硫唑嘌呤的药物基因型及其在天疱疮治疗中的作用

硫唑嘌呤是最常用于天疱疮的免疫抑制剂之一,但骨髓抑制和肝肾毒性等不良反应限制了其临床应用。TPMT基因突变引起的活性下降与硫唑嘌呤的不耐受有关,但亚洲人群该位点突变频率较低。近期研究发现,NUDT15 c.415 C>T基因突变与亚洲人群的白细胞减少症等副作用的关系更为密切,该位点的检测有利于指导嘌呤类药物在天疱疮患者中的个体化应用,减少联合治疗方案中糖皮质激素的长期用量。     

顾菊林

硫唑嘌呤用于某些皮肤病的治疗其主要不良反应为骨髓抑制、中毒性肝炎、胰腺炎和脱发等。笔者应用硫唑嘌呤治疗2例大疱性类天疱疮患者，在较短时间内发生严重的骨髓抑制，现报告如下。     

硫唑嘌呤在皮肤科的临床应用

硫唑嘌呤(azathioprine,AZA)是临床常用的免疫抑制剂之一,在自身免疫性及炎症性皮肤病的治疗中占有重要地位。然而,其不良反应的产生使其临床应用受到一定限制。该文将从硫唑嘌呤的药物代谢、药理机制,及其在相关皮肤病治疗过程中的用法、疗效、安全性评估等方面进行综述,以更好地指导皮肤科医生合理应用硫唑嘌呤,尽可能减少或避免其所致的不良反应。     

硫唑嘌呤治疗关节病型银屑病

某些严重的关节病型银屑病经各种治疗无效时可应用免疫抑制剂。氨甲喋呤毒性很大故很少应用。作者应用硫唑嘌呤治疗5例关节病型银屑病,随访6个月至4年,疗效显著,无明显不良反应。5例治疗情况和结果如下:     

巯嘌呤甲基转移酶遗传多态性与硫唑嘌呤不良反应相关性研究进展

巯嘌呤甲基转移酶是硫唑嘌呤代谢过程中的重要代谢酶,巯嘌呤甲基转移酶遗传多态性与硫唑嘌呤的药物不良反应密切相关.充分认识巯嘌呤甲基转移酶在硫唑嘌呤药物体内代谢过程中的作用及其遗传多态性与药物不良反应的关系,并在使用药物治疗之前,对患者进行酶活性测定及基因型分析,可为指导临床个体化、安全用药提供依据.

Abstract：

Thiopurine methyltransferase(TPMT)is a key enzyme involved in the metabolism of azathioprine(AZA).There is a close association between the TPMT polymorphism and AZA-related adverse drug reactions.To fully recognize the role of TPMT in the metabolism of AZA as well as the relationship between TPMT polymorphism and AZA-related adverse drug reactions, and to assess the activity and genotypes of TPMT prior to prescribing, may offer a basis for individualized and safe medication.     

硫唑嘌呤在皮肤科中的应用

硫唑嘌呤(Azathioprine)是一种具有免疫抑制活性的、生理性嘌呤类(如腺嘌呤、鸟嘌呤和次黄嘌呤)的化学同类物,其免疫抑制作用尚未完全明瞭。硫唑嘌呤在体内转变成6巯基嘌呤,进而变成具有免疫抑制作用的核苷酸。已知硫唑嘌呤能抑制核分裂,抑制抗各种抗原的抗体的形成(特别是IgG和IgM),减低T细胞反应和抑制肉芽组织生成。已发现硫唑嘌呤在治疗多种皮肤病中是有效的。虽然具有一定的毒性作用,但在仔细的观察下,不失为一种有用的治疗措施。本文旨在对硫唑嘌呤的作用机理、应用时间和使用法作一介绍。     

环磷酰胺治疗寻常型天疱疮的临床应用

对于中重度及系统应用糖皮质激素治疗抵抗的寻常型天疱疮患者,临床上常联合免疫抑制剂治疗.环磷酰胺联合地塞米松冲击疗法应用广泛,临床试验证实有效.联合环磷酰胺可以减少糖皮质激素激素的用量,优于环孢素、硫唑嘌呤.一般不推荐口服环磷酰胺.国内缺乏设计科学的随机对照临床试验.其不良反应需要长期随访,尤其应警惕发生严重感染、致癌和生育能力受损.概述环磷酰胺的使用方法、对地塞米松环磷酰胺冲击治疗的相关评估、常规用法、不良反应及预防等,尤其权重随机对照临床试验、诊疗指南及系统评价文献.     

