An intravenous loading dose of azathioprine decreases the time to response in patients with Crohn's disease

Azathioprine, an effective therapy for Crohn's disease, is limited by a prolonged time to response. The aim of this study was to determine the safety and utility of a loading dose of azathioprine to decrease the time to response in patients with Crohn's disease. Twelve patients were studied: 6 with 13 fistulae and 6 with inflammatory disease. All patients received an intravenous infusion of azathioprine (50 mg/h for 36 hours). Response was determined by physical and radiographic examination for fistulae and by the Crohn's Disease Activity Index for inflammatory disease. Erythrocyte concentrations of azathioprine metabolites were measured by chromatography. Seven of 13 fistulae closed by week 4, and three had a temporary decrease in drainage. One fistula improved at week 16. Two fistulae failed to improve. Four of 6 patients with inflammatory disease achieved remission, and 1 improved temporarily. Improvement was rapid (≤4 weeks). Peak concentrations of azathioprine metabolites occurred within 3 days. Clinical response did not correlate with azathioprine metabolite concentrations at the azathioprine dose studied. No adverse events occurred. An 1800-mg intravenous loading dose of azathioprine is safe and may decrease the time to response to ≤4 weeks in patients with Crohn's disease. Correlation between clinical response and azathioprine metabolite concentrations at larger azathioprine doses should be determined.     

Dramatic response after an intravenous loading dose of azathioprine in one case of severe and refractory ankylosing spondylitis

We describe a 37-yr-old Caucasian male suffering from ankylosing spondylitis (AS) with long-standing severe inflammatory lumbar pain and hip arthritis who was refractory to non-steroidal anti-inflammatory drugs, sulphasalazine and methotrexate up to 25 mg/week. In this patient, administration of an i.v. loading dose of azathioprine (AZA; 40 mg/kg for 36 h followed by 2 mg/kg oral AZA therapy) induced a dramatic response in his clinical condition. Indeed, objective and subjective clinical variables improved within 1 week and were corroborated by a decline in the levels of the inflammatory parameters; anaemia was reported at month 3 but was rapidly reversible. If confirmed, an i.v. loading dose of AZA could represent a valuable alternative in severe and refractory AS, but toxicity of this regimen should be carefully analysed.     

小剂量硫唑嘌呤在风湿病治疗中的不良反应

目的 了解小剂量硫唑嘌呤(AZA)在风湿病治疗中的不良反应,为临床提供参考.方法 对109例接受小剂量AZA治疗的风湿病患者进行回顾性分析,参照国家药物不良反应监测中心对药物不良反应(ADR)关联性评价进行筛选.结果 20例出现不同程度的不良反应,发生率为18.3%,白细胞减少、胃肠道反应、继发感染最常见;100 mg/d者不良反应发生率高于50 mg/d者(P＜0.05);联合其他改变病情抗风湿病药(DMARDs)的不良反应发生率与单独用药无差异(P＞0.05);联合激素者白细胞下降出现的时间较无联合激素者迟(P＜0.05);系统性红斑狼疮(SLE)组不良反应发生率高于非SLE组(P＜0.01).结论 小剂量AZA不良反应多数比较轻微,发生率与剂量相关;联合用药并不一定增加AZA不良反应的发生率:联合激素治疗者白细胞下降可能较晚出现.     

Glucocorticoid dose dependent downregulation of glucocorticoid receptors in patients with rheumatic diseases

