心肌肌钙蛋白Ⅰ对环磷酰胺冲击治疗狼疮肾炎心脏毒性评估的临床意义

目的探讨心肌肌钙蛋白I（cTnI）对环磷酰胺冲击治疗狼疮肾炎的心脏毒性评估的临床意义。方法应用美国贝克曼库特公司生产的进入2免疫分析系统（Access Immunoassay System2,AIS2）对环磷酰胺冲击治疗狼疮肾炎前后cTnI水平进行测定,比较治疗前后cTnI的变化,对环磷酰胺的心脏毒性进行评估。结果环磷酰胺冲击治疗前患者血清cTnI为（0.034±0.013）ng/L,冲击治疗后次日患者血清cTnI为（0.038±0.012）ng/L,冲击治疗后1周患者血清cTnI为（0.037±0.011）ng/L,冲击治疗后2周患者血清cTnI为（0.036±0.012）ng/L,以上3组结果两两比较,差别无统计学意义。结论环磷酰胺以20mg/kg剂量冲击治疗狼疮肾炎未发现有cTnI明显升高,说明该剂量冲击治疗狼疮肾炎未引起心脏毒性的发生。     

Pulse cyclophosphamide for severe neuropsychiatric lupus.

We studied the effect of parenteral pulse cyclophosphamide therapy in nine patients with active systemic lupus erythematosus and severe central nervous system involvement. Seven patients had focal neurological deficits and/or seizures associated with abnormalities on cerebrospinal fluid analysis and/or magnetic resonance imaging. Two patients had organic brain syndrome with psychosis and normal cerebrospinal fluid and/or magnetic resonance imaging analysis. Six patients were unresponsive to treatment with high dose corticosteroid. Cyclophosphamide, 0.75-1.0 g/m2 body surface area, was administered intravenously every month for at least 2 months. Eight patients had a complete recovery or recovered with minor residuals. Cyclophosphamide was well tolerated with few side effects. We conclude that parenteral pulse cyclophosphamide is an effective adjunctive therapy for the management of patients with active systemic lupus erythematosus and central nervous system symptoms.     

Effective treatment with cyclosporine A of a child with systemic lupus erythematosus resistant to cyclophosphamide pulse therapy

Intermittent intravenous cyclophosphamide pulse therapy (IVCY) has been reported to be effective for the treatment of refractory systemic lupus erythematosus (SLE). However, there is a proportion of patients with SLE, who are IVCY-resistant and need a long-term therapy to sustain the remission. We report here a case of a 6-year-old Japanese girl with SLE refractory to IVCY. She suffered from persistent hypocomplementemia and recurrent flares despite receiving methylprednisolone pulse, mizoribine pulse and IVCY therapy. Administration of cyclosporine A (CsA) was, therefore, initiated. Within 2 months of the start of CsA administration, the serum levels of C3, C4 and complement hemolytic activity began to increase rapidly, and finally returned to the normal levels. The serum anti-dsDNA antibody titer was decreased significantly after the initiation of this treatment. The prednisolone dose could be successfully tapered without precipitation of any flares. No adverse effects of CsA were observed. Based on these clinical observations, we suggest that CsA might be an effective treatment option for selected cases of refractory SLE.     

Plasmapheresis and subsequent pulse cyclophosphamide versus pulse cyclophosphamide alone in severe lupus: design of the LPSG trial. Lupus Plasmapheresis Study Group (LPSG)

A group of clinics are collaborating in the Lupus Plasmapheresis Study Group (LPSG) to investigate whether repeated plasmapheresis prior to pulse cyclophosphamide improves the therapeutical results in severe systemic lupus erythematosus (SLE). The underlying rationale is the hypothesis that plasmapheresis 1) eliminates pathogenic autoantibodies and immune complexes and 2) induces compensatory lymphocyte activation via feedback mechanisms between circulating antibodies and their respective clones ("antibody rebound"). It should be possible to utilize this enhanced activity for increased clonal deletion if pulse cyclophosphamide is applied shortly after plasmapheresis. Accordingly, in a randomized study, the LPSG will be comparing the repeated application of pulse cyclophosphamide alone with a treatment involving repeated plasmapheresis prior to the cyclophosphamide pulses in severe SLE. A third arm of the study will be gathering experience with a more intensified procedure. This overview summarizes the most important details of the planned study.     

