European protocol: low dose may be better? Due to concerns about the long-term toxic side effects of CYC, foreign scholars have proposed a series of US NIH modified protocols, such as reducing the duration and dose of CYC and replacing CYC with relatively safe cytotoxic drugs (e.g. azathioprine, mycophenolate) for long-term maintenance therapy, the most famous of which is the European-Belgian The Euro-Lupus Nephritis Trial (ELNT; referred to as the European protocol) organized by Prof. Houssiau. From September 1996 to September 2000, a total of 90 patients with proliferative LN were enrolled in the trial, and the patients were randomly divided into two groups, one receiving One group received intravenous treatment with high-dose CYC (starting dose of 0.5 g/m²to 1.0 g/m², with monthly shocks for the first six months and every three months for the next six months, for a total of eight shocks. If no significant decrease in peripheral blood leukocytes was seen after 2 weeks of intravenous CYC shock, the next shock dose could be increased by 250 mg, otherwise the original dose was maintained, and the maximum dose did not exceed 1500 mg/dose), and the other group received intravenous treatment with low-dose CYC (dose of 500 mg/dose every two weeks for a total of six times). Patients in both groups were followed by AZA treatment (2 mg/kg/d) two weeks after the last CYC shock, applied for at least 2 years. All patients received methylprednisolone shock therapy (750 mg/d) once daily for the first three days of treatment, followed by a change to oral glucocorticoids at a starting dose equivalent to 0.5 mg/kg/d of prednisone, which was reduced by 2.5 mg every 2 weeks after 4 weeks, with a minimum maintenance dose of 5 mg/d to 7.5 mg/d, maintained for at least 30 months.August 2002, The Arthritis & Rheumatism published the results of this clinical trial with a follow-up (median) of 41 months and found that: the incidence of clinical futility was 20% and 16% in the high-dose CYC group and low-dose CYC group, respectively, with 54% and 71% of renal remissions and 29% and 27% of renal relapses, with no statistically significant differences between the groups; at one year follow-up, compared with Serum creatinine, albumin, complement C3, 24-hour urine protein, and disease activity scores were significantly improved in both groups compared to pre-treatment. The preliminary findings of this study concluded that the clinical efficacy of low-dose CYC (cumulative dose of 3 g) followed by maintenance remission with AZA in patients with proliferative LN was generally comparable to that of the high-dose CYC regimen. The investigators offered possible explanations for the above findings in terms of the enrollment population. Compared with the population enrolled in the NIH study, the European regimen was milder (only 22% had abnormal renal function and 28% presented with nephrotic syndrome), and the majority of patients were white, so a low-dose short course of CYC was effective in controlling the disease and inhibiting LN recurrence. In December 2004, Arthritis & Rheumatism published the results of this clinical trial with a median follow-up of 73 months. 18 of the 85 patients (8 in the low-dose CYC group and 10 in the high-dose group) developed permanent disease. A total of 18 patients (8 in the low-dose CYC group and 10 in the high-dose group) developed permanent kidney damage and were classified as having a poor long-term renal prognosis. Among them, there were 4 cases of ESRD (1 in the low-dose CYC group and 3 in the high-dose group), 8 cases of doubled serum creatinine values (7 in the low-dose CYC group and 1 in the high-dose group), and 6 cases of renal impairment with non-doubled serum creatinine values (0 in the low-dose CYC group and 6 in the high-dose group). The overall incidence of poor prognosis was 21% (18/85), 20% (8/41) in the low-dose group and 23% (10/44) in the high-dose group. data from the trial regarding the 10-year follow-up of patients on the European regimen were published again in the January 2010 issue of Ann Rheum Dis (Ann Rheum Dis 2010;69;61-64). The results confirmed that there were no significant differences in death (11% vs 4%), doubling of persistent serum creatinine values (14% vs 11%), or incidence of ESRD (5% vs 9%) between the low-dose CYC group and the high-dose CYC group. Mean creatinine values, 24-hour urine protein levels, and impairment scores were also essentially comparable between the two groups at the final follow-up. The final trial data from the European regimen suggest that low-dose intravenous CYC + AZA maintenance remission (European lupus regimen) can be used as an alternative treatment option to the classic high-dose CYC + glucocorticoid regimen (NIH regimen) with comparable long-term efficacy to the US NIH regimen. In summary, although the US NIH regimen can achieve clinical remission in the majority of LN patients (generally 50%-80%), there are many LN patients who are not sensitive to this regimen and who are prone to relapse during long-term maintenance therapy. In addition, the long-term application of CYC has many toxic side effects, which to some extent limits the application of this regimen in the broader LN population.