Longterm cyclosporine therapy in rheumatoid arthritis

Sixteen patients who had shown a good clinical response to cyclosporine therapy during a randomized 6-month double blind study comparing cyclosporine with D-penicillamine in active rheumatoid arthritis, had an opportunity to participate in an open study with cyclosporine. The initial daily dose of cyclosporine was 5 mg/kg. Before the planned maximal duration of 18 months, there were 6 premature discontinuations, 2 because of inefficacy, 2 because of side effects, and 2 for other reasons. During the study there was an improvement in all clinical variables. Even under the strict conditions of our trial there was an irreversible loss of about 15% of renal function. Suggestions are given to minimize the chance of nephrotoxicity.     

Guidelines for the use of cyclosporine in rheumatoid arthritis

Cyclosporine has now been tested in over 10 clinical trials in Rheumatoid Arthritis. These show that it provides clinically important benefit in 30–50% of patients with severe rheumatoid arthritis with an acceptable side-effect profile. It should be offered to patients who fail to (or only partially respond to Methotrexate. The use of Cyclosporine in combination with other slow acting agents shows promise and should be tested at different points in the natural history of the disease.     

Low dose cyclosporine in rheumatoid arthritis: a pilot study

A 6 month open trial of cyclosporine (CyA) was conducted in 20 patients with active rheumatoid arthritis unresponsive to second line therapy. The dosage was monitored to achieve a serum blood level of 75-150 ng/ml. A 25% reduction in ARA joint count (baseline mean 38.2; 6 month or time of CyA withdrawal mean 28.7; p less than 0.001) was observed for all patients. Fifteen completed the 6 month CyA regimen and 5 developed toxicity requiring CyA to be permanently withdrawn. For the 15 patients completing 6 months of CyA, improvement was 36% (baseline 34.7; 6 month mean 22.2; p less than 0.001). Corresponding improvements were also observed on the other main study outcomes of pain and functional ability. Improvement occurred between 12-20 weeks, somewhat later than in other studies. Toxicity included mild hypertension (4 patients) and gastrointestinal intolerance (2). Three patients were withdrawn from CyA due to nephrotoxicity. There was a clinically significant reduction in calculated creatinine clearance but this returned to baseline within 6 months after CyA was withdrawn for all except 2 patients who took 12 months to return to baseline.     

Tolerance of cyclosporine A in children with refractory juvenile rheumatoid arthritis

In an open trial, tolerance and safety of cyclosporine A was studied in 14 patients with refractory juvenile rheumatoid arthritis (JRA). The doses varied from 4-15 mg/kg/day. Treatment lasted for greater than 12 months in 11 and 6 to 9 months in 3 patients. Eleven patients were withdrawn due to lack of efficacy (4) or side effects (7). A drop of greater than 2 g/l in hemoglobin and a marked rise in serum creatinine were the cause of withdrawal in 5 patients. The effect of cyclosporine on disease activity seemed to be mainly symptomatic and temporary. Probably, the dose should be kept below 5 mg/kg/day. Future controlled studies should be aware of a risk of aggravation of anemia in children treated with cyclosporine.     

Legionnaires' disease in a patient with rheumatoid arthritis treated with cyclosporine

We report a patient with long-standing rheumatoid arthritis (RA) treated with cyclosporine A; she developed a flare of her arthritis and evidence of vasculitis, cavitary pulmonary disease, nephritis and hepatitis, and was found to have Legionella pneumophila serotype I infection. Cyclosporine is a relatively new and investigational therapy in RA. Thus, it is important that any unusual complications in patients with RA treated with cyclosporine should be documented.     

Combination of cyclosporine and leflunomide versus single therapy in severe rheumatoid arthritis

OBJECTIVE: This study assessed the efficacy and safety of combination (COMB) of cyclosporine (CSA) and leflunomide (LEF) versus each drug alone, in the treatment of severe rheumatoid arthritis (RA). METHODS: One hundred six patients with active RA refractory to at least one disease modifying antirheumatic drug (methotrexate obligatorily) were entered into a 12-month open, prospective trial and were randomly allocated to receive either CSA 2.5 to 5 mg/kg/day, or LEF 20 mg/day, or the combination of both at the same initiating dose. RESULTS: The American College of Rheumatology 50% (ACR50) response rates for the 3 groups were COMB 80%, CSA 40%, and LEF 42% (p = 0.001). Combination therapy was also significantly better than CSA and LEF at the more stringent 70% response rate (69% vs 34% vs 30%, respectively; p = 0.001). Comparable Disease Activity Score 28 reduction rates were noted at trial termination for all 3 treatment arms: COMB -2.74 vs CSA -2.53 vs LEF -2.28 (p nonsignificant). Discontinuation rates were more common in LEF vs CSA arm (p = 0.046). No unexpected or serious adverse drug effects were identified in the combination group during the 12-month period. CONCLUSION: The combination of CSA and LEF in patients with refractory RA provided statistically significant benefit in ACR50 and ACR70. Adverse events were not substantially increased.     