OBJECTIVE: The therapeutic success of low doses of glucocorticoids is mediated entirely by classical genomic effects, whereas that of high doses is also mediated to an as yet unknown extent by nongenomic effects. We assessed the relative therapeutic importance of these nongenomic effects in pulse therapy. METHODS: A [3H]dexamethasone radioligand binding assay was used to measure the number of glucocorticoid receptor sites (R, given as number of sites per cell) and glucocorticoid receptor binding affinity (Kd, given in nM) in peripheral blood mononuclear cells isolated from 26 healthy control blood donors and 27 patients with rheumatic diseases. Patients were divided into 4 groups on the basis of their glucocorticoid dose: 0 mg (Group A), < or = 0.25 mg (Group B), 0.25 to 1 mg (Group C), and > 1 mg (Group D) of prednisolone equivalent per kg per day. RESULTS: Sex independent normal values of 3605 +/- 1136 for R and 5.39 +/- 3.4 for Kd were found. At 5407 +/- 1968, the number of receptor sites in patients not receiving glucocorticoid therapy (Group A) was significantly higher than that of controls (p < 0.01). In patients receiving glucocorticoid therapy this value was reduced at 3855 +/- 866 (Group B), 3358 +/- 963 (Group C), and 2685 +/- 962 (Group D). The values in Groups C and D were significantly lower than those in untreated patients (p < 0.02). CONCLUSION: In pulse therapy doses of glucocorticoids that exceed receptor saturation are administered for several days, but in addition significant receptor downregulation occurs. Therefore, we assume an increase in the relative contribution of the nongenomic effects of glucocorticoids to the therapeutic success under these conditions.     

Safety and efficacy of intravenous quinidine

The safety and efficacy of intravenous quinidine were evaluated in a patient population with a high prevalence of left ventricular dysfunction and intraventricular conduction delays. Quinidine gluconate (mean dose 9.1 ± 1.6 mg/kg) was administered during electrophysiologic study to 100 patients with ventricular or supraventricular tachyarrhythmias. Clinical heart failure was present in 68 percent of the patients. Left ventricular end-diastolic pressure, cardiac index, and left ventricular ejection fraction were abnormal in 62, 48, and 70 percent, respectively. Major intraventricular conduction delays (QRS of 120 msec or more) were present in 27 percent, and the H-V interval was prolonged (over 55 msec) in 28 percent. Despite the prevalence of these abnormalities, quinidine was discontinued because of hypotension in only 10 patients. Saline solution was infused to maintain preload in 37 percent, and hypotension responded promptly to saline solution infusion or discontinuation of quinidine infusion in all subjects. Hypotension was not more common in patients with more severe left ventricular dysfunction. QRS duration, H–V interval, QTc, and right ventricular effective refractory period increased significantly (p < 0.001) after quinidine administration. Heart block or QRS widening of 50 percent or more did not occur. Quinidine prevented arrhythmia induction in 26 percent of patients who received full doses. Ventricular tachycardia cycle length increased in all 41 patients in whom identical forms were induced before and after quinidine (287 ±71 msec versus 361 ± 93 msec, p < 0.001). Intravenous quinidine may be administered safely to patients with intraventricular conduction delays and moderate heart failure. When antiarrhythmic efficacy is assessed by electrophysiologic study, quinidine compares favorably with other antiarrhythmic agents.     

Long-term efficacy of azathioprine treatment for proliferative lupus nephritis

BACKGROUND: Combination therapy with cytotoxic drugs and corticosteroids reduces the risk for renal failure in patients with proliferative lupus nephritis (PLN), but uncertainty remains about the best mode of immunosuppression and its long-term effects. We report long-term results of combined azathioprine-prednisolone treatment for PLN, which has been the therapy of choice for the treatment of PLN at our centre for 15 yr. PATIENTS AND METHODS: A retrospective cohort study was carried out of 26 lupus patients, seen between 1978 and 1993, with histological and/or clinical evidence of PLN. Therapy consisted of prednisolone 1 mg/kg daily, tapered after 4 weeks to the lowest possible maintenance dose combined with azathioprine up to 2.5 mg/kg. Median duration of azathioprine treatment was 53 months. Standard statistical lifetable analyses were performed. RESULTS: Median follow-up on 1 January 1998 was 119 months. Patient survival estimates after 5, 10 and 15 yr of follow-up were 96, 91 and 82%, respectively. Four patients (15%) developed end-stage renal failure and three received renal transplants after a mean period of 27 months on haemodialysis. Renal survival estimates after 5, 10 and 15 yr of follow-up were 92, 87 and 87%, respectively. No malignancies were seen during the study period. CONCLUSION: Azathioprine treatment for 4-1/2 yr was well tolerated in this cohort of Caucasian patients with PLN and was associated with outcomes similar to those reported for pulse cyclophosphamide therapy.     