Synchronised therapy and high-dose cyclophosphamide in proliferative lupus nephritis

The aim of this open study was to compare the outcomes and side effects of plasmapheresis (PP) in patients with proliferative lupus nephritis treated with cyclophosphamide (Cyc) boluses. The study involved 28 consecutive patients. All of the patients met the ACR modified criteria for SLE and underwent a qualifying renal biopsy. In group I, patients were treated with synchronised therapy (PP, 50 ml/kg, followed by pulse Cyc, 750 mg/m(2), repeated monthly for 6 months), whereas in group II, they were given only intermittent Cyc boluses (at the same dosage). The data were collected in the patients' records according to a standardised protocol. Patients were followed-up for a mean of 4 years. The disease-free survival was analysed using Kaplan-Meier estimated survival curves ([S(t)]). At the end of the 6-month treatment period, a statistically significant number of patients in group I (75%) was in complete remission in comparison to group II (31%) (P < 0.02), whereas at long-term follow-up, these percentages were similar (41% vs. 50%, P = n.s.). The main functional and immunological parameters showed a normalisation in both groups. The risk of a poor renal outcome significantly correlated with high serum creatinine levels at the onset of nephritis (P < 0.05). We documented a higher rate of infectious complications in group I. This study reports that synchronised therapy is useful in inducing a faster remission in patients with proliferative lupus nephritis. However, it is not superior to conventional therapy at long term follow-up analysis. Positive results should be reinforced by a long-term maintenance therapy.     

Immunological aspects of pulse therapy in systemic lupus erythematosus

Twenty SLE patients were examined against a background of pulse-therapy with methylprednisolone. The analysis showed that there was a decrease in the CIC concentration, antibodies to native DNA and an increase in the level of C3c and C4 components of the complement against a background of pulse-therapy. A more rapid time course of the CIC level was noted shortly after pulse-therapy as compared to changes in other immunological indices. A dynamic study of immunological indices in SLE against a background of pulse-therapy was appropriate for a clinical assessment and a study of the mechanisms responsible for the therapeutic efficacy of this method.     

Acute erythroid leukemia after cyclophosphamide therapy for multiple myeloma: report of two cases.

The diagnosis of multiple myeloma was made in two white men, aged 55 and 59 years. They were treated with cyclophosphamide for 98 and 44 months respectively. Patient 1 also received a nine-month course of combined therapy with melphalan, procarbazine, and prednisone. Both developed acute erythroid leukemia, 98 and 71 months after the original diagnosis of myeloma, and died of subarachnoid hemorrhage and cardiac arrest. Patient 1 developed squamous cell carcinoma of the skin with recurrence, and Patient 2 developed anaplastic carcinoma of the urinary bladder. Palliative radiation therapy was given. The development of erythroid leukemia plus carcinoma in these two men suggests mutagenic change secondary to cyclophosphamide therapy.     

Repeated pulse of methylprednisolone and cyclophosphamide with continuous dexamethasone therapy for patients with severe paraquat poisoning