免疫抑制剂在皮肤科的应用

硫唑嘌呤、环磷酰胺和环孢素是皮肤科医师常用的免疫抑制剂。硫唑嘌呤比较安全,用于治疗大疱性类天疱疮、血管炎、慢性湿疹及结缔组织病等。环磷酸胺对较严重的疾病(如Wegener肉芽肿、淋巴瘤样肉芽肿病,重症系统性红斑狼疮或天疱疮)证明更有效,虽然其毒性较大。环孢素对各种皮肤病均有效,但对银屑病、扁平苔藓、坏疽性脓皮病和慢性湿疹皮炎疗效最好。长期用环孢素的安全性尚未确定。皮肤科医师要熟悉这些制剂的适应证、副作用、剂量和监测。     

硫唑嘌呤治疗大疱性类天疱疮致严重骨髓抑制2例

硫唑嘌呤用于某些皮肤病的治疗其主要不良反应为骨髓抑制、中毒性肝炎、胰腺炎和脱发等。笔者应用硫唑嘌呤治疗2例大疱性类天疱疮患者,在较短时间内发生严重的骨髓抑制,现报告如下。1病历摘要例1.男,65岁。因全身水疱1个月,于2002年1月30日收入我院。入院诊断为大疱性类天疱疮。入院后给予静脉滴注地塞米松10mg/d,同时加用复方倍他米松注射液(得宝松)1mL肌内注射。因皮损控制不理想,6周后加服硫唑嘌呤100mg/d。此时血常规检查示白细胞19.1×109/L,血红蛋白140g/L,血小板230×109/L。用药3d后无新发皮损出现,此期间每周复查血常规2次,用药1…     

硫唑嘌呤治疗寻常型天疱疮致严重骨髓抑制2例

<正>硫唑嘌呤为嘌呤代谢阻断药物,临床上常与糖皮质激素联合,用于抑制天疱疮患者自身抗体的产生,同时可减少糖皮质激素的用量,其最严重的不良反应为骨髓抑制。本文使用糖皮质激素联合硫唑嘌呤治疗2例寻常型天疱疮患者时发生了严重的骨髓抑制,现报告如下。1临床资料例1.男,56岁,因头面部及躯干皮肤黏膜红斑、水疱伴痛痒2个月,于2017年6月6日收入我院。入院诊断:寻常型天疱疮。患者曾于外院完善组织病理检查后     

Severe thiopurine‐induced leukocytopenia and hair loss in Japanese patients with defective NUDT15 variant: Retrospective case–control study

Azathioprine (AZA)‐metabolizing enzyme gene polymorphism is strongly related to thiopurine‐induced leukocytopenia, which has not been well recognized in dermatological practice. We tried to see whether NUDT15 gene polymorphism can be the most susceptible genetic factor for AZA toxicity and the gene screening is beneficial to avoid the adverse events of AZA for the treatment of skin diseases. A retrospective study was carried out on 15 adult Japanese patients who were treated with AZA. Gene polymorphism of thiopurine‐metabolizing enzymes NUDT15 R139C, ITPA 94C>A, TPMT*2, TPMT*3B and TPMT*3C was analyzed. The single nucleotide polymorphisms were prospectively investigated in eight patients who were considered to have received AZA treatments. Two NUDT15 R139C homozygous patients developed agranulocytosis, severe thrombocytopenia and massive hair loss. The gene screening prior to AZA treatment identified one heterozygote of NUDT15 R139C and ITPA 94C>A, and three heterozygotes of ITPA 94C>A or TMPT*3C. Although this study was a retrospective single‐center case–control observational study that enrolled a small number of patients, NUDT15 R139C homozygosity is a genetic risk of thiopurine‐induced potentially fetal hematological abnormalities. To avoid serious adverse events, gene screening of thiopurine‐metabolizing enzymes, at least NUDT15 R139C, should be considered prior to administration in genetically predisposed populations, such as Japanese. We highlight that massive hair loss in the early period of the initiation of AZA would be a sign of impending severe myelotoxicity.     

