Leflunomide Plus Low-dose Prednisone in Patients with Progressive IgA Nephropathy: A Multicenter, Prospective, Randomized, Open-labelled and Controlled Trial

Leflunomide Plus Low-dose Prednisone in Patients with Progressive IgA Nephropathy: A Multicenter, Prospective, Randomized, Open-labelled and Controlled Trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research article Leflunomide Plus Low-dose Prednisone in Patients with Progressive IgA Nephropathy: A Multicenter, Prospective, Randomized, Open-labelled and Controlled Trial Zhaohui Ni, Zhen Zhang, Zanzhe Yu, Fuming Lu, Changlin Mei, Xiaoqiang Ding, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-99015/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 Jan, 2021 Read the published version in Renal Failure → Version 1 posted You are reading this latest preprint version Abstract Background: This trial was designed to assess the efficacy and safety of Leflunomide (LEF) plus low-dose prednisone for the treatment of progressive IgA nephropathy (IgAN). Methods: We did a prospective, randomized, open-labelled, multicenter, controlled trial, comprised of 3-month run-in, 12-month treatment and 12-month follow-up phases. After 3-month run-in phase, patients with biopsy-confirmed IgAN at a risk of progression were randomly allocated to LEF plus low-dose prednisone (LEF group) or conventionally accepted-dose prednisone (prednisone group). Our primary outcome was 24h urine protein excretion(UPE) and secondary outcomes were serum albumin(sALB), serum creatinine(Scr), and eGFR. Safety was evaluated in all patients who received the trial medications. Results: 108 patients (59 in LEF group, 49 in prednisone group) were enrolled and finished their treatment and follow-up periods. The difference in baseline data between the two groups was comparable. Compared with baseline, both groups showed significant decrease in 24h UPE(p<0.01) and increase in sALB (p<0.01), with stable Scr and eGFR throughout the 12-month treatment period. What’s more, these effects sustained through the 12-month follow-up period. However, there was no difference in 24h UPE, sALB, Scr and eGFR between the two groups (P>0.05). At 12 months, difference of overall response rate, relapsing rate and incidence of adverse events between the two groups was not significant. Conclusions: The efficacy and safety of LEF plus low-dose prednisone and conventionally accepted-dose prednisone in treatment of progressive IgAN are comparable. Trial registration: The trial is registered at isrctn.org with the ISRCTN97636235 on July 28, 2006. Urology & Nephrology IgA nephropathy leflunomide prednisone Figures Figure 1 Figure 2 Background IgA nephropathy (IgAN) is the most common type of primary glomerular disease[ 1 ], accounting for about 40% of primary glomerular diseases in our country[ 2 ]. Patients with IgAN have a variety of clinical presentations, ranging from isolated hematuria to rapidly progressive kidney failure. Evidence shows that nearly 50% of IgAN is progressive and eventually develops into end-stage renal failure (ESRD) in 10–20 years[ 3 ]. Persistent proteinuria, hypertension, and reduced estimated glomerular filtration rate (eGFR) are major risk factor for IgAN progression to ESRD[ 4 ]. Thus, patients with progressive IgAN should be treated aggressively. Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) as first-line treatment for patients with IgAN with proteinuria of more than 1 g/day (recommendation level 1B)[ 5 ]. For patients with overt proteinuria of more than 1 g/day and eGFR > 50 mL/min/1·73 m², 6 months’ treatment with high-dose systemic corticosteroids is recommended (recommendation level 2C)[ 5 ]. However, high-dose systemic corticosteroids are associated with increase of adverse events such as serious infections, hypertension, osteoporosis, weight gain, and diabetes[ 6 ]. Accordingly, Therapeutic Evaluation of Steriods in IgA Nephropathy Global (TESTING) trial was forced to stop early after recruitment, with significantly higher risk of serious, fatal adverse events in the high-dose corticosteroid group[ 7 ]. Thus, the chosen dose of corticosteroids for treatment of IgAN is extremely important. IgAN is recognized as an autoimmune kidney, which is one of the rationales for the use