The anti-inflammatory action of methotrexate is not mediated by lymphocyte apoptosis, but by the suppression of activation and adhesion molecules

Low-dose methotrexate (MTX) is an established and highly effective treatment for severe psoriasis and rheumatoid arthritis; however, its mechanism of action remains unclear. We investigated the effects of low-dose MTX on antigen-stimulated peripheral blood mononuclear cells and explored through which cellular pathways these effects are mediated. We show that MTX caused a dose-dependent suppression of T cell activation and adhesion molecule expression, and this was not due to lymphocyte apoptosis. The suppression of intercellular adhesion molecule (ICAM)-1 was adenosine and folate-dependent, while MTX suppression of the skin-homing cutaneous lymphocyte-associated antigen (CLA) was adenosine-independent. The effect of MTX on CLA, but not ICAM-1, required the constant presence of MTX in cultures. Thus, the suppression of T cell activation and T cell adhesion molecule expression, rather than apoptosis, mediated in part by adenosine or polyglutamated MTX or both, are important mechanisms in the anti-inflammatory action of MTX.     

Evidence and consensus based GKJR guidelines for the treatment of juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children and adolescents. Immunomodulatory drugs are used frequently in its treatment. Using the nominal group technique (NGT) and Delphi method, we created a multidisciplinary, evidence- and consensus-based treatment guideline for JIA based on a systematic literature analysis and three consensus conferences. Conferences were headed by a professional moderator and were attended by representatives who had been nominated by their scientific societies or organizations. 15 statements regarding drug therapy, symptomatic and surgical management were generated. It is recommended that initially JIA is treated with NSAID followed by local glucocorticoids and/or methotrexate if unresponsive. Complementing literature evidence with long-standing experience of caregivers allows creating guidelines that may potentially improve the quality of care for children and adolescents with JIA.     

Contributions of mucosal immune cells to methotrexate-induced mucositis

The use of high doses of the anti-cancer drug methotrexate (MTX) is associated with intestinal damage. As a result, mucosal immune cells become increasingly exposed to a vast amount of microbial stimuli. We aimed at determining whether these cells are still functional during MTX treatment. Furthermore, we assessed if activation of the mucosal immune system would play a role in the pathogenesis of mucositis. A contributive role to mucositis for the adaptive immune system was established by showing that mucosal lymphocytes from MTX-treated mice secreted enhanced amounts of cytokines upon ex vivo polyclonal stimulation. Next, in vitro experiments revealed that macrophages were not affected by MTX in the capacity to produce tumor necrosis factor-alpha (TNF-alpha) and IL-10 after LPS exposure. Moreover, peritoneal macrophages from MTX-treated mice produced more IL-10 and TNF-alpha upon LPS stimulation, compared with cells derived from control mice. These data indicate a persistence of both innate and adaptive immune responses in this model. The clinical relevance of these findings was further established by the fact that LPS exposure prior to MTX treatment aggravated the course of mucositis. Furthermore, LPS-responsive mice recovered more slowly compared with LPS-unresponsive mice from MTX treatment. Finally, we found an increase in weight loss and intestinal damage upon MTX treatment in IL-10-deficient mice in comparison to wild-type controls, suggesting a protective role for IL-10 in mucositis. We conclude that mucosal immune responses remain resilient during MTX-induced mucositis. Whereas TNF-alpha production may contribute to mucosal damage, IL-10 may regulate by restricting excessive mucositis.     

宫腔镜输卵管妊娠插管注射MTX治疗宫外孕24例

目的利用宫腔镜插管对输卵管妊娠保守治疗,探讨其临床价值。方法2006～2008年24例宫外孕患者行患侧输卵管插管注入MTX 20～40mg,成功杀死胚胎。结果方法简便可行,费用少,值得推广。结论采用宫腔镜输卵管妊娠插管保守治疗成功率高,消除了手术的痛苦,保存了完整输卵管,减少并发症。     

How much progress has there been in the second-line treatment of multiple sclerosis: A 2017 update

In 1993, the US Food and Drug Administration (FDA) approved the first drug specifically for treating multiple sclerosis (MS). More than two decades later, a dozen such treatments are now available. Of these, four are considered second-line treatments for use in escalation strategies and two new drugs are currently undergoing accreditation procedures. Soon, they will provide clinicians with a range of six effective disease-modifying treatments (DMTs) to thwart the inflammatory processes in MS patients with active disease. However, while such a large number of DMTs for MS can help to control early inflammation, any decisions to be made by clinicians have also been made substantially more complex. This complexity is increased by the lack of head-to-head studies comparing these second-line therapies and the benefit–risk profiles for each of these drugs, which are likely to vary among patients. Ultimately, good awareness of the benefits and, more important, the risks of each MS DMT is crucial for the effective management of inflammation in MS.     

