治疗犬猫自体免疫性皮肤病药物的药理学:一个叙述性的回顾 ...

王帆

Pharmacology of drugs used in autoimmune dermatopathies in cats and dogs: A narrative review

治疗犬猫自体免疫性皮肤病药物的药理学:一个叙述性的回顾

 

作者：Heng L. Tham | Jennifer L. Davis

 

翻译：王帆

 

Abstract

摘要

Immunosuppressive drugs are the mainstay of treatment for many feline and canine autoimmune skin diseases, either as monotherapy or in combination with other drugs. Treatment with these drugs is often lifelong and may have long-term consequences on the affected animal's overall quality-of-life.Clinicians need to understand the pharmacology of immunosuppressants in planning and executing the treatment regimen for the best possible clinical outcome, as well as reducing the risk of adverse effects. This review paper will focus on the mechanism of action, pharmacokinetics and pharmacodynamics, clinical uses and adverse effects of immunosuppressive drugs used to treat autoimmune dermatoses in cats and dogs. These include glucocorticoids, ciclosporin A, azathioprine, chlorambucil, mycophenolate mofetil, oclacitinib and Bruton's tyrosine kinase inhibitors.

免疫抑制药物是治疗许多猫犬猫自体免疫性皮肤病的主要药物，无论是单药治疗还是与其他药物联合治疗。这些药物的治疗通常是终身的，可能会对患病动物的整体生活质量产生长期影响。临床医生在规划和执行治疗方案时需要了解免疫抑制剂的药理学，以获得尽可能好的临床结果，并降低副作用的风险。本文将重点介绍免疫抑制药物治疗猫犬自体免疫性皮肤病的作用机制、药代动力学和药效学、临床应用和副作用。这些药物包括糖皮质激素、环孢素、硫唑嘌呤、苯丁酸氮芥、吗替麦考酚酯（霉酚酸酯）、奥拉替尼和布鲁顿酪氨酸激酶抑制剂。

 

KEYWORDS

关键词

Autoimmune dermatoses, cats, dogs, immunosuppressants, mechanism of action, pharmacodynamic, pharmacokinetic

自体免疫性皮肤病，猫，犬，免疫抑制剂，作用机制，药效学，药代动力学

 

INTRODUCTION

介绍

Autoimmune dermatoses are uncommon-to-rare in cats and dogs. For instance, pemphigus foliaceus (PF) was diagnosed in 26 of 9750 dogs between 1975 and 1984 in one institution. Autoimmune dermatopathies pose a challenge regarding the choice of treatment for induction and maintenance of clinical remission (CR).This requires the usage of immunosuppressive drugs, either as monotherapy or combination therapy, and lifelong treatment is often required. Clinicians need to understand the pharmacology of immunosuppressants to help with decision-making associated with treatment efficacy and adverse effects. This review will focus on the mechanism of action (MoA), pharmacokinetic and pharmacodynamics of immunosuppressive drugs used to treat feline and canine autoimmune skin diseases, including extra-label uses. Information in this review is based on the published supporting evidence.

自体免疫性皮肤病在犬猫中罕见。例如，1975年至1984年间，在一家机构的9750只犬中，有26只被诊断出患有落叶型天疱疮(PF)。自体免疫性皮肤病对诱导和维持临床缓解(CR)的治疗选择提出了挑战。这就需要使用免疫抑制药物，无论是单一治疗还是联合治疗，并且通常需要终身治疗。临床医生需要了解免疫抑制剂的药理学，以帮助与治疗疗效和副作用相关的决策。本文将重点介绍用于治疗猫和犬自体免疫性皮肤病的免疫抑制药物的作用机制(MoA)、药代动力学和药效学，包括标签外使用。本综述中的信息基于已发表的支持证据。

 

GLUCOCORTICOIDS

糖皮质激素

Glucocorticoids (GC) are synthesised from cholesterol through steroidogenesis. predominantly in the adrenal cortex, although local GC production also has been reported in the lungs, intestine and skin. The production of adrenal GCs are controlled by the hypothalamic–pituitary–adrenal (HPA) axis which is activated by physiological (e.g. circadian cycles), physical (e.g. inflammation) and/or psychological (e.g. stress) signals.

糖皮质激素(GC)是由胆固醇通过甾体生成合成的。虽然主要在肾上腺皮质，但在肺、肠和皮肤也有局部GC产生的报道。肾上腺GC的产生受下丘脑-垂体-肾上腺(HPA)轴的控制，该轴由生理(如昼夜节律周期)、机体(如炎症)和/或心理(如压力)信号激活。

 

Synthetic GCs (i.e. prednisone, triamcinolone and dexamethasone) are more potent immunosuppressive and immunoregulatory agents than endogenous cortisol with the synthetic GCs having relatively minimal mineralocorticoid activity.

合成GC(即泼尼松、曲安奈德和地塞米松)是比内源性皮质醇更有效的免疫抑制剂和免疫调节剂，合成GC具有相对最小的盐皮质激素激素活性。

 

Mechanism of action

作用机理

Glucocorticoids are lipophilic and diffuse easily through the cell membranes. Once in the cell cytosol, GCs bind to glucocorticoid receptors (GR) and translocate into the nucleus as GC–GR complexes via binding to proteins known as importins. In the nucleus, the GR interacts with DNA and proteins to alter gene expression (Figure 1).

糖皮质激素是亲脂性的，很容易通过细胞膜扩散。一旦进入细胞质，GC与糖皮质激素受体(GR)结合，并通过与称为进口蛋白的蛋白质结合，以GC-GR复合物的形式转运到细胞核中。在细胞核中，GR与DNA和蛋白质相互作用，改变基因表达(图1)。

 

 

FIGURE 1 Schematic drawing of the mechanism of action of glucocorticoids and ciclosporin A. AP-1, activator protein-1; Cp, cyclophilin; CsA, ciclosporin; GC, glucocorticoid; GR, glucocorticoid receptor; IL-2, interleukin-2; NFAT, nuclear factor of activated T cells; NFκB, nuclear factor-κB.

图1糖皮质激素与环孢素A的作用机制示意图AP-1：激活蛋白-1;Cp：亲环蛋白;CsA,：环孢素;GC：糖皮质激素;GR：糖皮质激素受体;IL-2：白介素-2;NFAT：活化T细胞核因子;NFκB：核因子-κ b。

 

The genomic effects of GCs occur via several mechanisms: direct binding of the ligand-bound GR to DNA via positive glucocorticoid response elements(+GREs) or negative GREs (nGREs) and physical interaction with another transcription factor without direct contact with DNA (called ‘tethering’). Direct binding to +GREs induces transcription of genes that have anti-inflammatory and immunomodulatory properties such as annexin-A1 (ANAX1, also known as lipocortin 1), GC-induced leucine zipper (GLIZ) and mitogenactivated protein kinase phosphatase 1 (MPK1). By contrast, binding to nGREs inhibits the transcription of genes such as those associated with corticotropinreleasing hormone, melanocyte-stimulating hormone and β-endorphin.

GC的基因组效应通过几种机制发生:通过糖皮质激素阳性反应元件(+GREs)或负性GRE(nGREs)将与配体结合的GR与DNA直接结合，以及与另一种转录因子的物理相互作用，而不与DNA直接接触(称为“拴系”)。与+GRE直接结合，可诱导具有抗炎和免疫调节特性的基因转录，如膜联蛋白a1 (ANAX1，也称为脂皮质蛋白1)、GC诱导亮氨酸拉链(GLIZ)和有丝分裂原激活的蛋白激酶磷酸酶1 (MPK1)。相反，与nGRE结合会抑制与促肾上腺皮质激素释放激素、黑色素细胞刺激激素和β-内啡肽相关的基因的转录。

 

Tethering interferes with NF-κB and activator protein-1 (AP-1)—two transcriptional activators that produce a repertoire of inflammatory cytokines, chemokines and adhesion molecules involved in most, if not all, of the inflammatory and autoimmune dermatoses. It also interferes with key proinflammatory transcription factors from members of the signal transducer and activator (STAT) and nuclear factor of activated T cells (NFAT). Finally, GR may also bind to both DNA and protein (composite GRE binding), resulting in the aforementioned anti-inflammatory and immunosuppressive effects.

拴系干扰NF-κB和激活蛋白-1 (AP-1)，这两种转录激活因子产生一系列炎症细胞因子、趋化因子和黏附分子，参与大多数(如果不是全部的话)炎症性和自体免疫性皮肤病。它还干扰来自信号传导和激活因子(STAT)和活化T细胞核因子(NFAT)成员的关键促炎转录因子。最后，GR还可能与DNA和蛋白质结合(复合GRE结合)，从而产生上述抗炎和免疫抑制作用。

 

Our understanding of the effects of GCs on B cells and antibody production remain incomplete. It has been suggested that GCs have effects on B-cell selection as B cells express the GR throughout development and immature B cells are more sensitive to apoptosis. Chronic use of GC is also associated with the inhibition of antibody production in B cells.

我们对GC对B细胞和抗体产生的影响的理解仍然不完整。有研究表明，由于B细胞在发育过程中表达GR，而未成熟的B细胞对凋亡更敏感，因此GC对B细胞的选择有影响。长期使用GC也与B细胞抗体产生的抑制有关。

 

Glucocorticoids can also exert their effects via a nongenomic mechanism that occurs more rapidly (within minutes) than the genomic mechanism, which may take hours to days. In the nongenomic pathway,interaction of GCs with membrane-specific GR, cytosolic GR (resulting in the release of a variety of proteins without the need to translocate into the nucleus) and nonspecific interactions with cell membranes leads to alteration of transmembrane currents, signal transduction and intracellular calcium levels—all of which have anti-inflammatory effects.

糖皮质激素也可以通过非基因组机制发挥作用，这种机制比基因组机制更快(在几分钟内)，而基因组机制可能需要几小时到几天的时间。在非基因组途径中，GC与膜特异性GR、细胞质内GR(导致多种蛋白质的释放而不需要转运到细胞核)的相互作用以及与细胞膜的非特异性相互作用导致跨膜电流、信号转导和细胞内钙水平的改变，所有这些都具有抗炎作用。

 

Pharmacokinetics and pharmacodynamics

药代动力学和药效学

The pharmacokinetics (PK) of GCs in dogs and cats are sparsely reported, possibly because the effects of GCs do not necessarily correlate to the time they are detectable in plasma. Doses are therefore often derived from human use, or based on the pharmacodynamic (clinical) response in the individual animal.Current literature on prednisone, prednisolone and dexamethasone is summarised below, with an emphasis on their use as immunosuppressive agents.There are no relevant publications on triamcinolone PK currently in the literature.

GC在犬和猫中的药代动力学(PK)很少报道，可能是因为GC的作用不一定与它们在血浆中被检测到的时间相关。因此，剂量通常来源于人的使用，或基于个体动物的药效学(临床)反应。目前关于泼尼松、泼尼松龙和地塞米松的文献总结如下，重点是它们作为免疫抑制剂的使用。目前文献中没有关于曲安奈德药代动力学的相关报道。

 

Prednisone is used clinically in dogs owing to their ability to rapidly absorb the drug and efficiently metabolise it to prednisolone. Following oral administration of prednisone, prednisolone concentrations in the plasma of healthy dogs are approximately sixfold higher than the concentrations of prednisone. Over a dose range of 0.5–4.0mg/kg, the kinetics of prednisone and prednisolone were not linear based on a disproportionate increase in drug exposure at the 1mg/kg dose using the area under the curve (AUC), which is a measure of overall drug exposure. Relatively proportional increases in maximum concentrations were seen, and the half-life remained consistent. This finding is consistent with data in other species and is thought to be due to concentration-dependent protein binding.

泼尼松在临床上用于犬，因为犬能够迅速吸收药物并有效地将其代谢为泼尼松龙。口服泼尼松后，健康犬血浆中的泼尼松龙浓度约为泼尼松浓度的六倍。在0.5-4.0mg /kg的剂量范围内，泼尼松和泼尼松龙的动力学不是线性的，基于1mg/kg剂量下使用曲线下面积(AUC)的药物暴露不成比例地增加，这是总体药物暴露的度量。最大浓度相对成比例地增加，半衰期保持一致。这一发现与其他物种的数据一致，被认为是由于浓度依赖性蛋白质结合。

 

In man and laboratory animals, prednisone is converted to prednisolone in the liver via the hepatic enzyme 11-β-hydroxysteroid dehydrogenase type 1. Studies in cats show that this enzyme, while present to a certain degree in the liver, is not capable of dehydrogenase activity when evaluated in the context of the ability to convert cortisol to cortisone. This may explain the low conversion of prednisone to prednisolone in cats. Following administration of prednisone, only approximately 20% of drug is converted to prednisolone. The prednisolone AUC following administration of prednisolone is reported as 3230.6ng/mL/h versus 672.63ng/mL/h following administration of prednisone. These differences may represent an inability to convert the drug to prednisolone in the liver, yet could also be a result of lower oral absorption of prednisone.Because of this, prednisolone is recommended for use in cats over prednisone.