减轻环孢素A肾毒性的研究进展

环孢素Ａ(ＣｓＡ)是一种强力免疫抑制剂 ,已广泛用于器官移植及一些免疫性疾病 ,其最主要的副作用是肾毒性 ,发生率高 (30 %～ 74 % ) ,对肾移植而言 ,将损害移植肾脏本身。因此 ,寻求对ＣｓＡ肾毒性 (ＣｓＡ ＮＴ)的防护方法 ,具有非常重要的意义。现综述如下。　　改变药物的介质用鱼油代替橄榄油作为ＣｓＡ的介质可使ＣｓＡ ＮＴ大为改善。鱼油可与花生四烯酸竞争环氧合酶和肢氧合酶 ,抑制花生四烯酸代谢 ,减少对肾脏血管有收缩作用的血栓素Ａ2 (ＴＸＡ2 )和白三烯Ｂ4 (ＬＴＢ4 )的合成量 ,改善ＣｓＡ急慢性肾损害。　　减低ＣｓＡ的剂量…     

The safety and efficacy of cyclosporine (Neoral) in rheumatoid arthritis.

OBJECTIVE: To assess the safety and efficacy of cyclosporine (Neoral), its steroid sparing effect, and its usefulness in combination therapy with methotrexate (MTX) in the treatment of refractory rheumatoid arthritis (RA). METHODS: All patients given cyclosporine for refractory RA over a 21 month period were included in an open, prospective study. Patients were reviewed initially fortnightly then monthly with clinical evaluation and serum creatinine. There were no restrictions on the use of other disease modifying agents, nonsteroidal antiinflammatory drugs, or corticosteroids. RESULTS: Forty-six patients with severe RA were included in the study, 33 (72%) female and 13 (28%) male, with a mean age of 54.8 years (range 20-74). At the completion of the study 30 (65%) were still taking cyclosporine at a mean dose of 2.94 mg/kg/day for a mean duration of 10.5 months. Thirteen patients discontinued cyclosporine due to side effects, most commonly gastrointestinal, and 3 due to inefficacy. Thirty-seven of the 46 patients were taking prednisolone at the start of the study at a mean dose of 10.36 mg/day, which decreased to 7.068 mg/day at the end of the study (p < 0.001). Thirty patients used cyclosporine in combination with MTX. The mean dose of MTX decreased from 15.08 to 13.67 mg/wk (p = 0.02). The mean serum creatinine increased by 13% from 74 to 83.7 micromol/l. Patients who continued therapy had a shorter duration of disease, with a mean of 9.93 years compared to 15.73 years in those who stopped therapy (p = 0.004). CONCLUSION: Cyclosporine (Neoral) was a safe and effective therapy in this population of patients with RA refractory to standard therapy. We observed a significant steroid sparing effect and have shown that combination therapy with MTX does not increase side effects and allows for a decrease in MTX dose. Renal function is not adversely affected if guidelines are followed.     

Cyclosporine nephrotoxicity in rheumatoid arthritis: no effect of short term misoprostol treatment.

We assessed the effect of the prostaglandin E1 analog misoprostol on cyclosporine nephrotoxicity in patients with rheumatoid arthritis (RA). Thirteen patients with RA were given cyclosporine with misoprostol tablets, 800 micrograms/day for one week in a randomized, double blind, placebo controlled crossover trial. All had cyclosporine nephrotoxicity, documented by an increase in serum creatinine of at least 15% over the values before the start of cyclosporine treatment. Mean glomerular filtration rate (GFR) (single shot 51Cr-EDTA plasma clearance) at baseline was 77.3 ml/min (SD, 22.0). After misoprostol, it was 80.0 ml/min (SD, 18.9); after placebo, 79.1 ml/min (SD, 20.0). None of these changes were statistically significant. Serum creatinine levels and whole blood cyclosporine levels were also unchanged. Power to detect at least a 5 ml/min rise in GFR was 0.92. Short term misoprostol treatment does not improve the GFR of patients with RA on cyclosporine.     

A study of the longterm efficacy and toxicity of cyclosporine A in rheumatoid arthritis.

We determined the longterm efficacy and toxicity of cyclosporine A in rheumatoid arthritis (RA) in an open clinical trial, at a single centre, outpatient rheumatology clinic. The initial dose was 5 mg/kg/day increased to 10 mg/kg/day with adjustments for toxicity and plasma cyclosporine A levels. We measured efficacy by the Ritchie articular index, pain and function on a 10 cm visual analog scale, C-reactive protein (CRP) and erythrocyte sedimentation rate. Toxicity was evaluated by patient reports, serum creatinine, cyclosporine A levels and liver function tests. Median treatment duration was 29 months (16.5-38). At 24 months median reduction in Ritchie articular index was 50% (9-79); pain: 49% (21-77), with a 50% (4-76) improvement in function; and CRP fell by 72.5% (22-87). The main side effect was a 40% (27-47) decline in estimated creatinine clearance. We conclude that cyclosporine A at doses below 5 mg/kg/day is associated with clinically significant improvements in indices of disease activity in RA. Renal dysfunction was the most frequent side effect.     

