical and histological similarity to FIUD, as the lesions in these cases and FIUD appear to be fundamentally self-traumatic in nature. Larger studies including further histopathological evaluation are required to better understand the pathogenesis, guide treatment and anticipate the outcome.
本病例系列进一步描述了夫卢维单抗给药后可能发生的皮肤不良事件。我们推测其机制主要是感觉过敏/感觉异常伴神经性瘙痒导致自损，导致脱毛、溃疡和可能继发的细菌感染。在临床和组织学上与FIUD有相似性，因为这些病例和FIUD的病变在本质上似乎是自损。需要更大规模的研究，包括进一步的组织病理学评估，以更好地了解发病机制，指导治疗和预测结果。
Figure 1 Case 1: 16 weeks after the second frunevetmab injection (3 weeks after the incisional biopsy). There is a demarcated area of ulceration on the right ventrolateral neck
图1病例1:第二次注射夫卢维单抗后16周(切开活检后3周)。右颈腹外侧有明显的溃疡区。
Figure 2 Case 1: incisional biopsy of skin 13 weeks after the second frunevetmab injection. There is epidermal ulceration that is overlain by a serocellular crust. Necrosis extends to the superficial dermis. Beneath the ulceration, the superficial dermis contains a relatively mild perivascular inflammatory infiltrate, consisting of mainly neutrophils. There is an abrupt transition to intact, hyperplastic epidermis. Haematoxylin and eosin, ×4
图2病例1:第二次注射夫卢维单抗后13周皮肤切开活检。表皮溃疡被血清性结痂覆盖。坏死延伸至真皮表层。溃疡下方，真皮浅层有相对轻度的血管周炎性浸润，主要由中性粒细胞组成。有一个突然过渡到完整的，增生的表皮。HE染色，×4
Figure 3 ×4 Case 1: excisional biopsy of skin 18.5 weeks after the second frunevetmab injection. There is a demarcated epidermal ulcer, the edge of which is overlain by a serocellular crust. Necrosis extends to the superficial dermis. Beneath the ulceration, the superficial dermis exhibits fibrosis and fibrovascular hyperplasia accompanied by relatively mild inflammation. Haematoxylin and eosin, ×4
图3 ×4病例1:第二次注射夫卢维单抗后18.5周皮肤切除活检。有边界的表皮溃疡，边缘覆盖有血清性结痂。坏死延伸至真皮表层。溃疡下方，真皮表层呈现纤维化和纤维血管增生，并伴有相对轻微的炎症。HE染色，×4
Figure 4 ×20 Case 1: excisional biopsy of skin 18.5 weeks after the second frunevetmab injection. The ulcerated area is overlain by a serocellular crust. Necrosis extends to the superficial dermis. Within the crust and necrotic debris, there are numerous clusters of coccoid bacteria. Haematoxylin and eosin, ×20
图4 ×20病例1:第二次注射夫卢维单抗后18.5周皮肤切除活检。溃疡区被血清性结痂覆盖。坏死延伸至真皮表层。在结痂和坏死的碎屑中，有大量的球菌。HE染色，×20
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发表于 2024-1-5 20:55:07
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