在人和实验动物中，泼尼松通过肝酶11-β-羟基类固醇脱氢酶1型在肝脏中转化为泼尼松龙。对猫的研究表明，这种酶虽然在肝脏中有一定程度的存在，但在将皮质醇转化为可的松的能力的背景下进行评估时，它不具备脱氢酶活性。这也许可以解释猫体内泼尼松到泼尼松龙的低转化率。在给予泼尼松后，只有大约20%的药物转化为泼尼松龙。据报道，泼尼松龙治疗后的泼尼松龙AUC为3230.6ng/mL/h，而泼尼松治疗后的泼尼松龙AUC为672.63ng/mL/h。这些差异可能表明药物无法在肝脏中转化为泼尼松龙，但也可能是口服泼尼松吸收较低的结果。正因为如此，泼尼松龙被推荐用于猫而不是泼尼松。

 

Prednisolone has excellent oral absorption in both dogs and cats and can be used for long-term administration in either species. As discussed, it is preferred over prednisone in cats, and should be used in dogs with altered hepatic function, where metabolism of prednisone to prednisolone may be diminished. In over-conditioned cats [body condition score (BCS) of 4–5 of 5], plasma concentrations of prednisolone were, on average, twofold higher than the concentrations in normal cats (BCS 3–3.5 of 5), suggesting that the drug may be better dosed on lean body mass.

泼尼松龙在犬和猫都能很好的口服吸收，可以长期使用。如前所述，泼尼松龙比泼尼松更适合用于猫，也应该用于肝功能改变的犬，在肝功能改变时，泼尼松到泼尼松龙的代谢可能会减少。在肥胖猫[体况评分(BCS)为4-5 / 5]中，泼尼松龙的血浆浓度平均比正常猫(BCS为3-3.5 / 5)的浓度高两倍，这表明该药物可能更适合瘦体重猫服用。

 

Data on dexamethasone PK in dogs and cats are even scarcer. Dogs administered 1mg/kg of dexamethasone in alcohol (intravenously) or as isonicotinate (intramuscularly) had drug detectable for 10h postadministration. Using a very sensitive assay, dexamethasone was detected in the plasma of Greyhound dogs for ≤96h post-administration of approximately 0.05mg/kg dexamethasone sodium. Despite the long detection time, dexamethasone suppression of endogenous cortisol production was not significant after 24h.The PK of oral dexamethasone in dogs is not published.There are studies available that report the PK of oral dexamethasone in cats following a single dose of injectable dexamethasone sodium phosphate administered at 0.05 or 0.2mg/kg. Oral absorption is adequate, although variable in cats. Willis-Goulet et al (2003) also examined transdermal absorption of dexamethasone in cats. Following transdermal administration, plasma concentrations were low to undetectable; this route should not be used.

地塞米松在犬和猫身上的PK数据甚至更少。以酒精(静脉注射)或异烟酸盐(肌肉注射)形式给予1mg/kg地塞米松的犬在给药后10小时可检测到药物。采用一种非常灵敏的方法，在给药约0.05mg/kg地塞米松钠后≤96小时，在灵缇犬血浆中检测到地塞米松。尽管检测时间较长，但24h后地塞米松对内源性皮质醇生成的抑制不显著。口服地塞米松给犬的药代动力学没有发表。已有研究报告了口服地塞米松在给猫注射单剂量地塞米松磷酸钠0.05或0.2mg/kg后的药代动力学。口服吸收是足够的，但在猫中有变化。Willis-Goulet等人(2003)也研究了地塞米松在猫体内的透皮吸收。经皮给药后，血浆浓度低至检测不到;不应使用此给药途径。

 

In general, immunosuppressive doses of GCs are higher and require more frequent administration than anti-inflammatory doses. For example, in dogs, prednisolone plasma concentrations necessary to suppress cortisol, neutrophil and lymphocyte responses are 0.04, 10 and 22.5ng/mL, respectively. At 1mg/kg prednisolone i.v., plasma neutrophil counts increased and lymphocyte counts decreased, and had returned to baseline within the suggested 24-hour dosing interval.

一般来说，GC的免疫抑制剂量比抗炎剂量更高，需要更频繁的给药。例如，在犬上，泼尼松龙抑制皮质醇、中性粒细胞和淋巴细胞反应所需的血浆浓度分别为0.04、10和22.5ng/mL。在1mg/kg泼尼松龙静脉注射时，血浆中性粒细胞计数增加，淋巴细胞计数减少，并在建议的24小时给药间隔内恢复到基线。

 

Species differences in responsiveness to GCs also need to be taken into account. Cats are less responsive to the anti-inflammatory, immunosuppressive and adverse effects of GCs compared to dogs. This is due to a reduced number of GR in the skin and liver of cats compared to dogs. Those receptors present are also lower-affinity receptors in cats. Therefore, doses of GCs used in cats are higher than those used in dogs.

物种不同对GC的反应差异也需要考虑在内。与犬相比，猫对GC的抗炎、免疫抑制和副作用反应较弱。这是因为猫的皮肤和肝脏中GR的含量比犬少。这些受体在猫体内也是低亲和力的受体。因此，用于猫的GC剂量高于用于犬的剂量。

 

Glucocorticoid resistance (i.e. absence of clinical response to optimal dosage of GCs) has been reported in humans with conditions such as asthma, nephrotic syndrome and ulcerative colitis. In animals, GC resistance has been recognised in several diseases such as canine mast cell tumour, feline lymphoma and canine protein-losing enteropathy. The exact pathomechanism of GC resistance in animals is not wellunderstood, yet low expression of GR and alterations in the metabolic pathways have been suggested. Although GC resistance in feline and canine autoimmune dermatoses has not been reported, the possibility exists, especially if there is poor response to GC therapy during the induction phase.

据报道，在患有哮喘、肾病综合征和溃疡性结肠炎等疾病的人群中存在糖皮质激素耐药性(即对最佳剂量的GC缺乏临床反应)。在动物中，GC耐药性已在犬肥大细胞瘤、猫淋巴瘤和犬蛋白丢失性肠病等几种疾病中得到证实。动物GC耐药的确切病理机制尚不清楚，但GR的低表达和代谢途径的改变已被提出。虽然尚未报道猫和犬自体免疫性皮肤病的GC耐药，但存在这种可能性，特别是在诱导阶段对GC治疗反应不佳的情况下。

 

Use for autoimmune dermatopathies in dogs and cats

用于犬和猫的自体免疫性皮肤病

Immunosuppressive doses of systemic GCs, either as monotherapy or in combination with other immunosuppressants/immunomodulators, are the mainstay and often first-line therapy for many autoimmune dermatoses in cats and dogs. GC is considered as the standard first-line treatment for the induction phase of therapy in all untreated patients with active disease, except for those patients for whom GCs are contraindicated. Pemphigus foliaceus, autoimmune subepidermal blistering dermatoses (AISBD) [e.g. mucous membrane pemphigoid (MMP) and epidermolysis bullosa acquisita (EBA)], cutaneous lupus erythematosus (CLE) and pemphigus vulgaris (PV) are examples of autoimmune dermatoses that are treated with systemic GCs. Dosing regimens vary and are likely need to be tailored to individual patients. In one comparative study, dogs with PF treated with oral GC pulse therapy (10mg/kg once daily for threedays, consecutively, followed by a dose of <2mg/kg/day between pulses) had higher proportions of clinical remission (CR) during the first threemonths and a lower average maximal oral GC dosage given between pulses.The benefit of pulse therapy over conventional daily GC dosing was not apparent in a small case series of 12 cats with PF. In a critically appraised topic on the dosage of prednisone or prednisolone for the treatment of canine PF, there was no compelling evidence that oral prednisone or prednisolone at the dose of 2mg/kg/day was effective in induction and/or maintenance of CR, and the authors suggested that a higher dose is more likely to be associated with CR. Likewise, high doses of oral GCs (≥3mg/kg/day for dogs and ≤3mg/kg twice daily for cats)—often in combination with another immunosuppressant—have been recommended for the treatment of canine and feline PV, and canine uveodermatological syndrome (UDS). In cats with PF, GC monotherapy was the most common treatment administered at the time of CR.

免疫抑制剂量的全身性GC，无论是单独治疗还是与其他免疫抑制剂/免疫调节剂联合治疗，是猫和犬许多自体免疫性皮肤病的主要和一线治疗方法。除GC禁忌症患病动物外，所有未经治疗的活动性疾病患病动物均将GC作为诱导期治疗的标准一线治疗。落叶型天疱疮、自体免疫性表皮下疱性皮肤病(AISBD)[如黏膜类天疱疮(MMP)和获得性大疱性表皮松解症(EBA)]、皮肤红斑狼疮(CLE)和寻常型天疱疮(PV)是系统性GC治疗的自体免疫性皮肤病的例子。给药方案各不相同，可能需要针对个别患病动物量身定制。在一项比较研究中，对患有PF的犬进行口服GC脉冲治疗(10mg/kg每日一次，连续三天，然后在两次脉冲之间给予<2mg/kg/天的剂量)，在前三个月的临床缓解(CR)比例较高，两次脉冲之间给予的平均最大口服GC剂量较低。在一个12只PF患猫小案件系列中，脉冲疗法比传统GC每日剂量的优势不明显。一个关于泼尼松或泼尼松龙治疗犬PF的剂量的批判性评价的主题中,并没有令人信服的证据表明口服泼尼松或泼尼松笼的剂量2毫克/公斤/天是有效的诱导和/或维护CR,且作者表明,高剂量更可能达到CR。同样地,高剂量口服GC(犬≥3mg/kg/天，猫≤3mg/kg每日两次)-通常与另一种免疫抑制剂联合使用-已被推荐用于治疗犬和猫PV以及犬葡萄膜皮肤病综合征(UDS)。在患有PF的猫中，GC单药治疗是CR时最常见的治疗方法。

 

Adverse effects

副作用

Owing to the wide distribution of GR in all nucleated cells, the chronic use of GC results in many systemic adverse effects. These include iatrogenic hyperadrenocorticism, gastrointestinal ulceration, cutaneous atrophy, diabetes mellitus resulting from insulin resistance, opportunistic infections and delayed wound healing.Chronic dosing of GCs in cats can result in different dermatological adverse effects to those in dogs; cats tend to develop extreme thinning of the skin with possible tearing and curling of the pinna caused by attenuation of the cartilage, whereas dogs uniquely develop calcinosis cutis. Long-acting methylprednisolone acetate has been associated with the induction of congestive heart failure in cats. This is believed to be the consequence of a shift in fluids resulting in an increased plasma volume secondary to glucocorticoid-induced hyperglycaemia; it is noteworthy that this conclusion was from a study that was conducted over 24days and, therefore, the aforementioned pathomechanism could be a short-term adverse effect. Although the anti-inflammatory dose of the intermediate-acting steroid prednisolone (1–2mg/kg/day, p.o.) given to healthy cats with allergic dermatitis for 14days did not result in significant haemodynamic and echocardiographic changes, these results should not be extrapolated to cats requiring immunosuppressive doses of GC for the long-term treatment of autoimmune dermatoses.

由于GR在所有有核细胞中广泛分布，长期使用GC会导致许多全身副作用。这些包括医源性肾上腺皮质亢进、胃肠道溃疡、皮肤萎缩、胰岛素抵抗引起的糖尿病、条件致病性感染和伤口愈合延迟。猫长期服用GC会导致与犬不同的皮肤副作用;猫往往会出现皮肤极度变薄，并可能因软骨的衰减而导致耳廓撕裂和卷曲，而犬则会出现皮肤钙质沉着症。长效醋酸甲基泼尼松龙与猫的充血性心力衰竭的诱导有关。这被认为是继发于糖皮质激素诱导的高血糖的液体变化导致血浆容量增加的结果;值得注意的是，这一结论来自于一项为期24天的研究，因此，上述病理机制可能是一种短期副作用。虽然给患有过敏性皮肤病的健康猫服用抗炎剂量的中效类固醇泼尼松龙(1-2mg /kg/天，p.o) 14天没有导致明显的血流动力学和超声心动图变化，但这些结果不应推断出需要免疫抑制剂量的GC来长期治疗自体免疫性皮肤病的猫。

 

Adverse effects of GCs are related to both the dose used and the duration of therapy. In humans, the cumulative dose administered is often calculated to determine the risk for adverse effects developing. One study of patients being treated with steroids showed that the risk for complications developing increased by 3%–8% for each 1 g of cumulative steroid dosed (most frequently prednisone or prednisolone). To the best of the author's knowledge, similar data are not available in veterinary species, yet chronicity of dosing should be considered when determining risk for adverse effects. One strategy to potentially decrease risk for adverse effects is to dose on a mg/m2  basis, rather than a mg/kg basis. Large-breed dogs had higher Cmax and AUC when dosed with prednisolone at 2mg/kg compared to 40mg/m2 , and to small dogs dosed at 2mg/kg. Optimal dosing regimens still require further study.