of immunosuppression to IgAN treatment[ 8 ]. The evidence for immunosuppressive therapy in IgAN is still insufficient. The benefit of systemic immunosuppression in treating IgAN has been questioned in the STOP-IgAN trial, which showed no significant effect of using immunosuppression both in terms of change in eGFR after 3 years of follow-up or the development of ESRD in patients with IgAN and persistent proteinuria with protein excretion 0.75 g/day, despite supportive care including blockers of the renin-angiotensin system (RAS). Recently, it was showed that Mycophenolate mofetil plus prednisone could reduce adverse events in patients with IgAN, and the histopathologic lesions were taken into consideration in the study[ 9 , 10 ]. However, clinical and laboratory indicators, such as 24 h urine protein excretion(UPE), eGFR, serum albumin(sALB), serum creatinine(Scr), were not taken into consideration in this study, and as such, it is impossible to determine whether its conclusions apply to patients with overt proteinuria and reduced eGFR. Moreover, our previous single-center study showed that leflunomide(LEF) combined with low-dose corticosteroid could reduce proteinuria and severe adverse events during long-term follow-up[ 11 ]. Thus, large-scale, multi-center randomized controlled trial (RCT) is needed to further evaluate the efficacy and safety of LEF for treatment of patients with IgAN who are at risk of progression to ESRD. LEF is a new immunosuppressant and anti-inflammatory drugs, by blocking the de novo synthesis of pyrimidines which interfere with DNA synthesis; and inhibiting inflammatory cytokine mediated activation of Nuclear Factor κB and protein tyrosine phosphorylation. It is now widely applied in rheumatoid arthritis, systemic lupus erythematosus and organ transplant rejection, and achieves approval effects. However, the efficacy and safety of LEF in treatment of progressive IgAN is still unclear and large-scale, multi-center randomized controlled study of progressive IgAN is limited[ 12 , 13 ]. Hence, a prospective, multicenter, open, randomized, parallel controlled study was conducted to observe the clinical efficacy and safety of LEF plus low-dose prednisone in the treatment of progressive IgAN. Methods 1. Patients: Patients were recruited from 12 renal units in Shanghai, China. They were aged 18-65 with biopsy-confirmed primary IgAN in recent 3 months, and with any one of the following cases: 24-UPE>1.0g/day; eGFR<60ml/min/1.73m 2 (calculated by CKD-MDRD equation); and renal histological lesions defined as Lee’s IV, or glomerulus and/or segmental sclerosis ≥ 40%. Patients with anyone of the following conditions were excluded: (a) rapidly progressive IgAN (IgAN with rapid renal function loss, characterized histopathologically by necrotizing capillaritis or active crescent formation>50%); (b) secondary IgAN such as Henoch-Schonlein purpura nephritis, hepatitis-associated glomerulonephritis, and lupus nephritis, diabetic nephropathy, etc.; (c) receiving immunosuppressive and cytotoxic drugs for over 1 weeks or corticosteroid more than 20mg/day for more than 4 weeks within 6 months; (d) eGFR <30ml/min/1.73m 2 ; (e) malignancy, HIV infection, acute central nervous system diseases, serious gastrointestinal diseases; (f) pregnancy or lactation. This study was approved by local ethics committees and all patients provided written informed consent before enrollment. 2. Procedures: Before randomly allocation, eligible patients were enrolled into a 3-month run-in phase, during which, RAS blockade was optimised by adjusting ACEIs and ARBs to a maximum recommended dose or maximum tolerated dose (in keeping with established clinical practice), to a target blood pressure of less than 130/80 mmHg. At the end of run-in, patients according to the inclusion criteria were randomly allocated to LEF plus low-dose prednisone (LEF group) or conventionally accepted-dose prednisone group (prednisone group). All patients continued optimised ACEIs or ARBs treatment throughout the trial. Patients in LEF group received LEF 40mg/day for 3 days, after which the dose was reduced to 20 mg/day and administered for 12 months, combined with oral prednisone 0.5-0.8mg/kg/day for 8-12 weeks with a maximum daily dose of 40mg. Then prednisone