Abstract】Objective: To study the treatment of elderly PRCA patients with reduced dose CsA combined with traditional Chinese medicine, to investigate the efficacy of CsA serum blood concentration and to evaluate its safety, and to provide a basis for the clinical treatment of elderly PRCA. RESULTS: All 24 elderly patients with PRCA were given CsA 75 mg/dose orally twice daily. In the 19 effective cases, the mean value of HGB before treatment was 49.34±7.40 (g/L), which increased to 114.30±14.35 (g/L) after treatment, and the onset of effect was about 4 weeks. /Among all 24 cases, one case failed to adhere to the dose due to gastrointestinal adverse effects, and one case showed a mild increase in total bilirubin and direct bilirubin, which decreased to normal after hepatoprotective treatment. Conclusion: Reduced-dose CSA is safe and effective in the treatment of PRCA in the elderly population, with an efficiency of 79.17% and no significant liver and kidney function damage, and can be considered as the preferred treatment option for elderly PRCA patients. Key words】Acquired pure red cell aplastic anemia; plasma CSA concentration; clinical efficacy; safety analysis Pure red cell aplasia (PRCA) is anemia caused by a significant decrease or absence of red blood cells in the bone marrow. The development of acquired pure red cell aplasia is mostly immune-related. Immunosuppressive agents such as glucocorticoids, cyclosporine A (CsA), and cyclophosphamide (CTX) are currently preferred for treatment. Older patients with PRCA often have hypertension, type II diabetes, osteoporosis, and multiple organ hypofunction, and are not suitable for long-term glucocorticoid or cytotoxic immunosuppressive therapy, and are often not easily tolerated by conventional doses of CsA due to hepatic and renal toxicity. We have applied CsA alone to treat PRCA with satisfactory efficacy [[1]]. This study was conducted to reduce the dosage of CsA to 75 mg twice daily according to the poor tolerability of CSA in elderly PRCA patients, to investigate the plasma trough concentration at the onset of the reduced dose of CsA and to evaluate its efficacy and safety, and to provide an objective basis for the use of CsA dosage in elderly PRCA patients. I. Cases and methods 1. Cases: 24 elderly patients with PRCA who were seen in our hospital from May 2011 to September 2013. The diagnostic criteria were referred to the third edition of the Diagnostic and Efficacy Criteria for Hematological Diseases [[2]]. Among them, 6 cases were male and 18 cases were female, with an age distribution of 60 to 84 years old and a mean age of 76 ± 7.09 years ( ). There were 2 cases of combined thymoma, 1 case of combined rheumatoid arthritis, 8 cases of combined hypertensive disease, and 7 cases of combined type II diabetes. All patients with PRCA were given CsA 75mg/dose orally twice daily. The basic drugs include: Cuscuta sinensis, Radix et Rhizoma tonicum, Xian Ling Spleen, Radix et Rhizoma shou Wu, Radix Angelicae Sinensis, Rhizoma Chuanxiong, Radix Rehmanniae, Radix et Rhizoma Yi, Radix et Rhizoma Yam, Cornu Cervi Pantotrichum, Radix et Rhizoma Kwangmu Xiang, etc. According to the strength and weakness of kidney yin and yang of the patients, we should add Bacopa monniera and Fructus lockorum; for kidney yin deficiency, we should add Radix et Rhizoma chasteensis and Radix et Rhizoma drynariae; for spleen qi deficiency, we should add Si Jun Zi Tang. During the treatment period, blood tests were repeated 2 weeks, serum CsA valley concentration was monitored, and liver and kidney functions were rechecked every month. Analyze the plasma blood concentration with reduced dose CsA onset to evaluate its effectiveness and safety. After the hemoglobin rises to the optimal value, CsA is maintained at 75mg-100mg/day. 3.Efficacy Determination The criteria of efficacy determination refer to the third edition of the Diagnostic and Efficacy Criteria of Hematological Diseases. 1）Basic cure: anemia symptoms disappear, hemoglobin rises to normal, 120 g/L for men and 110 g/L for women, white blood cell and platelet counts are normal, and bone marrow image returns to normal. (2) Remission: symptoms disappear, hemoglobin rises to normal, 120 g/L for men and 110 g/L for women, white blood cell and platelet counts are normal, and bone marrow image is normal. Stable or continue to progress after 3 months of drug discontinuation and follow-up. 3) Obvious progress: symptoms improve without blood transfusion. The hemoglobin increased by more than 30g/L compared with that before treatment and did not decrease for 3 months. 4) Ineffective: The hemoglobin did not increase after treatment or increased by less than 30g/L. II. Results 1. Relationship between CsA dose and efficacy All 24 cases of elderly patients with PRCA, 19 cases were effective and 5 cases were ineffective. 79.17% of the effective rate was achieved by reducing CsA dose. Among the ineffective 5 cases, CsA was increased to 100-125mg/time twice a day in 3 cases, and HGB rose close to normal, in fact, the total effective rate of CsA was 91.67%. Among these 3 cases, 1 female patient was switched to hormone therapy at a later stage due to a rise in blood creatinine (CREA: 124 mmol/L). 1 case was ineffective even after increasing the dose of CsA, and 1 case stopped CsA therapy and switched to other regimens due to digestive discomfort. 