GC的副作用与使用的剂量和治疗时间有关。在人体中，通常计算给药的累积剂量，以确定发生副作用的风险。一项对接受类固醇治疗的患者的研究表明，每累积1克类固醇剂量(最常见的是泼尼松或泼尼松龙)，并发症发生的风险增加3%-8%。据作者所知，在兽医物种中没有类似的数据，但在确定副作用风险时应考虑给药的慢性。可能降低副作用风险的一种策略是以mg/m2为基础而不是以mg/kg为基础给药。泼尼松龙剂量为2mg/kg时，大型犬的Cmax和AUC高于40mg/ kg，小型犬的Cmax和AUC也高于2mg/kg。最佳给药方案仍需进一步研究。

 

CICLOSPORIN A

环孢素

Ciclosporin A (CsA) is derived from the soil fungus Beauveria nivea. In veterinary medicine, oral ciclosporin is formulated into an ultramicronised (microemulsified) preparation, in which absorption is more consistent and predictable. Although microemulsified oral ciclosporin is only approved for the treatment of canine atopic dermatitis (AD) and feline atopic skin syndrome, it has been used to treat many autoimmune and immune-mediated dermatoses. This is a result of its immunomodulatory and immunosuppressive effects.

环孢素A (CsA)是由土壤真菌白僵菌(Beauveria nivea)衍生而来。在兽医学中，口服环孢素被配制成一种超微(微乳化)制剂，在这种制剂中吸收更加一致和可预测。虽然微乳化口服环孢素仅被批准用于治疗犬特应性皮炎(AD)和猫特应性皮肤综合征，但它已被用于治疗许多自体免疫性和免疫介导性皮肤病。这是其免疫调节和免疫抑制作用的结果。

 

Mechanism of action

作用机理

Ciclosporin A is classified as a calcineurin inhibitor; its primary immunosuppressive effect is the inhibition of T-lymphocyte function. Calcineurin is an intracellular protein that activates gene transcription factors by dephosphorylation. When an antigen (e.g. self-antigen) binds to the T cell receptor (TCR), it triggers calcium ion release from the endoplasmic reticulum. The increase of intracellular calcium ions causes the activation of several downstream signalling effectors such as mitogenactivated protein (MAP) kinases, protein kinase C (PKC) and calcineurin. Activated calcineurin dephosphorylates nuclear factor of activated T cells (NFAT), thereby allowing its translocation into the nucleus, which subsequently upregulates transcription of genes important for innate and adaptive immunity such as interleukin (IL)-2, IL-4, tumour necrosis factor (TNF)-α and TNFγ.Interleukin-2 in particular, is a potent T-lymphocyte stimulator: it induces proliferation and differentiation of naïve CD8+ T cells into effector T cells by promoting secretion of granzyme B and perforins; it stimulates the proinflammatory activity of T helper (Th)-dependent B cells, antigen-presenting cells, mast cells, basophils and eosinophils; and it influences the differentiation of CD4+ T cells into Th1 or Th2, and subsequently affects the proliferation and differentiation of natural killer (NK) cells and B cells.

环孢素被归类为钙调磷酸酶抑制剂;其主要免疫抑制作用是抑制T淋巴细胞功能。钙调磷酸酶是一种细胞内蛋白，通过去磷酸化激活基因转录因子。当抗原(如自身抗原)与T细胞受体(TCR)结合时，它触发钙离子从内质网释放。细胞内钙离子的增加导致下游几种信号效应物的激活，如有丝分裂原激活蛋白(MAP)激酶、蛋白激酶C (PKC)和钙调神经磷酸酶。活化的钙调磷酸酶使活化T细胞(NFAT)的核因子去磷酸化，从而使其易位到细胞核中，随后上调对先天和适应性免疫重要基因的转录，如白细胞介素(IL)-2、IL-4、肿瘤坏死因子(TNF)-α和TNFγ。特别是白细胞介素-2，是一种有效的T淋巴细胞刺激剂:它通过促进颗粒酶B和穿孔素的分泌，诱导naïve CD8+ T细胞增殖和分化为效应T细胞;它刺激辅助性T (Th)依赖性B的促炎活性细胞、抗原呈递细胞、肥大细胞、嗜碱性细胞和嗜酸性细胞;影响CD4+ T细胞向Th1或Th2分化，进而影响自然杀伤细胞(NK)和B细胞的增殖和分化。

 

Ciclosporin A acts by binding to intracellular cyclophilin, which creates a complex that has a high affinity for calcineurin. The binding of the ciclosporin–cyclophilin complex with calcineurin inhibits its function of dephosphorylating NFAT and thus prevents the translocation of NFAT into the nucleus. Without NFAT in the nucleus, the aforementioned inflammatory cytokines are not transcribed and full T-lymphocyte activation is impaired (Figure 1).

环孢素通过与细胞内亲环蛋白结合而起作用，亲环蛋白产生一种对钙调磷酸酶具有高亲和力的复合物。环孢素-亲环蛋白复合物与钙调磷酸酶的结合抑制了其去磷酸化NFAT的功能，从而阻止了NFAT转位进入细胞核。细胞核中没有NFAT，上述炎症细胞因子无法转录，T淋巴细胞的完全激活受损(图1)。

 

Pharmacokinetics and pharmacodynamics

药代动力学和药效学

The pharmacokinetics and pharmacodynamics of CsA have been explored extensively in dogs, and to a lesser degree, cats. Formulation is important and the FDA-approved formulations for dogs and cats should be used. The use of generic human formulations in dogs has been shown to result in a threefold variability in drug absorption between formulations; likewise compounded formulations are not recommended. With a microemulsified formulation (Atopica), the bioavailability of CsA in cats and dogs when administered per os was reported to be 25%–29% and 35%, respectively. An oral solution (Cyclavance) is also available and has been shown to be bioequivalent to Atopica in dogs with a relative bioequivalence of approximately 101%. Administration of food along with CsA reduces the mean bioavailability by 22% in dogs,although this did not affect the clinical outcome in 15 dogs treated for AD. However, this result cannot be extrapolated when treating cats or dogs with autoimmune dermatoses as no data are currently available. Other routes of administration of CsA include transdermal and subcutaneous. A study involving six healthy cats reported that the absorption of transdermal CsA in the majority of the cats is poor.Median concentrations in that study following sevendays of oral administration were 2208ng/mL at twohours post-dosing, compared to 37ng/mL at twohours after transdermal applications of equivalent doses.

CsA的药代动力学和药效学已经在犬上进行了广泛的研究，在猫上也进行了较少的研究。配方很重要，应该使用FDA批准的犬和猫的配方。在犬上使用通用的人类配方已被证明会导致配方之间药物吸收的三倍变异性;同样，不建议使用复合配方。据报道，使用微乳化制剂(Atopica)时，CsA在猫和犬体内的生物利用度分别为25%-29%和35%。一种口服溶液(Cyclavance)也可用，并已被证明与犬的阿托皮卡具有生物等效性，相对生物等效性约为101%。与CsA一起服用的食物使犬的平均生物利用度降低了22%，但这并未影响15只接受AD治疗的犬的临床结果。然而，由于目前没有相关数据，因此在治疗患有自体免疫性皮肤病的猫或犬时，无法推断出这一结果。其他给药途径包括经皮和皮下给药。一项涉及6只健康猫的研究报告称，大多数猫对透皮CsA的吸收很差。在该研究中，口服7天后，给药后2小时的中位浓度为2208ng/mL，而同等剂量经皮给药后2小时的中位浓度为37ng/mL。

 

Ciclosporin is primarily metabolised in the liver by the cytochrome P450 3A (CPY3A) family of metabolising enzymes. Several drugs that also are metabolised by this enzyme will affect the blood concentration of CsA if given concurrently. Of these drugs, azole antifungals (e.g. ketoconazole and fluconazole) are often used along with CsA (especially in large dogs) because they decrease the metabolism of CsA, and therefore increase blood and skin CsA concentrations. This enables a CsA dose reduction of 50%–70%, which reduces the overall cost of therapy. The interaction of CsA with other drugs is reviewed elsewhere. Ciclosporin is also a substrate for p-glycoprotein efflux pumps, which may result in other significant drug–drug interactions. This also implies that caution must be used when dosing CsA in dogs with the MDR1 (ABCB1-1Δ) mutation. Animals heterozygous for this mutation may develop excessive immunosuppression at lower-thanexpected doses, potentially resulting in severe infections. Because a similar mutation has been identified in cats, this caution may apply to affected feline patients as well.

环孢素主要在肝脏中由细胞色素P450 3A (CPY3A)代谢酶家族代谢。几种同样由该酶代谢的药物如果同时给予，也会影响CsA的血药浓度。在这些药物中，唑类抗真菌药物(如酮康唑和氟康唑)通常与CsA一起使用(特别是在大型犬中)，因为它们会降低CsA的代谢，从而增加血液和皮肤的CsA浓度。这使得CsA剂量减少50%-70%，从而降低了治疗的总成本。CsA与其他药物的相互作用在其他地方进行了综述。环孢素也是p-糖蛋白外排泵的底物，这可能导致其他重要的药物-药物相互作用。这也意味着在MDR1 (ABCB1-1Δ)突变犬中给药CsA时必须谨慎。这种突变的杂合动物在低于预期剂量时可能产生过度的免疫抑制，可能导致严重感染。因为在猫上发现了类似的突变，所以这种谨慎也适用于患猫。

 

Disease states also may affect CsA PK. In an experimental model of diabetic dogs, overall drug exposure (as measured by AUC) was decreased by 52%, clearance was significantly increased and, subsequently, half-life was significantly decreased (9.32h vs. 22.56h) compared to healthy dogs.55 The mechanism for this is not fully understood, although it was speculated to be caused by increased clearance secondary to hyperglycaemia or alterations in the lipid profile of these dogs.Similar changes in PK were reported in human diabetic transplant patients placed on CsA,5and it would be assumed that a similar phenomenon be seen in diabetic cats.

疾病状态也可能影响CsA PK。在糖尿病犬的实验模型中，与健康犬相比，总药物暴露(以AUC测量)减少了52%，清除率显著增加，随后半衰期显著缩短(9.32h对22.56h)其机制尚不完全清楚，但推测是由高血糖引起的清除率增加或这些犬的脂质谱改变引起的。在接受CsA治疗的人类糖尿病移植患者中也报道了类似的PK变化，并且可以假设在糖尿病猫中也可以看到类似的现象。

 

In order to determine the effectiveness of CsA in dogs, there are two types of tests; therapeutic drug monitoring (TDM) and quantitative reverse transcription polymerase chain reaction (qRT-PCR). However, there is a poor correlation between CsA blood concentration and the clinical response in dogs with AD, and therefore TDM should only be interpreted in conjunction with clinical assessment of skin lesions and signs.Although data on this correlation in dogs or cats with autoimmune dermatoses are lacking, it is reasonable to suggest that clinical response plus TDM is superior to TDM alone when using oral CsA as a treatment. An alternative way to determine the effect of CsA dosing in a particular animal is through a pharmacodynamic assay that measures cytokine (IL-2) gene expression using qRT-PCR technology to detect the percentage suppression in the animal.

为了确定CsA对犬的有效性，有两种类型的测试;治疗药物监测(TDM)和定量逆转录聚合酶链反应(qRT-PCR)。然而，CsA血药浓度与AD犬的临床反应相关性较差，因此TDM只能与临床评估的皮肤病变和症状相结合来解释。虽然在患有自体免疫性皮肤病的犬或猫中缺乏这种相关性的数据，但有理由认为，当使用口服CsA作为治疗时，临床反应加TDM优于单独使用TDM。确定CsA剂量对特定动物的影响的另一种方法是通过药效学分析，使用qRT-PCR技术测量细胞因子(IL-2)基因表达，以检测动物体内的百分比抑制。

 

Use for autoimmune dermatopathies in cats and dogs

用于猫和犬的自体免疫性皮肤病

Ciclosporin A is used to treat many autoimmune dermatoses in cats and dogs; these include, and are not limited to, PF, CLE, PV, UDS, perianal fistula, sebaceous adenitis and ischaemic dermatopathies. The efficacy of oral CsA for the treatment of generalised discoid and vesicular variants of CLE has been reported in a comprehensive review. In a recent retrospective study, CR of PF was achieved in nine of 11 dogs treated with oral CsA along with oral GC; of these, in five dogs, the disease was maintained in CR with tapered oral CsA monotherapy. The authors of that study proposed that the efficacy of CsA in these cases may be associated with inhibition of B-cell activation (via inhibition of Th cell function), reduction in metalloproteinase-9 expression and blocking of the c-Jun N-terminal kinase (JNK) and p38 signalling pathways that are involved in the pathogenesis of pemphigus. Ciclosporin A may be effective as monotherapy for cell-mediated autoimmune dermatoses such as chronic cutaneous lupus erythematosus and sebaceous adenitis as studies showed that they are associated with cell-mediated autoimmunity involving high expression of T lymphocytes in the epidermis and dermis, and sebaceous glands, respectively. However, for canine and feline PF, the usage of CsA as the sole immunosuppressant for maintenance therapy may not be sufficient for all patients, yet it is valuable as a steroid-sparing agent. Tables 1 and 2 summarise the response to CsA in selected autoimmune dermatoses in cats and dogs.Clinicians need to be aware that treatment of autoimmune dermatoses with CsA is considered an extra-label use in cats and dogs.