寻常性银屑病患者血清sCD40L水平及甲氨蝶呤的干预作用

目的研究可溶性CD40配体(sCD40L)在寻常性银屑病发病中的作用及甲氨蝶呤(MTX)对其的调节作用,探讨MTX治疗银屑病的机制。方法应用双抗体夹心酶联免疫吸附法(ELISA)检测30例寻常性银屑病患者经MTX治疗前、后外周血清中sCD40L的水平变化。结果寻常性银屑病患者血清中sCD40L的水平显著高于经MTX治疗后及正常人对照组(P<0.05),其中进行期患者组显著高于静止期(P<0.05),且血清sCD40L浓度变化与寻常性银屑病严重程度指数PASI有相关性(r=0.435,P<0.05)。结论检测血清sCD40L水平有助于判断寻常性银屑病病情的严重程度,MTX可通过降低血清sCD40L水平而起到治疗作用。     

阿维A与MTX治疗泛发性脓疱型银屑病的疗效比较

目的　比较阿维A与MTX治疗泛发性脓疱型银屑病的疗效。方法　回顾调查我科自 1995年～ 2 0 0 1年的泛发性脓疱型银屑病的住院病历 ,其中糖皮质激素合用MTX治疗的病例 2 0例 ,糖皮质激素合用阿维A治疗的病例10例。用t检验比较发热、红斑和脓疱的平均消退时间 ,χ2 检验随访 1个月的复发率。结果　发热、脓疱的平均消退时间差异无显著性 (P >0 .0 5 ) ,红斑平均消退时间差异有显著性 (P <0 .0 5 ) ,阿维A组优于MTX组 ;两组复发率比较差异无显著性 (P >0 .0 5 )。结论　在泛发性脓疱型银屑病的系统治疗中 ,糖皮质激素合用阿维A的疗效优于糖皮质激素合用MTX的疗效。     

人骨保护素在CHO细胞内初步稳定表达

目的构建人OPG的稳定表达载体,并在DHFR-型CHO细胞内稳定表达。方法用RT-PCR的方法获得人全长OPG的编码基因,并将其克隆入载体pcDNA3.1-DHFR/CT-GFP,鉴定无误后,转染DHFR-型CHO细胞,经MTX筛选获得阳性表达OPG的细胞株。结果成功构建人OPG的稳定表达载体,并获得阳性表达OPG的细胞株。结论全长人OPG基因可以在CHO细胞内成功稳定表达,这为OPG的功能研究及临床应用奠定物质基础。     

100例异位妊娠保守治疗的临床观察

目的 探讨MTX配伍中药治疗稳定型异位妊娠的效果.方法 采用单次MTX肌内注射,剂量为50mg/m2,不用四氢叶酸解毒,用药后五天服中药治疗,定时检测血β-HCG值,直至正常.结果 观察组患者44例治疗成功,成功率为88.0%,对照组患者38例成功,成功率为76.0%,两组比较差异有显著性.结论 在治疗稳定型异位妊娠中MTX配伍中药的疗效比单用MTX好,特别是在包块比较大的患者中效果更好,值得推广.     

ACNU, MTX And 5-FU Penetration of Rat Brain Tissue and Tumors

The distribution of radio-labeled ACNU, MTX and 5-FU in brain and tumor tissue was studied in female Wistar rats by macroautoradiography after intrathecal administration. In normal rats, ACNU and 5-FU, administered intracisternally, distributed rapidly in the subarachnoid space, ventricular system and cerebrospinal fluid (CSF). 5-FU and MTX penetrated the brain deeply; the diffusional transport of ACNU was limited to a depth of 1 or 2mm from the CSF surface of the brain. MTX and 5-FU clearance into the blood circulation was rather slow while ACNU cleared relatively quickly. The half time of ACNU, 5-FU and MTX radioactivity at the ventricular surface was 10, 21, and 110min, respectively, at their maximal concentration after intracisternal administration. In rats with leptomeningeal tumor induced by intracisternal inoculation of Walker 256 cells, the distribution patterns of ACNU, 5-FU, and MTX were essentially the same as in normal rats despite 10–20 cell layers of tumor growing in the subarachnoid space. 5-FU and MTX were able to penetrate tumor masses in the subarachnoid space; MTX penetration was slower than that of 5-FU and ACNU failed to penetrate to more than a depth of 1 or 2mm from the tumor surface.