Estudio retrospectivo del tratamiento sistémico de la dermatitis atópica grave con azatioprina. Eficacia y tolerancia en 11 pacientes pediátricos

BackgroundAtopic dermatitis (AD) is a chronic inflammatory skin disease that typically affects children. Severe forms may have a profound effect on patients’ quality of life. Some forms are resistant to conventional treatment and require the use of systemic immunosuppressants such as azathioprine (AZA) to adequately manage the disease.ObjectiveTo evaluate the effectiveness and tolerance of AZA in children with severe AD.Patients and methodsWe performed a retrospective study of children with severe AD treated with AZA between January 2007 and May 2017.ResultsWe reviewed the cases of 11 patients (6 boys and 5 girls) with a mean age of 13 years (range, 8-18 years). The mean (SD) age at start of treatment was 10.9 (2.2) years (95% CI 8.6-13.1). The mean initial dosage of AZA was 1.8 (0.2) mg/kg/d. We evaluated treatment response after 4 weeks, 12 to 16 weeks, and 6 months. Mean treatment duration was 10.8 (5.7) months. Treatment had to be suspended in 2 patients because of adverse effects. Seven of the 9 remaining patients presented complete or almost complete clearance of the AD after 6 months of treatment.ConclusionIn our experience, AZA is well tolerated and may be considered as a treatment option in children with severe AD resistant to conventional treatment.     

Cutaneous adverse events induced by azacitidine in myelodysplastic syndrome patients: Case reports and a lesson from published work review

Subcutaneous injection of azacitidine (AZA) is an important treatment option for myelodysplastic syndrome (MDS), which improves overall survival. In hematology, the incidence of AZA-induced cutaneous adverse events (AE) has been known to be relatively high, which has not been well recognized by dermatologists. Discontinuation of AZA can result in the deterioration of MDS disease activity. Therefore, on dermatological consultation, precise evaluation of AE severity and careful consideration is required for post-AE medication management. To enhance our understanding of AZA-induced cutaneous AE, we report four cases with two representative cutaneous AE subtypes and summarize the clinicopathological phenotypes and courses of the cases in the published work. Case 1, a 71-year-old man, developed neutrophilic dermatosis involving the dermis and subcutaneous tissue. The other three cases, a 75-year-old man, a 78-year-old woman and a 68-year-old man, presented injection-site erythema associated with flare-up reaction. Discontinuation of AZA was necessary for case 1 alone. The published work review delineated three major subtypes of AZA-induced cutaneous AE: systemic cutaneous reaction, neutrophilic dermatosis type and erythematous type injection-site reaction. Histologically, the first two subtypes are mostly characterized by neutrophil infiltration, while the third subtype presents lymphocytic cell infiltration. Neither AZA discontinuation nor intensive interventions were required for the erythematous type injection-site reaction, while AZA termination or systemic treatments, represented by corticosteroid administration, were preferentially conducted for the systemic cutaneous reaction or the neutrophilic dermatosis type injection-site reaction subgroup. These observations support the necessity of subtype-dependent treatment strategies for the management of AZA-induced cutaneous AE.     