环孢素用于治疗猫和犬的许多自体免疫性皮肤病;这些包括但不限于PF、CLE、PV、UDS、肛周瘘、皮脂腺炎和缺血性皮肤病。口服CsA治疗全身性盘状CLE和水疱型CLE的疗效已在一项综合综述中报道。在最近的一项回顾性研究中，在口服CsA和口服GC治疗的11只犬中，有9只实现了PF的CR;其中，在5只犬中，通过口服CsA减量单药治疗，疾病在CR中得以维持。该研究的作者提出，CsA在这些病例中的疗效可能与抑制B细胞活化(通过抑制Th细胞功能)，降低金属蛋白酶-9表达以及阻断参与天疱疮发病的c-Jun n -末端激酶(JNK)和p38信号通路有关。环孢素作为细胞介导的自体免疫性皮肤病(如慢性皮肤红斑狼疮和皮脂腺炎)的单药治疗可能有效，因为研究表明它们与细胞介导的自体免疫有关，分别涉及表皮和真皮和皮脂腺中T淋巴细胞的高表达相关。然而，对于犬和猫的PF，使用CsA作为维持治疗的唯一免疫抑制剂可能并不足以适用于所有患病动物，但它作为类固醇节省剂是有价值的。表1和表2总结了选定的猫和犬的自体免疫性皮肤病对CsA的反应。临床医生需要意识到，用CsA治疗自体免疫性皮肤病被认为是在猫和犬的标签外使用。

 

 

 

TABLE 1 Response to ciclosporin A in dogs with autoimmune dermatoses.

表1自体免疫性皮肤病犬对环孢素的反应

 

TABLE 2 Response to ciclosporin A in cats with autoimmune dermatoses.

表2自体免疫性皮肤病患猫对环孢素的反应

 

 

Owing to the difference in the MoAs, the combination of CsA and azathioprine (AZA) as immunosuppressive agents has been used successfully to treat dogs diagnosed with PF, PF with concurrent immune-mediated thrombocytopaenia and idiopathic aplastic pancytopenia. Because CsA and AZA target different pathways, the risk of myelosuppression from the combination can be expected to be no higher than that from AZA monotherapy, yet there are still no data available to make this conclusion and severe immunosuppression may still occur.Therefore, administration of these combinations should be carefully considered.

由于MoA的差异，CsA联合硫唑嘌呤(AZA)作为免疫抑制剂已被成功用于治疗诊断为PF、PF并发免疫介导的血小板减少症和特发性再生全细胞减少症的犬。由于CsA和AZA靶向的途径不同，联合用药的骨髓抑制风险预计不会高于AZA单药，但目前尚无数据支持这一结论，仍可能发生严重的免疫抑制。因此，这些组合的管理应仔细考虑。

 

Adverse effects

副作用

The most common adverse effect reported with CsA is gastrointestinal (GI) upset, with vomiting (28%) and diarrhoea (14%) the most frequently reported clinical signs in dogs. Gastrointestinal upset is usually transient and resolves with dose reduction. Anecdotally, storing CsA capsules (Atopica) in the freezer for 30–60min before oral administration reduces the incidence of vomiting, and the author has found this beneficial in preventing vomiting in some dogs. When stored in a –20°C freezer for onemonth, the stability and absorption of CsA in dogs is not impacted. Other adverse effects include gingival hyperplasia, cutaneous papillomatosis and opportunistic infections. Opportunistic bacterial (Nocardia spp., Burkholderia cepacian complex) and fungal (Alternaria spp., Curvularia spp. and Aspergillus spp.) infections have been reported in dogs treated with CsA, particularly when used in combination with GC.

CsA最常见的副作用是胃肠道(GI)不适，呕吐(28%)和腹泻(14%)是犬最常见的临床症状。胃肠道不适通常是短暂的，随剂量减少而消退。有趣的是，在口服给药前将CsA胶囊(Atopica)在冰箱中储存30 - 60分钟可减少呕吐的发生率，并且作者发现这有助于预防某些犬的呕吐。在-20°C的冰箱中储存一个月，不影响CsA在犬体内的稳定性和吸收。其他副作用包括牙龈增生、皮肤乳头状瘤病和条件致病性感染。据报道，在接受CsA治疗的犬中，特别是与GC联合使用时，出现了条件致病性细菌(诺卡菌属、伯克霍尔德菌)和真菌(链格孢属、弯孢霉属和曲霉属)感染。

 

Similar to dogs, the most common adverse effects of oral CsA in cats are diarrhoea and vomiting. In cats that were previously infected with feline herpesvirus-1 (FHV-1), administration of oral CsA at the dose of 7mg/ kg/day for 42days could result in reactivation of FHV-1 yet the clinical signs were mild and self-limiting. Acute fatal toxoplasmosis secondary to CsA therapy has been reported in cats yet is still considered rare. In a study by Lappin et al, cats receiving oral CsA 42days after experimental infection with Toxoplasma gondii did not show reactivation of toxoplasmosis and oocyst shedding. It is unlikely that toxoplasma-naïve cats would develop clinical toxoplasmosis induced by oral CsA at 7mg/kg/day, yet measures to reduce the risk of exposure (e.g. prevent hunting and consuming raw meat) should be emphasised to cat owners. Finally, subcutaneous administration of CsA (50mg/mL injection USP; Sandimmune, Novartis) was administered to 11 cats with nonseasonal allergic dermatitis; although all cats showed a significant decrease in Feline Dermatitis Extent and Severity Index (FeDESI) and pruritus Visual Analog Scale (PVAS) scores, five cats were withdrawn from the study; reasons for withdrawal include behavioural changes and owner-perceived lack of efficacy (n=1), injection site adverse reaction (n=2) and owner discomfort in the administration of the subcutaneous injections (n=2). Cats receiving chronic, high-dose CsA following renal transplants had a higher incidence of neoplasia compared to control populations of cats that did not receive transplants.

与犬一样，口服CsA对猫最常见的副作用是腹泻和呕吐。在先前感染过猫疱疹病毒-1 (FHV-1)的猫中，以7mg/ kg/天的剂量口服CsA 42天可导致FHV-1再激活，但临床症状轻微且自限性。急性致死性弓形虫病继发于猫的CsA治疗已被报道，但仍被认为是罕见的。在Lappin等人的一项研究中，猫在实验感染弓形虫42天后口服CsA后，没有出现弓形虫病的再激活和卵囊脱落。弓形虫-naïve猫不太可能因口服7mg/kg/天的CsA而患上临床弓形虫病，但应向猫主人强调减少暴露风险的措施(例如防止狩猎和食用生肉)。最后皮下给药CsA (50mg/mL注射USP;给11只患有非季节性过敏性皮炎的猫服用山地明(诺华公司);虽然所有猫在猫皮炎程度和严重程度指数(FeDESI)和瘙痒视觉模拟量表(PVAS)得分上都有显著下降，但有5只猫被退出了研究;停药的原因包括行为改变和饲主认为缺乏疗效(n=1)、注射部位副作用(n=2)和皮下注射时的宠主不适(n=2)。肾移植后接受慢性高剂量CsA治疗的猫与未接受肾移植的对照组相比，肿瘤的发病率更高。

 

Azathioprine

硫唑嘌呤

Azathioprine is a drug that was first used to reduce the risk of organ transplant rejection. It is a pro-drug of 6-mercaptopurine (6-MP) that exerts its immunosuppressive effects by interfering with nucleotide synthesis. In addition to its use as a drug to prevent transplant rejection, AZA is used to treat Crohn's disease, ulcerative colitis and AD in humans; the latter as an extra-label use for moderate to severe AD that is nonresponsive to CsA. In dogs, a pilot study on the usage of AZA for canine AD concluded that this drug has insufficient efficacy and carries too high a risk for adverse effects (compared to CsA) to be recommended as a treatment.

硫唑嘌呤是一种最初用于降低器官移植排斥风险的药物。它是6-巯基嘌呤(6-MP)的前药，通过干扰核苷酸合成发挥免疫抑制作用。除了用作预防移植排斥反应的药物外，AZA还用于治疗人类的克罗恩病、溃疡性结肠炎和AD;后者作为对CsA无反应的中度至重度AD的标签外用药。在犬上，一项关于使用AZA治疗犬AD的初步研究得出结论，该药物疗效不足，而且与CsA相比，其副作用风险过高，因此不推荐作为一种治疗方法。

 

Mechanism of action

作用机理

After oral ingestion, AZA is absorbed in the intestinal tract. In the intestinal wall, liver and red blood cells (RBCs), AZA is converted to 6-MP. Thereafter, 6-MP undergoes further conversion via three different metabolic pathways associated with three different enzymes: xanthine oxidase (XO), thiopurine-S-methyltransferase (TPMT) and hypoxanthine-guanine phosphoribosyltransferase (HPRT). The metabolic pathways associated with XO and TPMT result in the formation of 6-thiouric acid and 6-merthymecaptopurine (6-MMP), respectively. These two metabolites have minimal to no immunosuppressive effects. However, the metabolic pathway involving HPRT converts 6-MP to 6-thioguanine nucleotide (6-TGN) which has cytotoxic effects (Figure 2).

口服后，AZA在肠道被吸收。在肠壁、肝脏和红细胞中，AZA转化为6-MP。此后，6-MP通过三种不同的代谢途径进一步转化，这些途径与三种不同的酶有关:黄嘌呤氧化酶(XO)、硫嘌呤- s -甲基转移酶(TPMT)和次黄嘌呤-鸟嘌呤磷酸化核糖基转移酶(HPRT)。与XO和TPMT相关的代谢途径分别导致6-硫醛酸和6-甲基甲巯嘌呤(6-MMP)的形成。这两种代谢物对无免疫抑制作用。然而，涉及HPRT的代谢途径将6-MP转化为具有细胞毒性作用的6-硫鸟嘌呤核苷酸(6-TGN)(图2)。

 

FIGURE 2 Schematic drawing of the mechanism of action of azathioprine, mycophenolate mofetil and chlorambucil. 6-MMP, 6-methylmercaptopurine; 6-MP, 6-mercaptopurine; 6-TA, 6-thiouric acid; 6-TGN, 6-thioguanine; AZA, azathioprine; HPRT, hypoxanthineguanine phosphoribosyltransferase; IMPDH, inosine monophosphate dehydrogenase; MMF, mycophenolate mofetil; MPA, mycophenolic acid; TIMP, 6-thioinosine monophosphate; TPMT, thiopurine S-methyltransferase; XO, xanthine oxidase.

图2硫唑嘌呤、霉酚酸酯和苯丁酸氮芥的作用机理示意图。6-MMP 6-甲巯基嘌呤;6-MP-巯基嘌呤;6-TA, 6-硫脲酸;6-TGN 6-硫代鸟嘌呤AZA：硫唑嘌呤;HPRT，次黄嘌呤鸟嘌呤磷酸核糖转移酶;IMPDH：磷酸肌苷脱氢酶;MMF，霉酚酸酯;MPA，霉酚酸;TIMP, 6-硫代氨基甘氨酸单磷酸;TPMT：硫嘌呤s -甲基转移酶;XO，黄嘌呤氧化酶。

 

 

6-TGNs can be considered ‘false’ nucleotides (e.g. nonfunctioning purines). During the normal cell cycle, in the S phase, DNA is synthesised from the pairing of nucleotides. The generation of 6-TGNs ‘provides’ a pool of nonfunctioning purine, which when incorporated into DNA, results in mutation and subsequent cessation of the cell cycle. This effect is most profound in cells that are actively dividing such as lymphocytes (B and T cells) and thrombocytes.Amidotransferase enzymes and purine ribonucleotide interconversion are also inhibited by 6-TGNs, therefore reducing the formation of purine nucleotides. Finally, AZA and its toxic (active) metabolites affect T cell migration and adhesion, and reduce survival and proliferation of T cells through inhibition of RASrelated C3 botulinum toxin substrate-1 (RAC1) and/ or B-cell lymphoma-extra large (BCL-XL). The antiinflammatory effects of the metabolites from AZA also expand to nonimmune cells such as endothelial cells. 6-MP is also shown to inhibit the function of RAC1, which is important for the formation of ICAM-1 and VCAM-1. As such, leucocyte adhesion to endothelial cells is impaired.

6- TGN可以被认为是“假”核苷酸(例如无功能嘌呤)。在正常的细胞周期中，在S期，DNA由核苷酸配对合成。6- TGN的产生“提供”了一个无功能嘌呤库，当这些嘌呤与DNA结合时，会导致突变和随后的细胞周期停止。这种效应在活跃分裂的细胞中最为显著，如淋巴细胞(B细胞和T细胞)和血小板。氨基转移酶和嘌呤核糖核苷酸的相互转化也被6- TGN抑制，从而减少嘌呤核苷酸的形成。最后，AZA及其毒性(活性)代谢物通过抑制RAS相关的C3肉毒毒素底物-1 (RAC1)和/或B细胞淋巴瘤-特大型(BCL-XL)，影响T细胞的迁移和黏附，降低T细胞的存活和增殖。AZA代谢物的抗炎作用也扩展到非免疫细胞，如内皮细胞。6-MP还抑制了RAC1的功能，这对ICAM-1和VCAM-1的形成很重要。因此，白细胞黏附内皮细胞受损。

 

Because AZA is a cytotoxic drug, it should be used with caution with other alkylating agents that interfere with DNA synthesis (e.g. cyclophosphamide) as it may lead to profound myelosuppression. There is some evidence that concurrent use of GC and AZA may increase the risk of acute pancreatitis. Concurrent administration of allopurinol with AZA is not recommended because the antagonism of xanthine oxidase may interfere with the metabolism of AZA.