Reversible infliximab-related lymphoproliferative disorder associated with Epstein-Barr virus in a patient with rheumatoid arthritis

Abstract

A 63-year-old woman with active rheumatoid arthritis (RA) had been treated with methotrexate and prednisolone. She developed cervical lymph node swelling 30 months after the initiation of infliximab therapy. A computed tomography revealed cervical and mediastinal lymph node swelling and multiple nodules (up to 13 mm in diameter) in the lungs. A lymph node biopsy showed infiltration of numerous Hodgkin-like and Reed-Sternberg-like cells. Immunohistological studies showed that these cells were positive for CD15, CD30, and Epstein-Barr virus (EBV) latent membrane protein. In site hybridization revealed the presence of EBV RNA in the nuclei of these cells. EBV DNA was detected in the biopsy specimen by southern blot analysis. She was diagnosed as having EBV-associated lymphoproliferative disorder (LPD). Immunodeficiency-associated LPD related with infliximab therapy was considered. Cessation of infliximab therapy only led to dramatic regression of LPD. This case illustrates that EBV-associated LPDs can occur as part of infliximab adverse effects in patients with RA.     

Reversible infliximab-related lymphoproliferative disorder associated with Epstein-Barr virus in a patient with rheumatoid arthritis

A 63-year-old woman with active rheumatoid arthritis (RA) had been treated with methotrexate and prednisolone. She developed cervical lymph node swelling 30 months after the initiation of infliximab therapy. A computed tomography revealed cervical and mediastinal lymph node swelling and multiple nodules (up to 13 mm in diameter) in the lungs. A lymph node biopsy showed infiltration of numerous Hodgkin-like and Reed-Sternberg-like cells. Immunohistological studies showed that these cells were positive for CD15, CD30, and Epstein-Barr virus (EBV) latent membrane protein. In site hybridization revealed the presence of EBV RNA in the nuclei of these cells. EBV DNA was detected in the biopsy specimen by southern blot analysis. She was diagnosed as having EBV-associated lymphoproliferative disorder (LPD). Immunodeficiency-associated LPD related with infliximab therapy was considered. Cessation of infliximab therapy only led to dramatic regression of LPD. This case illustrates that EBV-associated LPDs can occur as part of infliximab adverse effects in patients with RA.     

Reversible nephrotoxicity associated with cephalothin therapy.

A 53-year-old man with scalp cellulitis developed acute renal failure after sodium cephalothin therapy. The patient probably had preexisting renal disease. Discontinuance of cephalothin was followed by improvement of the renal function. Specimens from a renal biopsy performed during the recovery phase showed nonspecific changes in the renal tubular epithelium, similar to those seen in animals treated with large doses of cephalothin. Previously reported cases of cephalothin nephrotoxicity, along with this case, caution the clinician to proceed with care in the treatment of azotemic patients with cephalothin.     

细胞凋亡和细胞自噬在慢性环孢素A肾毒性中的作用

目的探讨细胞凋亡和细胞自噬在慢性环孢素A(CsA)肾毒性中的作用。方法 Sprague-Dawley大鼠分为两组:对照组:皮下注射橄榄油(1 ml·kg-1·d-1)4 w;慢性CsA肾毒性组:皮下注射CsA(15 mg·kg-1·d-1)4 w。检测两组大鼠的体重和肾功能;三色染色检测肾小管间质纤维化程度;ELISA法检测血、尿8羟基脱氧鸟苷(8-OHdG)水平;原位末端标记法(TUNEL)染色观察细胞凋亡;免疫印迹法检测细胞凋亡调控基因(Bcl-2、Bax、Caspase-3)和细胞自噬体膜型LC3-Ⅱ蛋白的表达;Pearson直线相关分析肾小管间质纤维化程度与细胞凋亡和LC3-Ⅱ蛋白表达的相关关系。结果与对照组相比,毒性组大鼠体重减轻、肾功能低下、血尿8-OHdG水平升高,同时肾毒性组可见明显的肾小管间质纤维化和大量TUNEL阳性细胞。免疫印迹结果表明,毒性组Bax、Caspase-3、LC3-Ⅱ蛋白的表达明显增加,反之,Bcl-2的表达显著减少。直线相关分析提示,肾小管间质纤维化程度与TUNEL阳性细胞数和LC3-Ⅱ蛋白表达呈正向相关。结论细胞凋亡和细胞自噬参与了慢性CsA肾毒性肾小管间质的损伤。