Rituximab for induction and maintenance therapy in granulomatosis with polyangiitis (Wegener's). Results of a single-center cohort study on 66 patients

The aim of this study was to evaluate the efficacy and safety of rituximab (RTX) associated with glucocorticoid treatment based on disease severity, as a remission induction treatment for granulomatosis with polyangiitis (GPA) (Wegener's) and to analyze the results of long-term maintenance therapy with low doses of RTX in a routine time-based protocol.This single-center retrospective study used standardized data collection from all GPA patients receiving RTX between 2002 and 2013. The remission induction regimen consisted of RTX and glucocorticoids, adapted according to disease severity. Once remission was achieved, patients received RTX maintenance treatment (500 mg every 6 months) for 18 months.Sixty-six GPA patients received RTX for remission induction. After six months, a response had been achieved in 78.8% of these patients, with a moderate oral prednisone regimen (mean dose at baseline, 32.8 ± 23.4 mg/day). Subglottic stenosis increased the risk of treatment failure (OR = 31.2, P = 0.0104). RTX maintenance treatment was continued for 18 months in 92% of the GPA patients, who were followed for 34.2 ± 26.2 months (mean total cumulative RTX dose of 4.6 ± 1.7 g). The relapse rate was 11.2/100 patient-years. The relapses occur a mean of 13.5 ± 14.7 months after the last RTX infusion. Twenty-one severe adverse events were recorded; 13.6% patients had severe infections.We conclude that in this single-center cohort, RTX associated with glucocorticoid treatment adapted for disease severity appeared to induce remission effectively in GPA patients. Maintenance treatment with low doses of RTX in a routine time-based protocol was safe and associated with low rates of relapse on treatment.     

糖皮质激素治疗重型肝炎有效性及安全性的Meta分析

目的综合评价糖皮质激素治疗重型病毒性肝炎的有效性及安全性。方法计算机检索2000年1月至2010年10月31日Cochrane图书馆、PubMed、OVID循证医学数据库、中国期刊全文数据库、万方数据库的中英文文献,提取糖皮质激素治疗重型病毒性肝炎的病例对照研究。采用RevMan 5.0软件进行Meta分析。结果纳入13个病例对照研究,包括770例重型病毒性肝炎患者。文献质量经改良Jadad评分平均为1.6分,均属于文献质量不高。Meta分析结果显示,糖皮质激素组患者病死率明显低于对照组[RR=0.39,95%CI（0.30~0.49）,P〈0.00001]。除在试验组出现一些能控制的特殊不良反应外,1个研究显示试验组主要并发症如感染、出血、肝性脑病、肝肾综合征发生率明显低于对照组,但因样本量太少,未作Meta分析。结论重型肝炎早期及时合理地应用糖皮质激素治疗,可降低患者病死率。但由于本研究的数量和质量的限制,影响了结果的准确性,尚需要更多高质量的随机对照试验验证。     

Reduced Bone Mass and Fat-Free Mass in Women with Multiple Sclerosis: Effects of Ambulatory Status and Glucocorticoid Use

Multiple sclerosis (MS) is associated with reduced bone mass and vitamin D deficiency. The underlying pathophysiology of the bone disease is uncertain, however, acute and long-term glucocorticoid use, progressive immobilization, vitamin D deficiency, and possibly skeletal muscle atrophy are likely to be determinants. The aims of this study were to determine (a) whether multiple sclerosis is associated with reduced fat-free mass and (b) whether in patients with multiple sclerosis, ambulation ability or glucocorticoid use is associated with bone mass and/or fat-free mass. Seventy-one female patients with MS were compared with 71 healthy, age-matched female controls. Total body bone mineral content (TBBMC, kg), fat mass (FM, kg), and fat-free mass (FFM, kg) were measured using dual X-ray absorptiometry. Disability status was graded according to the Kurtzke Expanded Disability Status Scale (EDSS) as ambulatory, with or without aide (EDSS score of 0 to 6.5), or predominantly wheelchair bound (EDSS score > 6.5). The patients with MS, when compared to age-comparable controls, had deficits in TBBMC (≈ 8%, −0.3 ± 0.1 SD, P < 0.04) and FFM (≈ 5%, −0.3 ± 0.1 SD, P < 0.01). Both TBBMC and FFM were negatively associated with EDSS score (r= 0.33, P < 0.01, and r= 0.41, P < 0.01, respectively). Patients with MS who were nonambulatory had even greater deficits in TBBMC and FFM as compared with age-matched controls (−0.6 ± 0.1 SD, P < 0.01, and −0.6 ± 0.1 SD, P < 0.01, respectively). By contrast, as compared with age-comparable controls, ambulatory patients with MS had no deficits in bone mass or soft tissue mass. When compared with ambulatory patients with MS, nonambulatory patients with MS had deficits in TBBMC and FFM (P < 0.01 and P < 0.01, respectively). The difference in TBBMC was largely caused by the difference in fat-free mass, whereas the difference in FFM was largely caused by the difference in glucocorticoid use based on analysis of covariance. We conclude that in patients with multiple sclerosis, physical disuse is the main determinant for the reduction in bone mass. Glucocorticoid treatment is the major determinant of the reduction in fat-free mass and thus also contributes to the reduction in bone mass. Received: 8 July 1996 / Accepted: 31 October 1996     