由于AZA是一种细胞毒性药物，应谨慎与其他干扰DNA合成的烷基化剂(如环磷酰胺)一起使用，因为它可能导致严重的骨髓抑制。有证据表明，同时使用GC和AZA可能增加急性胰腺炎的风险。不建议别嘌呤醇与AZA同时服用，因为黄嘌呤氧化酶的拮抗作用可能干扰AZA的代谢。

 

Pharmacokinetics and pharmacodynamics

药代动力学和药效学

Despite a relatively long history of use of AZA in veterinary medicine, there are no published PK studies in either dogs or cats. In humans, the beneficial effects of azathioprine may take weeks to months to occur.

尽管AZA在兽医学中使用的历史相对较长，但在犬或猫中没有发表的PK研究。在人类中，硫唑嘌呤的有益作用可能需要几周到几个月才能发生。

 

Use for autoimmune dermatopathies in cats and dogs

用于猫和犬的自体免疫性皮肤病

In dogs, AZA is used to treat several autoimmune skin diseases such as PF, PV, pemphigus vegetans, vesicular cutaneous lupus erythematosus (VCLE) and several variants of autoimmune subepidermal dermatoses (Table 3) owing to its effect on both B and T cells. It is often used as a steroid-sparing agent. Interestingly, AZA along with oral GC is the most common therapy at the time of optimal disease control in canine PF, UDS and canine PV. The use of AZA in cats is not recommended owing to the high risk of myelosuppression (see Adverse effects section below).

在犬中，由于AZA对B细胞和T细胞都有作用，它被用于治疗多种自体免疫性皮肤病，如PF、PV、增殖型天疱疮、水疱性皮肤红斑狼疮(VCLE)和几种自体免疫性表皮下皮肤病(表3)。它常被用作类固醇节省剂。有趣的是，在犬PF、UDS和PV中，AZA联合口服GC是最常见的疾病控制方法。由于存在骨髓抑制的高风险，不建议在猫上使用AZA(见下面的副作用部分)。

 

TABLE 3 Response to azathioprine in dogs with autoimmune dermatoses.

表3自体免疫性皮肤病犬对硫唑嘌呤的反应

 

 

 

Adverse effects

副作用

In humans, TPMT activity is variable and correlates with clinical outcomes and therefore, the measurement of TPMT activity is used to assess therapeutic efficacy and toxicity. Low activity of TMPT increases the risk of myelosuppression in people. Likewise, TPMT activity is detected in RBCs of dogs, cats and horses, and is highly variable in dogs. One study reported that Giant Schnauzers had much lower TPMT activity, whereas Alaskan Malamutes had higher TPMT activity when compared to the other dog breeds. Although lower TPMT activity may influence the development of myelosuppression in some dogs, there could be other pathways involved in AZA-induced myelosuppression because some dogs that experience marked myelosuppression did not have a deficiency of TPMT activity. More importantly, the measurement of TPMT activity in dogs thus far were from RBCs and therefore it is necessary to investigate further correlation (if any) between the activity of canine RBC TPMT and other organs that are more involved in the metabolism of AZA, such as the liver.

在人类中，TPMT活性是可变的，与临床结果相关，因此，TPMT活性的测量用于评估治疗效果和毒性。TMPT活性低会增加骨髓抑制的风险。同样，在犬、猫和马的红细胞中检测到TPMT活性，而在犬的红细胞中变化很大。一项研究报告称，与其他犬种相比，巨型雪纳瑞的TPMT活性要低得多，而阿拉斯加雪橇犬的TPMT活性要高得多。虽然较低的TPMT活性可能影响一些犬的骨髓抑制的发展，但可能有其他途径参与了AZA诱导的骨髓抑制，因为一些经历明显骨髓抑制的犬并不缺乏TPMT活性。更重要的是，迄今为止对犬体内TPMT活性的测量都是来自红细胞，因此有必要进一步研究犬红细胞TPMT活性与其他更多参与AZA代谢的器官(如肝脏)之间的相关性(如果有的话)。

 

Compared to dogs, blood TPMT activity in cats is much lower. Therefore, it is reasonable to assume that the risk of myelosuppression in cats is significantly higher if treated with AZA and this drug should be avoided in cats.

与犬相比，猫血液中的TPMT活性要低得多。因此，我们有理由认为，如果使用AZA治疗，猫出现骨髓抑制的风险明显更高，猫应该避免使用这种药物。

 

Hepatotoxicity [defined as a twofold increase in alanine aminotransferase (ALT) above the upper limit of the reference interval] is another adverse effect of AZA in dogs; this may be idiosyncratic or dose-dependent.In one study that included 34 dogs, the prevalence of hepatotoxicity was 15%, with the median time to onset of 14days (range 13–22days). However, in a more recent study, the prevalence of AZA-induced hepatotoxicity was 5% when AZA was administered every other day with tapering doses of GC. Therefore, it is recommended that liver enzymes are routinely monitored within 2–3weeks of initiation of AZA therapy.

肝毒性(定义为谷丙转氨酶(ALT)高于参考区间上限增加两倍)是AZA对犬的另一个副作用;这可能是特异性的，也可能是剂量依赖性的。在一项包括34只犬的研究中，肝毒性患病率为15%，中位发病时间为14天(范围为13 - 22天)。然而，在最近的一项研究中，当每隔一天给药AZA并逐渐减少GC剂量时，AZA引起的肝毒性发生率为5%。因此，建议在AZA治疗开始后2 - 3周内常规监测肝酶。

 

CHLORAMBUCIL

苯丁酸氮芥

Chlorambucil is an anticancer drug from the nitrogen mustard group. Other anticancer drugs in this group include melphalan, cyclophosphamide and ifosphamide. In humans, chlorambucil is widely used as a chemotherapy for chronic lymphocytic leukaemia and Hodgkin's lymphoma. Likewise, chlorambucil is most commonly used to treat low-grade T-cell lymphoma in cats. However, certain immune-mediated and autoimmune diseases have been treated with chlorambucil, more often in cats than dogs. One example is inflammatory bowel disease in cats.

苯丁酸氮芥是氮芥属的抗癌药物。该组中的其他抗癌药物包括美法兰、环磷酰胺和异环磷酰胺。在人类中，苯丁酸氮芥被广泛用作慢性淋巴细胞白血病和霍奇金淋巴瘤的化疗药物。同样地，苯丁酸氮芥素最常用于治疗猫的低级别T细胞淋巴瘤。然而，某些免疫介导的和自体免疫性疾病已经用苯丁酸氮芥治疗过了，在猫上比在犬上更常见。其中一个例子是猫的炎症性肠病。

 

Mechanism of action

作用机理

Chlorambucil is classified as an alkylating agent. In the liver, chlorambucil is converted into its active metabolite, phenylacetic and its cytotoxic effects are based on its ability to alkylate the nucleophilic portion of a DNA molecule through the formation of covalent bonds. Chlorambucil causes ‘unwanted’ crosslinking of DNA, by forming adducts at the guanine-N7 position. These ‘unwanted’ cross-linkages can occur within the same DNA strand (i.e. intrastrand crosslinks) or with the opposite DNA strand (i.e. interstrand cross-links). This results in a defect of the DNA (e.g.mutation) which will then lead to cell death. Interstrand cross-links are most cytotoxic as they generate doublestrand breaks. Chlorambucil has high activity against lymphoid cells (e.g. B cells) and is considered a slowacting drug (it may take ≤2weeks for its therapeutic effects).

苯丁酸氮芥是一种烷基化剂。在肝脏中，苯丁酸氮芥被转化为其活性代谢物苯乙酸，其细胞毒性作用是基于其通过形成共价键使DNA分子的亲核部分烷基化的能力。苯丁酸氮芥通过在鸟嘌呤- N7位置形成加合物，引起“不必要的”DNA交联。这些“不需要的”交联可以发生在相同的DNA链内(即链内交联)或相反的DNA链上(即链间交联)。这就导致了DNA的缺陷(例如:突变)，然后导致细胞死亡。链间交联是最具细胞毒性的，因为它们会产生双链断裂。苯丁酸氮芥对淋巴样细胞(如B细胞)具有高活性，被认为是一种慢效药物(可能需要≤2周才能达到治疗效果)。

 

Chlorambucil is a cytotoxic agent and therefore will potentiate other immunosuppressive drugs such as vincristine, doxorubicin and cisplatin. This may lead to severe myelosuppression if used together.

苯丁酸氮芥是一种细胞毒性药物，因此会增强其他免疫抑制药物，如长春新碱、阿霉素和顺铂。如果同时使用，可能会导致严重的骨髓抑制。

 

Pharmacokinetics and pharmacodynamics

药代动力学和药效学

In the literature, there are no PK studies for chlorambucil in dogs, and only one population PK study published for cats. In cats, it is rapidly absorbed from the GI tract, reaching a peak plasma concentration of 170ng/mL within 15min of oral administration, although a small secondary peak also was noted at fourhours. At a dose of 2mg/cat (0.28–0.74mg/kg), the terminal half-life was 1.8h, with no drug accumulation following twoweeks of every-other-day dosing. The PK of chlorambucil in cats with immune-mediated dermatoses may differ from those reported in this study, however, as the cats in the population PK analysis were being treated for lymphoproliferative malignancies, including GI involvement, which may have affected absorption. The therapeutic concentration of chlorambucil in cats is unknown and additional information is needed on this drug.

在文献中，没有关于苯丁酸氮芥在犬上的PK研究，只有一篇关于猫的PK研究发表。在猫体内，它从胃肠道被迅速吸收，在口服给药后15分钟内血药浓度达到170ng/mL的峰值，但在4小时时也出现了一个小的二次峰。剂量为2mg/cat (0.28-0.74mg /kg)时，终末半衰期为1.8h，每隔一天给药2周后无药物积累。然而，患有免疫介导性皮肤病的猫对苯丁酸氮芥的PK可能与本研究中报道的不同，因为人群PK分析中的猫正在接受淋巴增生性恶性肿瘤治疗，包括胃肠道患病，这可能影响了吸收。苯丁酸氮芥对猫的治疗浓度尚不清楚，需要进一步了解这种药物。

 

Use for autoimmune dermatopathies in cats and dogs

用于猫和犬的自体免疫性皮肤病

In the cat, similar to CsA, chlorambucil is most often used as an adjunct or steroid-sparing agent for the treatment of PF. Indeed, in two retrospective studies, combination therapy of chlorambucil with GC is often required for maintenance of CR. Chlorambucil is less frequently used in dogs for the treatment of autoimmune dermatoses. There are two case reports of the usage of chlorambucil in dogs for the treatment of vaccine-induced ischaemic dermatopathy and canine eosinophilic granuloma, both of which required concurrent therapy with ciclosporin and oral prednisolone.Table 4 summarises the usefulness of chlorambucil for selected autoimmune dermatoses in cats and dogs.

在猫中，与CsA类似，苯丁酸氮芥通常被用作治疗PF的辅助剂或类固醇节省剂。事实上，在两项回顾性研究中，苯丁酸氮芥与GC的联合治疗通常需要维持CR，而苯丁酸氮芥在犬中较少用于治疗自体免疫性皮肤病。有两例使用苯丁酸氮芥治疗疫苗引起的缺血性皮肤病和犬嗜酸性肉芽肿的病例报告，这两种情况都需要同时使用环孢素和口服泼尼松龙治疗。表4总结了苯丁酸氮芥对猫犬自体免疫性皮肤病的疗效。

 

TABLE 4 Response to chlorambucil in cats and dogs with autoimmune dermatoses.

表4患有自体免疫性皮肤病的猫和犬对苯丁酸氮芥的反应

 

 

Adverse effect

副作用

Chlorambucil is generally well-tolerated in cats and dogs, although GI effects such as inappetence, vomiting and diarrhoea may be seen. However, cytotoxic myelosuppression can occur 7–14days after initiation of treatment. Other less common adverse effects include reversible myoclonus and Fanconi syndrome, both of which were reported only in cats.

猫和犬对苯丁酸氮芥的耐受性一般良好，但可能会出现食欲不振、呕吐和腹泻等胃肠道影响。然而，细胞毒性骨髓抑制可在治疗开始后7 - 14天发生。其他不太常见的副作用包括可逆性肌阵挛和范可尼综合征，这两种情况都只在猫上报道过。

 

MYCOPHENOLATE MOFETIL

霉酚酸酯

Mycophenolate mofetil (MMF) is a pro-drug that is converted to mycophenolic acid (MPA), where it exerts its pharmacological activity. Interestingly, MPA was first isolated from Penicillium stonoliferum in 1913 where it was discovered to possess antibiotic, antiviral and antiinflammatory properties. In the early 1970s, MPA's anti-inflammatory properties were utilised to treat moderate-to-severe psoriasis in humans, although it causes undesirable GI upset. This led to the creation of MMF which has higher oral bioavailability and fewer GI adverse effects. In veterinary medicine, the use of MMF as an immunosuppressive drug for the treatment of various autoimmune diseases in dogs (and to a lesser extent in cats) has gained momentum for the past decade. Examples of these diseases include immune-mediated haemolytic anaemia, thrombocytopaenia and polyarthritis, immune-complex glomerulonephritis,meningoencephalitis and several autoimmune/ immune-mediated dermatoses.