OBJECTIVE: Paraquat is widely used in the world, and all treatments for paraquat poisoning have been unsuccessful. Many patients have died of paraquat poisoning in developing countries. A novel anti-inflammation method was developed to treat severe paraquat-poisoned patients with >50% to <90% predictive mortality: initial pulse therapy with methylprednisolone (1 g/day for 3 days) and cyclophosphamide (15 mg/kg/day for 2 days), followed by dexamethasone 20 mg/day until Pao2 was >11.5 kPa (80 mm Hg) and repeated pulse therapy with methylprednisolone (1 g/day for 3 days) and cyclophosphamide (15 mg/kg/day for 1 day), which was repeated if Pao2 was <8.64 kPa (60 mm Hg). DESIGN: Randomized controlled trial. SETTING: Academic medical center in Taiwan. PATIENTS: Twenty-three paraquat-poisoned patients with >50% and <90% predictive mortality assessed by plasma paraquat levels were prospectively and randomly assigned to the control and study groups at a proportion of 1:2. INTERVENTIONS: The control group received conventional therapy and the study group received the novel repeated pulse treatment with long-term steroid therapy. MEASUREMENTS AND MAIN RESULTS: We measured patient mortality during the study period. There was not a different distribution of basal variables between the two study groups. The mortality rate (85.7%, six of seven) of the control group was higher than that of the study group (31.3%, five of 16; p = .0272). CONCLUSIONS: The novel anti-inflammatory therapy reduces the mortality rate for patients with severe paraquat poisoning.     

Improved survival in severe paraquat poisoning with repeated pulse therapy of cyclophosphamide and steroids

Purpose  

To clarify the efficacy of repeated methylprednisolone (MP) and cyclophosphamide (CP) pulse therapy and daily dexamethasone (DEX) therapy in patients with severe paraquat (PQ) poisoning.     

Elevated interleukin-12 in progressive multiple sclerosis correlates with disease activity and is normalized by pulse cyclophosphamide therapy.

Multiple sclerosis is postulated to be a Th1-type cell-mediated autoimmune disease. We investigated cytokine profiles in patients with progressive multiple sclerosis by using intracytoplasmic staining. We found increased IL-12 production by monocytes and increased IFN-gamma production by T cells in untreated patients as compared with controls. In patients treated with methotrexate, methylprednisolone, or cyclophosphamide/methylprednisolone (CY/MP), only CY/MP treatment normalized the elevated IL-12 production. Furthermore, CY/MP-treated patients had decreased IFN-gamma and increased IL-4, IL-5, and TGF-beta expression. Patients followed prospectively before and after starting CY/MP treatment showed a gradual decrease in IL-12 and IFN-gamma production and an increase in IL-4 and IL-5. In vitro, addition of 4-hydroperoxycyclophosphamide, a metabolite of cyclophosphamide decreased IL-12 production in mononuclear cell cultures. When patients were classified as having active or stable disease, IL-12 production correlated with disease activity. In summary, our results demonstrate a Th1-type cytokine bias in peripheral blood mononuclear cells of untreated progressive MS patients that is reversed by CY/MP treatment and is associated with Th2 and TGF-beta (Th3) type responses. These findings provide a basis for immune monitoring of patients with MS and suggest that treatments that downregulate IL-12 may prove to be beneficial in progressive MS.     

Selective effects of cyclophosphamide therapy on activation, proliferation, and differentiation of human B cells.

The immune function of B lymphocytes from 12 patients with nonneoplastic immune-mediated diseases receiving chronic low-dose (2 mg/kg per d) cyclophosphamide (CY) was evaluated. There was a selective and differential suppressive effect of CY therapy on the various stages of the B cell cycle including activation, proliferation, and differentiation. The proliferative responses to Staphylococcus aureus Cowan strain I (SAC) and mitogenic concentrations of anti-mu were suppressed. In contrast, B cells that have been presumably activated in vivo proliferated with a normal pattern when exposed to B cell growth factor in vitro. Chronic low-dose CY therapy also suppressed B cell differentiation. Secretion of immunoglobulin by B cells following in vitro triggering with SAC and a T cell supernatant was suppressed in CY-treated patients. Moreover, differentiation of the large in vivo-activated B cells (which do not require an in vitro activation signal) in the presence of appropriate T lymphocyte supernatant was also suppressed. This selective suppression of B cell function at multiple points in the B cell cycle may be responsible for the efficacy of CY therapy in certain antibody and immune complex-mediated diseases.     