Drug eruption caused by azathioprine: value of using the drug-induced lymphocytes stimulation test for diagnosis

Azathioprine (AZA) is an immunosuppressant commonly used for organ transplantation and autoimmune diseases. Allergic side effects of AZA are rare, and reported allergic skin eruptions from AZA are very limited in Japan. We report AZA-induced drug eruption that developed in two cases of systemic scleroderma with polymyositis. One case presented with Stevens-Johnson syndrome, and the other had systemic papular erythema. The stimulation indices of the drug-induced lymphocyte stimulation test (DLST) for AZA in these two patients were as high as 2,180% and 430%, respectively, but those of healthy volunteers were under 120% without nonspecific suppression of lymphocyte proliferation. Other drugs used simultaneously were ruled out by patch and challenge tests. The challenge test for Stevens-Johnson syndrome type drug allergy is very risky. DLST is a good diagnostic tool for AZA allergy, especially for severe drug allergy cases.     

Colorimetric assessment of the effects of azelaic acid on light-induced skin pigmentation.

A 20% azelaic acid (AZA) cream is currently used as a therapeutic agent in the treatment of acne vulgaris. Therefore, this product is intended to be applied on frequently or continuously sun-exposed skin. In certain disorders of hyperpigmentation, AZA has been reported to have a depigmenting effect as well, while showing no significant activity on normal skin. It has been suggested that AZA selectively inhibits hyperactive or malignant melanocytes. Knowing that light-stimulated melanocytes are in a state of hyperactivity, it seemed worthwhile to investigate AZA activity on light-induced skin pigmentation. This study aimed to assess the activity of 20% AZA cream on light-induced skin pigmentation in 10 subjects. There were 5 test zones, all located on the middle of the back: 2 were treated with AZA cream, 2 others with the vehicle and 1 was left untreated. Each product was applied twice daily, 5 days a week, for 4 weeks on one zone, and for 5 weeks on the other. In the middle of the fourth week, the tested zones were exposed to ultraviolet B (UVB) + UVA + visible light, with a total of 3 times the minimal erythema dose distributed progressively over 3 consecutive days. Seven and 10 days after the last irradiation, the induced photopigmentation was assessed by colorimetric and visual means. Compared with its vehicle, the AZA cream had neither a depigmenting effect nor a preventive effect on the light-acquired skin pigmentation. Moreover, interrupting or continuing the AZA treatment after skin irradiation had no influence on the resulting pigmentation.     

An evaluation of the effectiveness of azelaic acid as a depigmenting and chemotherapeutic agent

In the past five years, it has been reported that certain dicarboxylic acids (C8-C13) and azelaic acid (C9) (AZA), in particular, have a remarkable effect in the management of lentigo maligna, human malignant melanoma, and certain disorders of hyperpigmentation. Preclinical trials, therefore, were undertaken in order to evaluate the effectiveness of AZA as a depigmenting agent and as a chemotherapeutic agent. Twenty-seven uniformly black pigmented guinea pigs were given topical applications of various concentrations (3, 5, 10, 15, and 20%) of AZA preparations for 8 weeks, and their effects on the melanocytes of epilated skin of the backs and the nonepilated ears of guinea pigs were compared to the effects of well-known depigmenting agents. Whereas 4-isopropylcatechol, monobenzylether of hydroquinone, monoethylether of hydroquinone, hydroquinone, and 4-hydroxyanisole were found to be selectively cytotoxic to melanocytes in black-skinned guinea pigs, AZA has little or no visually recognizable effect on melanocytes in these animals. The therapeutic effect of local s.c. injections of various concentrations of AZA preparations on the development of s.c. implanted B-16 melanoma tumor was evaluated in 96 C57BL/6J mice. In addition, 31 BDF1 mice, implanted i.p. with B-16 melanoma tumor, were used to assess the effect of 100-500 mg/kg concentrations of AZA administered i.p. In both studies, AZA revealed no significant tumoristatic or tumoricidal effect on the size, color, and growth of melanoma. The effect of AZA was also evaluated on S-91A (melanotic or pigmented) and S-91B (amelanotic) human melanoma cells in culture. Low concentrations (10(-5) and 10(-3) M) of AZA had no inhibitory effect on the growth of these cells. Only at higher concentrations (greater than 10(-3) M) was a cytotoxic effect on cell viability observed. These observations indicate AZA is not selectively cytotoxic to normal and proliferative melanocytes and has no apparent inhibitory effect on the formative process of melanin pigmentation.     