霉酚酸酯(MMF)是一种转化为霉酚酸(MPA)的前药，在那里它发挥其药理活性。有趣的是，MPA最早是在1913年从石胆青霉中分离出来的，在那里发现它具有抗生素、抗病毒和抗炎的特性。在20世纪70年代早期，MPA的抗炎特性被用于治疗人类中重度牛皮癣，但它会引起不良的胃肠道不适。这导致了MMF的产生，它具有更高的口服生物利用度和更少的胃肠道副作用。在兽医学中，MMF作为一种免疫抑制药物用于治疗犬的各种自体免疫性疾病(在较小程度上用于猫)在过去十年中获得了发展势头。这些疾病的例子包括免疫介导的溶血性贫血、血小板减少症和多发性关节炎、免疫复合物肾小球肾炎、脑膜脑炎和几种自体免疫/免疫介导的皮肤病。

 

Mechanism of action

作用机理

Mycophenolate mofetil exerts its immunosuppressive effect by inhibiting the formation of guanine nucleotides Guanine is one of the four nucleotide bases that is needed for the formation of DNA. Guanine nucleotide is generated through two distinct pathways: the de novo pathway and the salvage pathway. In the de novo pathway, the generation of guanine nucleotides requires the enzyme inosine monophosphate dehydrogenase (IMPDH). Mycophenolate mofetil, via its active metabolite MPA, inhibits the function of IMPDH, thereby reducing the number of guanine nucleotide formations available for DNA replication.99 Lymphocytes are particularly affected by this drug because they rely solely on the de novo pathway for guanine nucleotide synthesis. The result is decreased DNA production and cessation of the proliferation of both activated T and B lymphocytes, which subsequently stop autoantibody production.

霉酚酸酯通过抑制鸟嘌呤核苷酸的形成发挥其免疫抑制作用鸟嘌呤是构成DNA所需的四种核苷酸碱基之一。鸟嘌呤核苷酸通过两种不同的途径产生:新生途径和挽救途径。在新生途径中，鸟嘌呤核苷酸的生成需要肌苷单磷酸脱氢酶(IMPDH)。霉酚酸酯通过其活性代谢物MPA抑制了IMPDH的功能，从而减少了用于DNA复制的鸟嘌呤核苷酸形成的数量淋巴细胞特别受这种药物的影响，因为它们完全依靠从头合成鸟嘌呤核苷酸的途径。其结果是DNA产生减少，活化的T淋巴细胞和B淋巴细胞增殖停止，随后停止自身抗体的产生。

 

Mycophenolate mofetil also affects other nonlymphocytic cells. It has been shown to inhibit the proliferation of fibroblasts, expression of cytokines and co-stimulatory receptors, and various adhesion molecules required for leucocyte chemotaxis and mobilisation to the target cells.

霉酚酸酯也影响其他非淋巴细胞。它已被证明可以抑制成纤维细胞的增殖，细胞因子和共刺激受体的表达，以及白细胞趋化和动员到靶细胞所需的各种黏附分子。

 

Pharmacokinetics and pharmacodynamics

药代动力学和药效学

The pharmacokinetics of MPA in dogs has been reported and show that oral absorption is highly variable, with maximum concentrations ranging from 380 to 5040 ng/mL and occurring at 45 min following a dose of 10 mg/kg MMF per os. Plasma concentrations of MPA decreased by 80% within eight hours of administration, suggesting a relatively high clearance and short half-life. In humans and, presumably, dogs, the elimination of MPA is mainly as the glucuronide conjugate. As cats are deficient in the glucuronyl transferase enzymes responsible for this reaction, there was concern that the drug could not safely be used in this species. However, there are several reports of MPA PK following MMF administration now published in cats. As with dogs, oral absorption is variable, yet as opposed to other species, the main metabolic route appears to be glucosidation.Using a two-hour intravenous infusion model, conversion of MMF to MPA appears to be relatively slow in cats, and peak MPA concentrations do not occur until 0.75–1.5 h after stopping the MMF infusion. This is suggested as a potential reason for the high intraand interindividual variability of MPA PK seen in cats, even with intravenous administration.

据报道，MPA在犬体内的药代动力学表明，口服吸收变化很大，最大浓度在380至5040纳克/毫升之间，在每次口服10毫克/千克MMF，后45分钟发生。在给药8小时内，MPA的血浆浓度下降了80%，表明清除率较高，半衰期短。在人类中，可能还有犬，MPA的消除主要是葡萄糖醛酸缀合物。由于猫缺乏导致这种反应的葡萄糖醛酸转移酶，因此有人担心这种药物在猫上使用不安全。然而，现在有几篇关于猫在服用MMF后MPA PK的报道。与犬一样，口服吸收是可变的，但与其他物种相反，主要的代谢途径似乎是葡萄糖苷化。在两小时静脉输注模型中，猫体内MMF向MPA的转化似乎相对较慢，直到停止MMF输注0.75-1.5小时后MPA浓度才出现峰值。这被认为是猫体内和个体间MPA PK高变异性的潜在原因，即使是静脉给药。

 

Using an ex vivo mitogen stimulation assay in dogs, a proposed target therapeutic concentration of between 600 and 1000ng/mL would result in a 50% inhibition in T-cell proliferation. These effects are not linearly increased at higher plasma MPA concentrations, yet chronic dosing (>14days) does seem to cause a cumulative effect, with a more prolonged duration of inhibition during the dosing interval. Chronic dosing (every 8–12h for eightdays per os or two-hour infusion i.v. every 12h for threedays) in cats did not alter total peripheral blood mononuclear cell counts, nor alter CD4+ or CD8+ cell counts. More information is still needed on the pharmacodynamics of this drug in cats, including the safety and efficacy of long-term dosing. TDM is available at the time of this writing for MMF, MPA and other metabolites using an immunoassay. Recommended sampling times include peak (1–2h post-dosing) and trough concentrations.

通过对犬进行体外有丝分裂原刺激试验，建议的目标治疗浓度在600至1000ng/mL之间将导致T细胞增殖抑制50%。这些效应在较高的血浆MPA浓度下不会线性增加，但长期给药(>14天)似乎确实会产生累积效应，在给药间隔期间抑制持续时间更长。猫的慢性给药(每8 - 12小时一次，连续8天，每12小时静脉输注2小时，连续3天)没有改变总外周血单个核细胞计数，也没有改变CD4+或CD8+细胞计数。关于这种药物在猫体内的药效学，包括长期给药的安全性和有效性，还需要更多的信息。在撰写本文时，TDM可用于MMF, MPA和其他代谢物的免疫测定。建议取样时间包括峰值(给药后1-2h)和谷浓度。

 

In humans, concurrent administration of CsA, antacid drugs (e.g. omeprazole) and certain antibiotics (e.g.ciprofloxacin and amoxicillin/clavulanic acid) with MMF reduces the oral bioavailability of MMF, yet this has not been recognised in animals.

在人类中，同时服用CsA、抗酸药物(如奥美拉唑)和某些抗生素(如。环丙沙星和阿莫西林/克拉维酸)与MMF一起使用会降低MMF的口服生物利用度，但在动物中尚未发现这一点。

 

 

Use for autoimmune dermatopathies in cats and dogs

用于猫和犬的自体免疫性皮肤病

Mycophenolate mofetil has been used to treat canine PF, exfoliative cutaneous lupus erythematosus (ECLE), epidermolysis bullosa acquisita, VCLE and MCLE. In all but the dog with ECLE, MMF was used as an adjunct therapy with GC, CsA and GC combined with topical tacrolimus. Of these autoimmune dermatoses, by far, most dogs that were treated with MMF were dogs with PF. In an earlier retrospective study, six and two of nine dogs with PF achieved a CR and PR, respectively. However, in a more recent retrospective study, the treatment outcome utilising combination therapy of MMF with GC for canine PF was not as favourable, as CR and PR were only achieved in two and four of eleven dogs, respectively, and none of the eleven dogs were successfully maintained in CR with MMF monotherapy. In the dog with ECLE, monotherapy with MMF resulted in marked improvement within threeweeks. The variable response to oral MMF in dogs is due to a narrow therapeutic index and high inter- and intrapharmacokinetic variability. This further complicates the use of oral MMF to treat dogs with immune-mediated diseases because of the lack of data to define the therapeutic MFF levels in dogs. There are too few data available to make any conclusion on the usefulness of MMF, compared to other immunosuppressants, for the treatment of various autoimmune dermatoses. However, based on the information available (Table 5), MMF may produce a better clinical outcome as a steroid-sparing agent compared to being utilised as a sole therapy.

霉酚酸酯已被用于治疗犬PF，表皮剥脱性皮肤红斑狼疮(ECLE)，获得性大疱性表皮松解症，VCLE和MCLE。除ECLE犬外，MMF作为GC、CsA和GC联合外用他克莫司的辅助治疗。在这些自体免疫性皮肤病中，到目前为止，大多数接受MMF治疗的犬都是患有PF的犬。在早期的回顾性研究中，患有PF的9只犬中分别有6只和2只达到了CR和PR。然而，在最近的一项回顾性研究中，使用MMF和GC联合治疗犬PF的治疗结果并不理想，因为11只犬中分别只有2只和4只实现了CR和PR，并且11只犬中没有一只成功地维持了MMF单药治疗的CR。在患有ECLE的犬中，MMF单药治疗在三周内显著改善。犬对口服MMF的可变反应是由于狭窄的治疗指数和高的药间和药内动力学变异性。由于缺乏确定犬体内治疗性MFF水平的数据，这使得使用口服MMF治疗免疫介导性疾病的犬变得更加复杂。与其他免疫抑制剂相比，MMF在治疗各种自体免疫性皮肤病方面的有用性数据太少，无法得出任何结论。然而，根据现有的信息(表5)，与作为单一治疗相比，MMF作为类固醇节省剂可能会产生更好的临床结果。

 

TABLE 5 Response to mycophenolate mofetil in dogs with autoimmune dermatoses.

表5自体免疫性皮肤病犬对霉酚酸酯的反应。

 

 

Adverse effects

副作用

The most common adverse effect reported in dogs receiving MMF is GI upset, particularly diarrhoea. In one recent retrospective study that included 127 dogs, 24% of dogs (n=31) experienced GI adverse effects, of which diarrhoea was reported in 23 dogs. In most dogs, these GI adverse effects resolve with discontinuation or dose reduction of MMF. In cats, doses of 10mg/kg given orally every 12h were well-tolerated, yet 15mg/kg per os every 12h caused mild and self-limiting diarrhoea in some cats, while 15mg/kg given orally every eighthours caused more severe GI upset in all cats treated.

据报道，接受MMF治疗的犬最常见的副作用是胃肠道不适，特别是腹泻。在最近的一项包括127只犬的回顾性研究中，24%的犬(n=31)出现了胃肠道副作用，其中23只犬报告了腹泻。在大多数犬中，这些胃肠道副作用通过停止或减少MMF剂量来解决。在猫中，每12小时口服10mg/kg的剂量耐受良好，但每12小时口服15mg/kg的剂量在一些猫中引起轻度和自限性腹泻，而每8小时口服15mg/kg的剂量在所有接受治疗的猫中引起更严重的胃肠道不适。

 

OCLACITINIB

奥拉替尼

Oclacitinib is a Janus kinase (JAK) inhibitor (JAKi) that was approved for the treatment of allergic dermatitis in dogs. At the approved dose for allergic dermatitis, oclacitinib has a high affinity for JAK1, which is involved in the pathogenesis of the allergic pathway. The human counterpart drug, ruxolitinib, was the first JAKi approved for the treatment of myelofibrosis and polycythaemia vera. Since then, many other JAKis have been approved in humans, mainly for the treatment of rheumatoid arthritis (RA); these include tofacitinib, baricitinib, fedratinib and upadacitinib.

奥拉替尼是一种Janus激酶(JAK)抑制剂(JAKi)，已被批准用于治疗犬的过敏性皮肤病。在过敏性皮肤病的标签剂量下，奥拉替尼对JAK1具有高亲和力，JAK1参与过敏反应途径的发病机制。人类的对应药物鲁索替尼是第一个被批准用于治疗骨髓纤维化和真性红细胞增多症的JAKi。从那时起，许多其他JAKis已被批准用于人类，主要用于治疗类风湿性关节炎(RA);这些药物包括托法替尼、巴瑞替尼,、federatinib和upadacitinib。

 

Mechanism of action

作用机理

Janus kinases are intracellular, nonreceptor tyrosine kinases. They reside in the cytoplasm of cells and are attached to the intracellular/proximal portion of Type I and Type II cytokine receptors. There are four family members of the JAKs—JAK1, JAK2, JAK3 and TYK2— and they play an important role in the transduction of cytokine-mediated signals through the JAK–signal transducers and activators of transcription (JAK–STAT) pathway. Upon binding of a ligand (e.g. cytokines and growth factors) to the receptor, the JAKs are activated and phosphorylate the intracellular domain of the receptor, thereby creating docking sites for the STAT molecules, which are signalling proteins. Once docked, the STAT molecules are further phosphorylated by the JAKs and then released back into the cytoplasm, where they form dimers with other phosphorylated STAT molecules. The dimerised STAT molecules translocate into the nucleus and bind with the DNA to transcript genes that regulate immunity, inflammation and haematopoiesis (Figure 3).