系统性红斑狼疮的个体化治疗

系统性红斑狼疮（systemic lupus erythematosus，SLE）是一种高度异质性的疾病，正确的治疗方案是在根据患者受损的脏器及程度评估SLE病情，并根据患者体质的耐受性，权衡风险与效益之比后，选取个体化的用药方案。     

Recovery of both acute massive pulmonary hemorrhage and acute renal failure in a systemic lupus erythematosus patient with lupus anticoagulant by the combined therapy of plasmapheresis plus cyclophosphamide

Acute massive pulmonary hemorrhage (AMPH) is a rare and highly fatal complication in systemic lupus erythematosus (SLE). We report here survival in a case of AMPH in a SLE patient with both rapidly progressive glomerulonephritis and lupus anticoagulant. The AMPH occurred while the nephritis was refractory to 2 courses of pulse methylprednisolone therapy. After combined therapy with plasmapheresis plus cyclophosphamide, circulating immune complex levels declined, AMPH recovered, and serum creatinine levels returned to normal. In conclusion, the combined therapy of plasmapheresis plus cyclophosphamide should be considered for treating AMPH especially in those SLE patients with rapidly progressive glomerulonephritis.     

静脉马利兰环磷酰胺联用预处理异基因造血干细胞移植19例

背景:由大剂量口服马利兰联合环磷酰胺组成的BuCy2是目前主要的移植前预处理方案之一,但存在较多口服马利兰相关副作用。目的:评价静脉马利兰预处理造血干细胞移植治疗恶性血液病的有效性及安全性。设计:病例观察。单位:华中科技大学同济医学院附属协和医院血液科。对象:选择2006-05/12在华中科技大学附属协和医院血液病研究所行改良静脉马利兰联用环磷酰胺为预处理方案的异基因的造血干细胞移植13例慢性粒细胞白血病患者及6例急性白血病患者,男12例,女7例,年龄14~50岁,平均33岁,其中亲缘性移植9例,非亲缘移植10例,造血干细胞来源:外周血18例,骨髓1例。所有患者及家属对治疗项目知情同意。方法:应用静脉注射马利兰组成的BuCy2预处理对患者进行异基因造血干细胞移植,即所有患者均采用目前国内外通用的改良马利兰联用环磷酰胺方案,即移植前10d口服羟基脲40mg/kg,移植前9d静脉滴注阿糖胞苷2g/m2,移植前8,7,6d应用马利兰针剂0.8mg/kg(该剂量根据既往研究与1mg/kg口服制剂等效),通过中心静脉插管由输液泵控制滴速大于2h输注完毕,1次/6h,共12次,静脉注射马利兰输注前可应用生理盐水或5%葡萄糖稀释至约0.5g/L(约稀释10倍)。移植前5,4d静脉注射环磷酰胺1.8g/(m2·d),移植前3d口服甲基环已亚硝脲250mg/m2。观察患者肝静脉闭塞病以及其他副作用的发生情况,术后进行中位6.5个月的随访观察,主要观察患者疾病复发及存活情况。主要观察指标:①移植后100d肝静脉闭塞病发生及副作用情况。②随访结果。结果:纳入患者19例均进入结果分析,术后13d内均获造血功能重建,经血型转变、染色体核型及DNA多态性证实为供者植入。①肝静脉闭塞病发生及副作用:患者在移植后100d内的肝静脉闭塞病发生率和100d时的肝静脉闭塞病相关死亡率均为0,未观察到与静脉马利兰相关的严重毒副反应。②随访结果:术后6.5个月随访,1例患者因移植后肝炎死亡,2例患者复发,其中1例经氟达拉滨 阿糖胞苷 粒细胞集落刺激因子方案化疗及供者外周血造血干细胞支持后目前已经获得完全缓解,经DNA多态性证实重新获得供者植入,另1例患者目前化疗进行中。其余患者目前均无病存活。结论:静脉马利兰的应用,可能在一定程度上减少了移植后肝静脉闭塞病的发生及其他口服马利兰相关的毒副作用,从而提高了移植疗效。