The Rate of Ethanol Absorption is Influenced by Corticosterone in Long-Sleep and Short-Sleep Mice

Ethanol was administered by intragastric (IG) injection and absorption was measured in long-sleep (LS) and short-sleep (SS) mice under various conditions that alter levels of adrenal steroids. In naive mice, LS mice absorbed ethanol more quickly than SS mice. Ethanol absorption was slower in both lines of mice after adrenalectomy (ADX). Short-term inhibition of corticosterone synthesis had no effect on ethanol absorption in either line of mice. The effect of ADX was most pronounced in SS mice at 24 hr after surgery and at 168 hr after surgery in LS mice. Therefore, the effects of various steroid replacements were examined at these times. At 24 hr after ADX, ethanol absorption was replaced to SHAM-operated values in SS mice receiving corticosterone treatments. Likewise, in LS mice at 168 hr after ADX, corticosterone implants reversed the effects of ADX while dexamethasome was ineffective. These results support a role for corticosterone in regulation of gastric ethanol absorption and suggest that the lack of repeatability for pharmacokinetic measures of ethanol absorption and metabolism in previous human and animal studies may relate to environmental impact on stress responses.     

糖皮质激素对大鼠内源性神经前体细胞增殖的影响

目的探讨大剂量糖皮质激素(GCs)对成年大鼠内源性神经前体细胞增殖的影响.方法将25只大鼠随机分为对照组和地塞米松(DEX)作用1、3、7、14 d组,应用免疫组化方法检测神经前体细胞标记物巢蛋白(nestin)的表达,并通过5-溴脱氧尿苷(BrdU)观察神经前体细胞的增殖.结果正常大鼠海马齿状回(DG)和室下区(SVZ)存在神经前体细胞,并且其中一些细胞处于分裂增殖状态.应用大剂量GCs作用3、7、14 d组与对照组相比DG的nestin和BrdU阳性细胞数明显减少,SVZ的nestin和BrdU阳性细胞数在DEX作用7、14 d组与对照组相比明显减少,并且DG与SVZ二者阳性细胞数随着作用时间的延长而减低更为明显.结论大剂量GCs持续作用可抑制大鼠脑内的内源性神经前体细胞的增殖,DG区的神经前体细胞对GCs的反应较SVZ更为敏感.     

失血条件下糖皮质激素对IL－1的作用

本文从在体、离体两个方面观察失血条件下糖皮质激素对ＩＬ－１的作用及其特点。大鼠３０％失血后立即给予０．５ｍｌ地塞米松磷酸钠注射液或生理盐水，２～３ｈ后地塞米松治疗组动物血浆ＩＬ－１活性明显低于生理盐水治疗组，但显著高于失血前及假处理组相应时点。分别取假处理、３０％失血２ｈ大鼠之腹腔巨噬细胞诱生ＩＬ－１，并加入不同浓度的皮质酮，发现各种浓度皮质酮对两种来源的巨噬细胞产生ＩＬ－１均有抑制作用，且呈量效关系。但相同浓度的皮质酮对两种来源的巨噬细胞产生ＩＬ－１有不同的抑制率，表现为对失血大鼠巨噬细胞的抑制作用弱于假处理者。实验结果提示：失血条件下糖皮质激素对ＩＬ－１的生成有明显的抑制作用，但这种抑制作用是有限的，其机制有待探讨。     

Etiology of hypercalcemia in a patient with Addison's disease

Summary A case is reported of a hypercalcemic patient with primary Addison's disease. A combination of increased calcium input into the extracellular space and reduced calcium removal by the kidney accounted for the hypercalcemia. The mechanisms responsible for the reduction in calcium removal were decreased glomerular filtration and increased tubular calcium reabsorption. Both renal factors were secondary to volume depletion and improved rapidly during rehydration with saline infusion. The enhanced calcium mobilization was probably of skeletal origin. It persisted irrespective of volume status until hydrocortisone treatment was instituted. Serum 1,25-dihydroxyvitamin D₃ levels were below 10 pg/ml, even after normalization of the glomerular filtration rate, but returned slowly to the normal range during corticosteroid substitution. Serum 25-hydroxyvitamin D₃ and parathyroid hormone levels were within the normal range. Our case report therefore demonstrates that physiological amounts of glucocorticoids reduce bone resorption, normalize serum calcium, and restore the production of 1,25-dihydroxyvitamin D₃.