Janus激酶是细胞内的非受体酪氨酸激酶。它们存在于细胞的细胞质中，附着在I型和II型细胞因子受体的细胞内/近端部分。JAKs有四个家族成员-JAK1、JAK2、JAK3和TYK2 ，它们通过JAK-信号转导和转录激活因子(JAK-STAT)途径在细胞因子介导的信号转导中发挥重要作用。当配体(如细胞因子和生长因子)与受体结合时，JAK被激活并磷酸化受体的细胞内结构域，从而为STAT分子(信号蛋白)创建对接位点。一旦停靠，STAT分子被JAK进一步磷酸化，然后释放回细胞质中，在那里它们与其他磷酸化的STAT分子形成二聚体。二聚的STAT分子转移到细胞核中，并与DNA结合，转录调节免疫、炎症和造血的基因(图3)。

 

 

FIGURE 3 Schematic drawing of the mechanism of action of oclacitinib and Bruton's tyrosine kinase inhibitors. Ab, antibody; AP-1, activator protein-1; BTKi, Bruton's tyrosine kinase inhibitor; DAG, diacylglycerol; IL, interleukin; IP3, inositol triphosphate; JAK, Janus kinase; NFAT, nuclear factor of activated T cells; NFκB, nuclear factor-κB; STAT, signal transducers and activators of transcription.

图3奥拉替尼和布鲁顿酪氨酸激酶抑制剂的作用机理示意图。Ab抗体;AP-1，激活蛋白-1;BTKi，布鲁顿酪氨酸激酶抑制剂;DAG甘油二酯;IL,白介素;IP3，三磷酸肌醇;Janus激酶;活化T细胞核因子NFAT;NFκB，核因子-κB;STAT，信号转导和转录激活因子。

 

 

 

Cytokine receptors can be grouped based on which JAKs are associated with the receptor complex. While cytokines involved in allergy, inflammation and pruritus bind receptor complexes that utilise JAK1, the binding of other cytokines or growth factors involved in haematopoiesis (e.g. erythropoietin) and innate immunity (e.g.IL-12) activate receptors which are associated with the pairing of JAK2/JAK2 or JAK2/TYK2.

细胞因子受体可以根据与受体复合物相关的JAK进行分组。而参与过敏、炎症和瘙痒的细胞因子结合利用JAK1的受体复合物，参与造血(如促红细胞生成素)和先天免疫(如IL-12)的其他细胞因子或生长因子的结合激活与JAK2/JAK2或JAK2/TYK2配对相关的受体。

 

Higher extra-label doses of oclacitinib are associated with immunosuppressive activity. Lymphocyteenriched cells treated with 10μM of oclacitinib (equivalent to 3–4mg/kg twice daily) resulted in reduced secretion of IL-2, IL-15, IL-18 and IFN-γ, which inhibits the proliferation of T cells. Higher doses of oclacitinib also have been shown to induce apoptosis of canine CD4+ and CD8+ T cells in vitro. In a more recent study, oclacitinib prevented the generation (rather than inducing depletion) of regulatory T cells and the production of IL-10, which are important to maintain immune tolerance.Taken together, higher doses of oclacitinib or doses used concurrently with another immunosuppressive drug can have immunosuppressive effects on the immune system.

较高的标签外剂量的奥拉替尼与免疫抑制活性相关。10μM奥拉替尼(相当于3-4mg /kg，每日2次)处理淋巴细胞素丰富的细胞可减少IL-2、IL-15、IL-18和IFN-γ的分泌，从而抑制T细胞的增殖。在体外实验中，高剂量的奥拉替尼也可诱导犬CD4+和CD8+ T细胞凋亡。在最近的一项研究中，奥拉替尼阻止了调节性T细胞的产生(而不是诱导消耗)和IL-10的产生，这对维持免疫耐受很重要。综上所述，较高剂量的奥拉替尼或与另一种免疫抑制药物同时使用可对免疫系统产生免疫抑制作用。

 

Pharmacokinetics and pharmacodynamics

药代动力学和药效学

The pharmacokinetics of oclacitinib in the dog have been published. It is rapidly absorbed following oral administration with 89% bioavailability, reaching a peak concentration of 259ng/mL within onehour of administration of label doses (0.4–0.6mg/kg once daily). There are no significant effects of feeding, sex or breed (Beagles versus cross-breeds) on oral absorption. Importantly, PK were linear over a range of 0.6–3.0mg/kg, with dose-proportional increases in Cmax and AUC being reported. Twice-daily dosing of 0.6mg/kg or once-daily dosing of 1.8mg/kg, as used in the treatment of immune-mediated disease noted above, resulted in maximum concentrations of 328 and 1030ng/mL, respectively, after 21days of dosing.There is one small PK study in cats, which confirmed values similar to those found in the dog, with excellent bioavailability (87%). Absorption and elimination were faster in cats, compared to dogs, however, and the concentrations were more variable.

奥拉替尼在犬体内的药代动力学已经发表。口服后吸收迅速，生物利用度89%，在给药后一小时内达到259ng/mL的峰值浓度(0.4-0.6mg /kg每日一次)。喂养、性别或品种(比格犬与杂交犬)对口服吸收没有显著影响。重要的是，PK在0.6-3.0mg /kg范围内呈线性，Cmax和AUC呈剂量比例增加。每日两次给药0.6mg/kg或每日一次给药1.8mg/kg在上述免疫介导性疾病的治疗中，在给药21天后，其最大浓度分别为328和1030ng/mL。有一项针对猫的小型PK研究，证实了与犬相似的值，具有出色的生物利用度(87%)。然而，与犬相比，猫的吸收和消除速度更快，而且浓度变化更大。

 

Use for autoimmune dermatopathies in cats and dogs

用于猫和犬的自体免疫性皮肤病

The first reported use of oclacitinib for the treatment of autoimmune dermatosis in veterinary medicine was in 2017 when a dog with autoimmune subepidermal blistering disease was successfully treated with oclacitinib monotherapy at the dosage of 0.5 mg/kg twice daily; a relapse occurred when the dose was tapered to once daily and resolved when it was increased to twice daily. Other autoimmune skin diseases that have been treated successfully with oclacitinib include PF in a cat, a dog with PV, and several variants of CLE (ECLE, MCLE and facial DLE) in seven dogs. Interestingly, in all of these cases, oclacitinib monotherapy (dosages between 0.5 mg/kg twice daily and 1.8 mg/kg once daily in dogs; 1 mg/ kg twice daily in a cat) was successful in inducing and maintaining CR; time-to-CR or significant improvement also was relatively short at between one and three weeks. Oclacitinib was also used successfully to treat immune-mediated dermatoses such as hyperkeratotic erythema multiforme, ear tip ulcerative dermatitis and ischaemic dermatopathy; the latter required a combination of oclacitinib (0.4– 0.7 mg/kg twice daily) with oral GC.

首次报道使用奥拉替尼治疗兽医学中的自体免疫性皮肤病是在2017年，当时使用奥拉替尼单药治疗一只患有自体免疫性表皮下大疱病的犬，剂量为0.5 mg/kg，每天两次;当剂量逐渐减少到每天一次时发生复发，当剂量增加到每天两次时缓解。奥拉替尼成功治疗的其他自体免疫性皮肤病包括一只猫的PF，一只患有PV的犬，以及7只犬的几种CLE亚型(ECLE, MCLE和面部DLE)。有趣的是，在所有这些病例中，奥拉替尼单药治疗(剂量在0.5 mg/kg之间，每天两次，1.8 mg/kg，每天一次，犬;1 mg/ kg(猫，每日2次)能成功诱导和维持CR;达到CR或显著改善的时间也相对较短，在一到三周之间。奥拉替尼也成功用于治疗免疫介导的皮肤病，如角化过度型多形红斑、耳尖溃疡性皮炎和缺血性皮肤病;后者需要将奥拉替尼(0.4 - 0.7 mg/kg，每日两次)与口服GC联合使用。

 

Recent studies in canine CLE involving skin lesions transcriptomes showed strongly activated IFNαβ signalling via JAK–STAT with upregulation of CXCL10, ISG15 and S100, suggesting that these CLE variants represent a form of interferonopathy. Thus, treatment with oclacitinib could be an effective therapeutic option either as monotherapy or as a steroidsparing agent. It is important to point out that the usage of oclacitinib for the treatment of autoimmune dermatopathies is considered as extra-label use in animals.Table 6 summarises the response to oclacitinib in dogs with selected autoimmune dermatopathies.

最近对犬CLE涉及皮肤病变转录组的研究表明，通过JAK-STAT强烈激活IFNαβ信号，上调CXCL10、ISG15和S100，表明这些CLE亚型代表一种干扰素病。因此，用奥拉替尼治疗可能是一种有效的治疗选择，无论是作为单一疗法还是作为类固醇节省剂。重要的是要指出，使用奥拉替尼治疗自体免疫性皮肤病被认为是在动物的标签外使用。表6总结了奥拉替尼对患有自体免疫性皮肤病的犬的反应。

 

TABLE 6 Response to oclacitinib in cats and dogs with autoimmune dermatoses.a

表6患有自体免疫性皮肤病的猫和犬对奥拉替尼的反应

 

Adverse effects

副作用

Owing to the MoA, higher doses of oclacitinib could lead to impaired T-cell proliferation and increased risk of infection. Indeed, during the initial animal safety study, oclacitinib induced papillomas in 12-month-old dogs, and led to the development of bacterial pneumonia and generalized demodicosis in 6-month-old dogs (package insert; Apoquel, Zoetis). In a retrospective study of 53 dogs with AD treated with prolonged twice-daily administration of oclacitinib (0.4–0.6mg/kg twice daily), pyoderma, gastrointestinal signs and otitis externa were the most common adverse effect reported; only three dogs developed mild neutropaenia. In an feline immunodeficiency virus (FIV)-positive cat, treatment with oclacitinib (1mg/ kg twice daily) for feline atopic skin syndrome resulted in fatal disseminated toxoplasmosis; the clinical signs developed fivemonths after initiation of this therapy. In cats, doses of 1–2mg/kg every 12h for 28days were shown to be safe and well-tolerated, although the higher doses did result in gastrointestinal signs in two of 10 cats. Long-term studies with a large number of cats have not been performed and therefore, the long-term safety of oclacitinib in cats is as yet unknown. At present, oclacitinib is not licensed for use in cats.

由于MoA，高剂量的奥拉替尼可能导致T细胞增殖受损和感染风险增加。事实上，在最初的动物安全性研究中，奥拉替尼在12个月大的犬中诱发了乳头状瘤，并导致6月龄大的犬发生细菌性肺炎和全身性蠕形螨病(包装说明;爱波克；硕腾)。在一项回顾性研究中，53只AD犬长期每日两次服用奥拉替尼(0.4-0.6mg /kg，每日两次)，报告的副作用中最常见的是脓皮病、胃肠道症状和外耳炎;只有三只犬患上了轻度中性粒细胞减少症。在猫的免疫缺陷病毒(FIV)阳性的猫，用奥拉替尼(1mg/ kg，每日两次)治疗猫特应性皮肤综合征导致致命的弥散性弓形虫病;临床症状出现在治疗开始5个月后。在猫中，每12小时1-2mg /kg的剂量连续28天被证明是安全且耐受性良好的，但较高的剂量确实导致10只猫中的2只出现胃肠道症状。目前还没有对大量猫进行长期研究，因此，奥拉替尼对猫的长期安全性尚不清楚。目前，奥拉替尼未获准用于猫。

 

BRUTON'S TYROSINE KINASE INHIBITOR

布鲁顿酪氨酸激酶抑制剂

Bruton's tyrosine kinase (BTK) is an important signalling protein that serves as a link between the B-cell receptor (BCR) and B-cell proliferation and survival. BTK is a Tec family tyrosine kinase that also is expressed in many other cells of haematopoietic origin, including monocytes, macrophages, neutrophils, mast cells, eosinophils and platelets and not in T cells. The role of BTK in B-cell proliferation and survival has been associated with several B-cell malignancies in humans such as chronic lymphocytic leukaemia (CLL), mantle cell lymphoma (MCL) and Waldenstrom's macroglobulinaemia. More recently, there is evidence that BTK plays a critical role in autoimmunity in animal models and human studies. For instance, transgenic mice overexpress BTK in B cells, which leads to the generation of antinuclear antibodies and results in systemic lupus erythematosus (SLE)-like autoimmune pathological results. In humans, enhanced BTK activity is found in peripheral blood B lymphocytes from patients with RA and Sjögren's syndrome. Therefore, small-molecule BTK inhibitors (BTKi) have gained greater attention as a therapy for several B-cell malignancies and autoimmune diseases. Ibrutinib is the first class of BTKi that is approved for the treatment of CLL. More recently, the first noncovalent (reversible) BTKi, pirtobrutinib, was approved for the treatment of patients with relapsing or refractory MCL. Many other BTKi are still being studied in clinical trials; these include acalabrutinib (for RA), fenebrutinib (for RA) and rilzabrutinib (for PV).