Safety and immunogenicity of varicella vaccine in patients with juvenile rheumatic diseases receiving methotrexate and corticosteroids

Objective

To evaluate the safety and immunogenicity of varicella vaccine (VV) in susceptible patients with juvenile rheumatic diseases receiving methotrexate and corticosteroids.

Methods

Twenty‐five patients with juvenile rheumatic diseases (ages 2–19 years) and 18 healthy children and adolescents (ages 3–18 years) received a single dose of VV. All 25 patients were receiving methotrexate; 13 were also receiving prednisone and 5 were also receiving other disease‐modifying antirheumatic drugs. None of the vaccinated patients or controls had a previous history of varicella. Anti–varicella‐zoster virus IgG antibody (anti–VZV‐IgG) titers were measured by enzyme‐linked immunosorbent assay immediately before, 4–6 weeks after, and 1 year after vaccination. The patients were monitored prospectively for adverse reactions related to the vaccine, exposure, and occurrence of varicella. Disease activity was assessed 3 months before and 3 months after VV.

Results

Twenty patients and all of the controls had negative preimmunization titers of VZV‐IgG, and 5 patients had equivocal levels. Positive VZV‐IgG titers were detected in 10 (50%) of 20 seronegative patients and 13 (72.2%) of 18 controls 4–6 weeks after VV (P = 0.2). One year after vaccination, 8 of 10 patients maintained positive VZV‐IgG titers. No overt varicella episodes and no severe adverse reactions were observed during the followup period. No worsening of clinical parameters and no flares of juvenile rheumatic diseases or changes in doses of medications used were detected after vaccination. In fact, the number of active joints in patients with juvenile idiopathic arthritis was significantly lower after VV (P = 0.009).

Conclusion

VV appears to be safe in patients with juvenile rheumatic diseases receiving methotrexate, as long as continuous prospective vigilance for side effects is performed.     

7例经贝伐珠单抗治疗晚期肺腺癌致恶性心包积液临床有效性、安全性分析

目的探讨贝伐珠单抗(bevacizumab, BEV)治疗晚期肺腺癌致恶性心包积液的有效性和安全性。 方法选择2014年1月至2019年4月我院收治的7例晚期肺腺癌合并中、大量恶性心包积液患者。在常规系统抗肿瘤治疗及对症治疗基础上接受静脉滴注BEV(400 mg/次)治疗,直至病情进展。对患者进行随访直至死亡,记录其病情是否缓解、无进展生存期、总生存时间以及不良反应。 结果5例患者在死亡前心包积液未再增加,其中2例患者完全缓解,3例患者部分缓解。另外2例患者症状未缓解。患者疾病无进展生存期平均为214天,疾病总生存期平均为24.28月。7例患者出现中有1例出现血栓性疾病,但经抗凝治疗后缓解,其余6例患者出现轻微药物相关不良事件。7例患者均未出现高血压。 结论在系统性抗肿瘤基础上静脉滴注BEV可有效控制恶性心包积液的生成、进展和复发,不良反应小,安全性高,但该结果仍需大规模临床研究进一步的验证。     

Biological treatment of rheumatic diseases

During recent two decades the progress in the understanding of the pathogenesis of the autoimmune diseases have led to new treatment targets, whose achievement claims new therapeutic advancings. Biological drugs complete or replace conventional immunosuppressive therapies in the treatment of autoimmune diseases. In the treatment of rheumatic diseases are currently used TNFalpha inhibitors and blockade of the IL-1, in phase of clinical trials or actual registration are agents blocking IL-6, the antibodies against B cell and inhibition of activation of T-cells by costimulating blockade with CTLA4Ig. In the Czech Republic are for treating of rheumatic diseases approved TNF blocking drugs. Treatment with this drugs is centred in biological therapy centres and patients are enroled into Registry of patients treated with anti TNFalpha drugs (ATTRA), which enable longterm observation of efficacy and toxicity.