was tapered by 5mg, 2.5mg to a maintenance dose of 10mg per day. Patients in prednisone group received oral prednisone 1mg/kg/day for 8-12 weeks, which was tapered by 5mg, 2.5mg to a maintenance dose of 10mg per day. The maximum daily dose of prednisone was 60mg. The followed-up is 12 months. During the treatment, when the disease relapsed, it is allowed to maintain the prednisone unchanged for 4 weeks, or increase to the dose before relapsing for 2-4 weeks and, if necessary, a temporary methylprednisolone was allowed (<1g). During the follow-up period, the patients were retreated with the original regimen when the disease relapsed. 3. Allocation Patients will be randomly assigned to either the LEF group or the prednisone group at a 1:1 allocation ratio, using a computer generated randomisation schedule of permuted blocks of random sizes ranging from 4 to 10. The creation of the randomisation sequentially numbered will be performed by persons not else involved in the trial. The final enrolment and subsequent allocation of participants will be conducted by investigators not taking part in any outcome assessment, who will be blinded to the randomisation sequence at all times during the intervention period. Outcome assessors will not take part in any of the processes related to allocation. 4. Outcome Patients were randomized to LEF group or prednisone group using a computer algorithm method of permuted blocks. Demographics and baseline characteristics were collected at month 0. When recording clinical and laboratory characteristics at month 3, month 6, month 9, month12, month 24, the medications and adverse events were recorded at the same time. Standardised questionnaires at each visit were used to ask patients about the presence of specific LEF-related and corticosteroid-related adverse events. The primary outcome is 24h UPE and secondary outcomes were sALB, Scr, and eGFR. Complete remission (CR) was defined as 24h UPE<0.3g/d, with stable Scr (changes in Scr £15% of baseline values) and sALB ≥ 35g/L; partial remission (PR) was defined as 24h UPE decreased by 50% of the baseline value and ≥ 0.3g/d, with stable Scr and sALB ≥ 30g/L; No response (NR) was defined as a 24h UPE > 3.5 g/d, or 1.0 g/d or an increase of > 50% from the lowest level of proteinuria after remission[14, 15]. 5. Statistical analysis Normal distribution variables were expressed by means ± SD and compared by t-test or ANOVA. Non-parametric variables were represented as median with range, and the either the Mann-Whitney U test or the Kruskal-Wallis test was used. The chi-square test was employed for the categorical variables. Statistical analyses were performed using SPSS 13.0, with p-values <0.05 considered statistically significant. Results 1. Baseline characteristics A total of 108 patients were enrolled and eligible for randomization in this study during June 1, 2004 to June 30, 2010 (Fig. 1 ). There were 59 cases in LEF group, including 32 males and 27 females, aged 35.7 ± 11.2 years, and 49 cases in prednisone group, including 23 males and 26 females, with an age of 35.5 ± 11.2 years. The baseline characteristics between the two groups were comparable (see Table 1 ). Table 1 Baseline characteristics Characteristics LEF group (n = 59) Prednisone group (n = 49) P value Male(n) 32(54%) 23(47%) 0.066 Female(n) 27(46%) 26(53%) Age(years) 35.7 ± 11.2 35.5 ± 11.2 0.185 Duration of disease (months) 19.4(4.1–46.8) 10.6(6.2–40.1) 0.184 UPE (g/24 h) 1.8(1.3–3.5) 1.9(1.2–2.9) 0.420 sALB(g/L) 37.7 ± 5.0 37.2 ± 5.1 0.609 BUN (mmol/L) 6.6 ± 2.4 6.0 ± 1.9 0.159 Scr (µmol/L) 112.3 ± 56.8 96.4 ± 38.6 0.099 eGFR(ml/m) 66.9 ± 40.6 64.6 ± 31.6 0.747 Hb(g/L) 132.0 ± 16.6 131.1 ± 19.6 0.797 ALT(IU/L) 20.3 ± 5.8 21.5 ± 11.0 0.470 AST(IU/L) 20.7 ± 11.4 23.6 ± 20.3 0.352 Note: Values for categorical variables are given as count; values for continuous variables, as mean ± standard deviation or median [IQR]. Abbreviations: UPE: urine protein excretion; sALB: Serum albumin; BUN: blood urea nitrogen; Scr: serum creatinine, eGFR: estimated glomerular filtration rate; Hb: hemoglobin; ALT: alanine transaminase; AST: aspartate aminotransferase; LEF: leflunomide. 