布鲁顿酪氨酸激酶(BTK)是一种重要的信号蛋白，是B细胞受体(BCR)与B细胞增殖和存活之间的纽带。BTK是Tec家族的酪氨酸激酶，它也在许多其他造血细胞中表达，包括单核细胞、巨噬细胞、中性粒细胞、肥大细胞、嗜酸性粒细胞和血小板，而不是在T细胞中表达。BTK在B细胞增殖和存活中的作用与几种人类B细胞恶性肿瘤有关，如慢性淋巴细胞白血病(CLL)、套细胞淋巴瘤(MCL)和原发性巨球蛋白血症。最近，有证据表明，在动物模型和人类研究中，BTK在自体免疫中起着关键作用。例如，转基因小鼠在B细胞中过度表达BTK，导致抗核抗体的产生，导致系统性红斑狼疮(SLE)样自体免疫病理结果。在人类中，在RA和Sjögren综合征患者的外周血B淋巴细胞中发现BTK活性增强。因此，小分子BTK抑制剂(BTKi)作为一种治疗多种B细胞恶性肿瘤和自体免疫性疾病的药物得到了越来越多的关注。依鲁替尼是第一类被批准用于治疗CLL的BTKi。最近，首个非共价(可逆性)BTKi药物pirtobrutinib被批准用于治疗复发或难治性MCL患者。许多其他BTKi仍在临床试验中进行研究;这些药物包括阿卡替尼(治疗RA)、fenebrutinib(治疗RA)和rilzabrutinib(治疗PV)。

 

Mechanism of action

作用机理

BTKi can be classified into two types: reversible inhibitors and irreversible inhibitors. Irreversible BTKi have been associated with more adverse effects as they may bind to off-target sites (e.g. endogenous thiols, which are important to protect cells from ionising radiation), while reversible BTKi may be safer yet less efficacious, depending on the degree of selectivity, clearance and maintenance of target inhibition. More recently, a new hybrid BTKi that can reversibly bind to BTK in a covalent manner (i.e. reversible covalent BTKi) has been developed with increased potency, prolonged duration of action and fewer off-targets effects (and, thus, fewer adverse effects). One example of this new hybrid BTKi is rilzabrutinib (PRN1008).

BTKi可分为可逆抑制剂和不可逆抑制剂两类。不可逆的BTKi与更多的副作用相关，因为它们可能结合到非靶标位点(例如内源性硫醇，这对保护细胞免受电离辐射很重要)，而可逆的BTKi可能更安全，但效果较差，这取决于选择性、清除和维持靶标抑制的程度。最近，一种能够以共价方式可逆结合BTK的新型杂交BTKi(即可逆共价BTKi)已经开发出来，其效力增强，作用持续时间延长，脱靶效应更少(因此，副作用更少)。这种新的混合BTKi的一个例子是rilzabrutinib (PRN1008)。

 

Receptors that activate BTK are antigen receptors that include BCRs, growth factor and cytokines receptors, chemokine receptors and integrins. In B cells, attachment of ligands to BCR leads to activation of BTK, which triggers several downstream signalling cascades, including the PI3K-ALT pathway, PLC, PKC and NFκB, which are important for B-cell survival, proliferation and differentiation to plasma cells that produce autoantibodies. BTK is also involved in downstream signalling vital for neutrophil recruitment such as macrophage antigen-1 (MAC-1).

激活BTK的受体是抗原受体，包括BCR、生长因子和细胞因子受体、趋化因子受体和整合素。在B细胞中，配体附着在BCR上导致BTK的激活，从而触发几个下游信号级联反应，包括PI3K-ALT途径、PLC、PKC和NFκB，这对于B细胞的存活、增殖和向产生自身抗体的浆细胞分化至关重要。BTK还参与对中性粒细胞募集至关重要的下游信号传导，如巨噬细胞抗原-1 (MAC-1)。

 

Altogether, BTK inhibition causes a blockade of different downstream signalling pathways related to the development of autoimmunity and B-cell malignancies (Figure 3).

总之，BTK抑制导致与自体免疫和B细胞恶性肿瘤发展相关的不同下游信号通路的阻断(图3)。

 

Pharmacokinetics and pharmacodynamics

药代动力学和药效学

The PK/PD of these drugs are not available in dogs and cats at the time of writing.

在撰写本文时，这些药物的PK/PD在犬和猫中没有。

 

Use for autoimmune dermatopathies in cats and dogs

用于猫和犬的自体免疫性皮肤病

The use of BTKi for the treatment of autoimmune dermatoses in veterinary medicine is still in its infancy and off-label. In 2020, two studies involving a total of 13 dogs investigated the efficacy and safety of two BTKis, PRN473 and PRN1008 (rilzabrutinib), for the treatment of PF. Treatment outcomes were evaluated based on a modified canine version of a validated human pemphigus disease activity index (cPDAI) and classified as good, fair or poor response. At the end of the study period (20weeks), five, three and two dogs had a good, fair and poor response, respectively. In all dogs, lesions reduction could be seen within 2weeks. Interestingly, in both studies, there was no sustained depletion of B-cell counts over the 20-week period and the authors commented that this does not mean that the studied BTKi does not induce pan-B-cell deficiency.There were only two dogs where the frequency of administration of BTKi was able to be reduced to every other day without resulting in a relapse.

使用BTKi治疗自体免疫性皮肤病在兽医学中仍处于起步阶段和标签外。2020年，两项涉及13只犬的研究调查了两种BTKis, PRN473和PRN1008 (rilzabrutinib)治疗PF的有效性和安全性，治疗结果基于经过验证的人类天疱疮疾病活动指数(cPDAI)的改良犬版本进行评估，并将其分为良好，一般或差反应。在研究期(20周)结束时，分别有5只、3只和2只犬的反应良好、一般和较差。在所有的犬中，病变在2周内都可以看到缩小。有趣的是，在这两项研究中，在20周的时间内，B细胞计数没有持续减少，作者评论说，这并不意味着所研究的BTKi不会诱导泛B细胞缺乏。只有两只犬服用BTKi的频率能够减少到每隔一天，而不会导致复发。

 

Adverse effects

副作用

Adverse effects reported from the study involving dogs with PF treated with PRN473 included immune-mediated polyarthritis (n = 1; Week 12), mast cell tumour (n = 1; Week 4), peripheral lymphadenopathy (n = 2) and pancreatitis (n = 1). Of the four dogs that received PRN1008 for canine PF, only one dog had pyometra, and increased ALT and aspartate aminotransferase. In tolerability studies using an unrelated BTKi (G278), hepatotoxicity was reported in dogs.

用PRN473治疗PF犬的研究中报告的副作用包括免疫介导的多关节炎(n = 1;12周)，肥大细胞瘤(n = 1;4周)，外周淋巴结病变(n = 2)和胰腺炎(n = 1)。在接受PRN1008治疗犬PF的4只犬中，只有1只犬有子宫蓄脓，ALT和AST升高。在使用不相关的BTKi (G278)的耐受性研究中，犬报告了肝毒性。

 

It is clear that more studies are needed to gather data on the safety profiles of BTKis in dogs, yet it is very important to be aware that the sample sizes for both studies in canine PF were small and it cannot be concluded that all of the adverse effects were a direct result of the BTKis administered. For instance, peripheral lymphadenopathy in two dogs resolved spontaneously while still receiving PRN472, while the one dog that developed pyometra was also an eight-yearold intact female dog.

很明显，需要更多的研究来收集BTKi在犬上的安全性数据，但重要的是要意识到这两项针对犬PF的研究都很小，因此不能断定所有的副作用都是服用BTKis的直接结果。例如，在接受PRN472治疗的情况下，两只犬的周围淋巴结病变自发消退，而一只发生子宫蓄脓的犬也是一只8岁的未绝育母犬。

 

TOPICAL GLUCOCORTICOID AND TACROLIMUS

外用糖皮质激素和他克莫司

Topical GCs are effective adjunct therapy for many autoimmune dermatoses. Topical GCs can be used as the first-line adjunct therapy for the induction of disease remission along with other systemic immunosuppressants. They are also a valuable therapy to treat localised relapses of skin lesions without the need to increase the existing dose of systemic immunosuppressive drugs. Although the adverse effects of topical GC are less severe than systemic GC, prolonged use of topical GC could lead to cutaneous atrophy. Adrenocortical suppression as a result of chronic use of topical GC has been reported in the veterinary literature and involved the usage of potent GC such as dexamethasone, betamethasone, fluocinonide and triamcinolone. It is reasonable to use a high-potency topical GC (e.g. dexamethasone) for a short period to rapidly induce CR, after which the topical GC should either be used sparingly (e.g. twice weekly) or a nonsteroidal immunosuppressant (e.g. topical tacrolimus) can be considered. If long-term usage of topical GC is needed as an adjunct therapy to maintain CR, topical mometasone furoate may be a safer long-term option as it has minimal effect on the adrenocortical function and low systemic availability.

外用GC是许多自体免疫性皮肤病的有效辅助疗法。外用GC可与其他全身免疫抑制剂一起作为诱导疾病缓解的一线辅助治疗。它们也是治疗局灶复发的皮肤病变一种有价值的疗法，而不需要增加现有的全身免疫抑制药物的剂量。虽然外用GC的副作用没有全身GC严重，但长期使用外用GC可能导致皮肤萎缩。兽医文献中已经报道了由于长期使用外用GC导致的肾上腺皮质抑制，包括使用强效GC如地塞米松、倍他米松、氟轻松和曲安奈德。短期使用高效的外用GC(如地塞米松)以快速诱导CR是合理的，之后外用GC应少量使用(如每周两次)或考虑使用非甾体免疫抑制剂(如外用他克莫司)。如果需要长期使用外用GC作为维持CR的辅助治疗，外用糠酸莫米松可能是一个更安全的长期选择，因为它对肾上腺皮质功能的影响最小，全身性药效低。

 

Tacrolimus is a calcineurin inhibitor that inhibits Tcell activation. However, unlike CsA, tacrolimus binds to FK506 binding protein, which then suppresses the activation of the NFAT pathway and inhibits early activation of T cells. This results in a broad range of antiinflammatory and immunomodulatory effects similar to CsA. Topical tacrolimus is poorly absorbed into the systemic circulation and therefore, the risk of systemic immunosuppression is low. It also does not cause cutaneous atrophy. In dogs, topical tacrolimus has been effectively used as an adjunct therapy for variants of CCLE, pemphigus erythematosus and canine immune-mediated perianal fistula; most of the cases used a 0.1% concentration. In humans, the most common adverse effect of topical tacrolimus is a localised burning sensation at the site of application. Although localised adverse effects have not been proven in animals, it is safe to assume that this may occur and the pet owner should be informed.

他克莫司是一种钙调磷酸酶抑制剂，可抑制T细胞活化。然而，与CsA不同，他克莫司与FK506结合蛋白结合，然后抑制NFAT途径的激活并抑制T细胞的早期激活。这使得抗炎范围更宽，免疫调节作用于CsA相似。外用他克莫司的体循环吸收较差，因此，全身免疫抑制的风险较低。它也不会引起皮肤萎缩。在犬中，外用他克莫司已被有效地用作CLE亚型、红斑型天疱疮和犬免疫介导的肛周瘘的辅助治疗;大多数病例中，使用0.1%的浓度。在人类中，外用他克莫司最常见的副作用是应用部位的外用烧灼感。虽然还没有在动物身上证实外用的副作用，但可以肯定的是，这种情况可能会发生，应告知宠物主人。

 

CONCLUSIONS

结论

The use of immunosuppressants for the treatment of canine and feline autoimmune dermatoses requires an understanding of the MoA of these drugs and where they will be beneficial in relation to the disease pathogeneses. Glucocorticoids are almost always used as the first-line therapy to induce clinical remission.Ciclosporin and oclacitinib may be effective as monotherapy for cell-mediated autoimmune dermatoses and interferonopathic dermatopathies, respectively.Azathioprine and chlorambucil are often used as a steroid-sparing agent. Compared to the human counterparts, data on the optimum treatment and outcome for autoimmune skin diseases in cats and dogs are lacking, and therefore, treatment algorithms, consensus or guidelines remain unavailable in veterinary medicine.As such, it is important that clinicians evaluate their patients frequently and tailor the treatment regimen based on the clinical response. Finally, the usefulness of immune checkpoint inhibitors for autoimmune dermatoses warrants further studies.

使用免疫抑制剂治疗犬和猫自体免疫性皮肤病，需要了解这些药物的MoA以及它们在疾病发病机制方面的有益作用。糖皮质激素几乎总是被用作诱导临床缓解的一线治疗。环孢素和奥拉替尼可能分别作为细胞介导的自体免疫性皮肤病和干扰素性皮肤病的单药有效治疗方法。硫唑嘌呤和苯丁酸氮芥常被用作类固醇节省剂。与人类相比，缺乏猫和犬自体免疫性皮肤病的最佳治疗方法和结果的数据，因此，兽医学中仍然没有治疗算法、共识或指南。因此，重要的是临床医生经常评估他们的病例，并根据临床效果量身定制治疗方案。最后，免疫检查点抑制剂对自体免疫性皮肤病的有用性值得进一步研究。

 

 

 

王帆

https://onlinelibrary.wiley.com/doi/epdf/10.1111/vde.13253
原文链接

龙医生

刘欣

药理学