2. relationship between CsA concentration and efficacy 19 effective cases with reduced CsA dose, the mean value of HGB before treatment was 49.34±7.40 (g/L) and rose to 114.30±14.35 (g/L) with treatment, the onset of effect was about 4 weeks, the plasma CsA trough concentration at the onset of effect was 96.59±28.52 ng/ml. after HGB rose to normal After the HGB rose to normal, CsA was reduced to 75 mg-100 mg/d, and the plasma CsA trough concentration was maintained at 50 ng/ml-60 ng/ml, and HGB was still maintained in a stable range. In the three effective cases after increasing CsA dosage, serum CsA trough concentrations were 40.2 ng/ml, 51 ng/ml and 59.3 ng/ml before CsA increase, and serum CsA trough concentrations reached 79 ng/ml, 128 ng/ml and 111 ng/ml after increase, and HGB increased to more than 100 g/L. In all 22 effective cases, HGB rose above 100 g/L. It took about 1-2 months from the onset of effect until HBG rose to the optimal value. 3. Safety analysis of reduced-dose CsA Our study found that the treatment of elderly PRCA with reduced-dose CsA was effective, safe and well tolerated by patients. Among all 24 cases, one case failed to adhere to the dose due to gastrointestinal adverse effects, and one case had a mild increase in total bilirubin and direct bilirubin (TBIL: 27.12 U/L; DBIL: 16.13 U/L), which decreased to normal after hepatoprotective and biliary treatment, with an adverse effect rate of 8.33%. Among the five cases in which CsA was increased to the conventional dose, one patient’s HGB rose to normal level, but blood creatinine rose to 124 mmol/L and was changed to hormone therapy. No abnormal renal function was observed in the reduced dose group. The blood pressure was well controlled during treatment in 8 cases with combined hypertension and 7 cases with combined type II diabetes mellitus, and the blood glucose rose to different degrees in 5 patients during treatment. III. Discussion PRCA is divided into two types: congenital and acquired. Acquired is further divided into acute hematopoietic arrest and chronic acquired PRCA. The pathogenesis of the latter is mostly related to immune abnormalities, such as immune rejection of red lineage cells by T cells; inhibition of primitive erythrocytes, BFU-E and CFU-E by an erythropoiesis inhibitory factor in IgG fraction; and poor bone marrow erythropoiesis by infectious factors such as microviruses. Glucocorticoids and immunosuppressants are usually preferred for treatment. Japanese scholars [[3]] summarized 185 patients with PRCA and evaluated immunosuppressive efficacy in a stratified study according to comorbidities. 62 patients with primary PRCA were treated with CsA in 31 cases and remission in 23 cases (74%), glucocorticoids in 20 cases and remission in 12 cases (60%), and other drugs in 11 cases. The median relapse-free survival (RFS) time was 103 months with CsA with or without glucocorticoid maintenance therapy, which was significantly longer than that with glucocorticoid maintenance therapy alone (33 months), demonstrating the effectiveness and advantages of CsA in the treatment of PRCA. This weakens the pro-proliferative response of killer T cells to IL-2, thereby blocking the expansion of suppressor T cells. Older patients with PRCA often have a combination of type II diabetes, hypertension, osteoporosis and other disorders, and are less tolerant of glucocorticoids than younger people, making them unsuitable for higher doses of hormones and immunosuppressive therapy. According to the characteristics of elderly patients with PRCA, we reduced the dosage of CsA to 150 mg daily, and nearly 80% of the patients could see the effect. Given the individual differences in CsA absorption and metabolism in vivo, it is necessary to monitor plasma CsA concentrations and liver and kidney function during treatment. This study showed that plasma CsA trough concentrations of about 100 ng/ml were 92% effective, and the lowest effective CsA trough concentration was about 70 ng/ml. Therefore, it is not necessary to overemphasize the need for plasma CsA trough concentrations of 200 ng/ml for PRCA, avoiding the resulting side effects such as liver and kidney damage in elderly patients. Our results show that reduced-dose CsA is safe in the treatment of PRCA in the elderly population, with no significant liver or kidney impairment and well tolerated by patients with hypertension and type II diabetes, and can be considered as the preferred regimen for elderly patients with PRCA; we also appreciate that the addition of Chinese herbal medicine rather than glucocorticoids as adjuvant therapy reduces many adverse effects associated with long-term glucocorticoid use, such as bone The combination of reduced doses of CsA and Chinese herbal medicine can achieve ideal clinical efficacy and reduce side effects; it also improves patient compliance and enables smooth implementation of the treatment plan. Also, CsA is a functional immunosuppressant for T-lymphocytes, which requires maintenance doses and concentrations, and most patients will eventually relapse once the drug is discontinued. In this study, only one patient successfully discontinued CsA after 1 year of treatment and is currently on maintenance treatment with Chinese herbal medicine, with normal HGB. 5 patients relapsed due to self-medication discontinuation or reduction, and the treatment was effective again after the original regimen of CsA. The remaining cases were treated with maintenance doses of CsA plus Chinese herbal medicine, and the blood picture was maintained stable. According to our study, CsA was maintained at 75 mg to 100 mg/day, plasma CsA concentration was maintained at 50 ng/ml to 60 ng/ml, and HGB could be maintained in the normal range. The number of cases in this study was small, and the number of cases needs to be expanded to further evaluate the effectiveness and safety of reduced-dose CSA in elderly PRCA.