In vitro immunosuppressive effects of methotrexate and azathioprine on Langerhans cells

The long-term use of immunosuppressive agents may cause profound suppression of the cutaneous immune function. Because epidermal Langerhans cells (LC) play an important role in the cutaneous immune system, they could be the target of immunosuppressants. Since little information is available about the direct immunosuppressive effects of methotrexate (MTX) and azathioprine (AZA) on LC, we studied the viability and immunostimulatory effects of purified LC after pulsation with MTX or AZA at various concentrations. Both MTX and AZA started to suppress the mixed LC-T lymphocyte reaction (MLCLR) significantly at a concentration of 1 μg/ml. However, the suppressive effect of MTX was not dose-dependent; no further suppression was seen up to a concentration of 1 mg/ml. MTX showed no inhibitory effect on the viability of LC even at concentrations as high as 1 mg/ml. In contrast, the suppressive effect of AZA on the MLCLR was dose-dependent and AZA at a concentration of 500 μg/ml or higher markedly decreased the viability of LC. Our study confirmed the immunosuppressive effect of MTX and AZA on epidermal LC. In comparison to MTX, AZA at pharmacological levels showed stronger inhibitory effects on alloantigen-presenting capacity of human epidermal LC and was more cytotoxic to LC. In the therapeutic range, however, MTX and AZA probably have no direct effect on epidermal LC. Our study supports the notion that long-term immunosuppressants deplete cutaneous LC by bone marrow suppression. Received: 20 March 1996     

Methotrexate and azathioprine for severe atopic dermatitis: a 5‐year follow‐up study of a randomized controlled trial

Atopic dermatitis (AD), commonly known as eczema, is a chronic inflammatory skin disease causing intense itching and/or pain, which can affect the sleep and health‐related quality of life of both the patient and their family. It affects around 10–20% of people in developed countries. Worldwide AD is in the top 50 of most common diseases. Systemic treatment, meaning a medicine that works within the body rather than just being applied to the skin, is used for patients suffering from moderate‐to‐severe AD, and for whom topical (applied to the skin) treatment is insufficient. Long‐term evidence of most systemic treatments is lacking, especially of off‐label (that is not registered for AD) prescribed methotrexate (MTX) and azathioprine (AZA). This study, from the Netherlands, aimed to find out if MTX and AZA are effective and safe treatments in the long‐term. Patients participated in a follow‐up study of a randomized controlled trial (a study which compares different treatments in actual patients) in which they were seen every 3 months for 5 years. MTX and AZA doses could be in‐ or decreased if the patients’ doctors felt it necessary. The measure how effective the treatments were, the researchers used scoring systems that allowed them to compare symptoms after 5 years compared with when the patients started treatment – in this case, the SCORing Atopic Dermatitis (SCORAD) index in which a reduction in the score shows an improvement in symptoms, and Investigator Global Assessment (IGA). Adverse events (unwanted side effects) were also investigated. Drug survival (that is how long a patient is on treatment) was also analysed. Thirty‐five of 43 originally included patients participated in this follow up study, of which 27 completed the whole 5 years follow up. At year 5, mean relative reduction in SCORAD index was similar in MTX and AZA group: 52.8% and 53.8%. Twelve serious adverse events occurred in 5 years; for three the treatment was the possible cause. Drug survival was longer for MTX, but low in both groups after 5 years (MTX n = 5, AZA n = 1). Based on this relatively small study, MTX and AZA seem to be effective and safe as maintenance treatments in moderate‐to‐severe AD up to 5 years. Few patients in both groups stayed on their originally allocated drug, although some stopped taking the treatment because their symptoms had cleared. This low drug survival underlines the need for effective treatments for AD patients. Further, more long‐term and good sampled studies are needed.