2. Efficacy 24 h UPE when patients with IgAN enrolled were 1.8(1.3–3.5) and 1.9(1.2–2.9) in LEF group and prednisone group, respectively. After 12 months treatment, 24 h UPE were significantly lower ([0.6(0.3–1.4) vs 1.8(1.3–3.5), p5<0.01] in LEF group, [0.6(0.3-1.0) vs 1.9(1.2–2.9), p<0.01] in prednisone group) in both groups versus baseline value. At month 3, 6, 9 months, 24 h UPE were also significantly lower in both groups compared to baseline data (Table 2 ). What’s more, the effect sustained during the 12-months follow-up period (Table 2 ). At 12 months, sALB was significantly higher ([44.7 ± 6.4 vs 37.7 ± 5.0, p<0.01] in LEF group, [43.3 ± 3.6 vs 37.2 ± 5.1, p<0.01] in prednisone group) in both groups versus baseline data. At month 3, 6, 9 months, sALB were also much higher in both groups compared to baseline (Table 2 ), and the effect sustained during the 12-months follow-up (Table 2 ). Scr and eGFR did not change significantly throughout the treatment and follow-up periods (Table 2 ), indicating renal function was stable in both groups through the treatment period. Difference of the 24 h UPE, sALB, Scr and eGFR between the two groups was not significant at each visit (p>0.05). It suggested that LEF plus low-dose prednisone and conventionally accepted-dose prednisone had the same effect on treatment of progressive IgAN. Table 2 Outcomes of Treatment Characteristics LEF group Prednisone group P value UPE(g/24h) Baseline 1.8(1.3–3.5) 1.9(1.2–2.9) 0.318 Month 3 0.8(0.4–1.9)** 0.9(0.3–1.3)** Month 6 0.8(0.3–1.9)** 0.8(0.2–1.6)** Month 9 0.6(0.3–1.8)** 0.7(0.2-1.0)** Month 12 0.6(0.3–1.4)** 0.6(0.3-1.0)** Month 18 0.4(0.1–0.9)** 0.5(0.2–1.1)** Month 24 0.5(0.1–1.1)** 0.5(0.3-1.0)** sALB(g/L) Baseline 37.7 ± 5.0 37.2 ± 5.1 0.073 Month 3 40.4 ± 3.8** 40.2 ± 3.4** Month 6 41.5 ± 4.6** 42.9 ± 4.4** Month 9 43.3 ± 4.2** 42.6 ± 4.0** Month 12 44.7 ± 6.4** 43.3 ± 3.6** Month 18 44.9 ± 2.8** 42.5 ± 5.2** Month 24 44.3 ± 3.0** 43.3 ± 3.8** Scr(umol/L) Baseline 112.3 ± 56.8 96.4 ± 38.6 0.689 Month 3 107.2 ± 39.4 97.9 ± 36.1 Month 6 106.5 ± 45.2 94.4 ± 32.4 Month 9 107.6 ± 36.4 92.3 ± 32.5 Month 12 111.4 ± 43.4 97.9 ± 42.6 Month 18 101.3 ± 34.0 98.6 ± 28.4 Month 24 108.3 ± 26.4 109 ± 65.6 eGFR(ml/min/1.73 m 2 ) Baseline 66.9 ± 40.6 64.6 ± 31.6 0.891 Month 3 73.4 ± 28.8 68.1 ± 26.4 Month 6 74.6 ± 29.8 73.6 ± 27.5 Month 9 70.3 ± 26 70.7 ± 23.2 Month 12 67.3 ± 26.7 72.8 ± 30.8 Month 18 71.5 ± 28.0 68.9 ± 30.0 Month 24 66.4 ± 18.7 63.9 ± 22.7 **P < 0.01 versus baseline value Abbreviations: UPE: urine protein excretion; sALB: Serum albumin; Scr: serum creatinine, eGFR: estimated glomerular filtration rate; LEF: leflunomide. At 12 months, 12 patents had complete remission, 13 patents had partial remission in LEF group; and 15 patients had complete remission, 10 patients had partial remission in prednisone group. Overall response rates were 69%(36 of 52 patients) in the LEF group and 67%(30 of 45 patients) in the prednisone group. There was no significant difference between the two groups (P = 0.959) (Table 3 ). Table 3 The complete, partial and overall response between LEF group and prednisone group LEF group Prednisone group p value n/N c Rate n/N c Rate Month 12 CR 17/52 33% 18/45 40% 0.592 PR 19/52 37% 12/45 27% 0.411 Overall response 36/52 69% 30/45 67% 0.959 c n/N: event number/total number Abbreviations: CR: complete remission; PR: partial remission At 24 months, relapse rates were 3%(2 of 59 patients) in the LEF group and 10%(5 of 49 patients) in the prednisone group. There was no significant difference between the two groups (P = 0.299) (Table 4 ). Table 4 The relapsing rate between LEF group and prednisone group LEF group Prednisone group p value n/N c Rate n/N c Rate Month 24 Relapsing 2/59 3% 5/49 10% 0.299 c n/N: event number/total number. Baseline daily oral prednisone dose in LEF group was much lower than that in prednisone group (40.4 ± 5.5 vs 55.7 ± 9.5, p < 0.001). At 3 and 6 months, daily oral prednisone doses in LEF group were 30.4 ± 9.2 and 15.9 ± 8.3, respectively, and they ([30.4 ± 9.2 vs 43.5 ± 9.2, P < 0.001]; [15.9 ± 8.3 vs 21.9 ± 7.8, P < 0.001]) were significantly lower than that in prednisone group (Table 6 , Fig. 2 ). Further, the total amount of prednisone in LEF group was lower than that in prednisone group (21.5 ± 13.41 vs 28.83 ± 19.95, p = 0.031) (Table 6 ). 3. Adverse events At the early induction stage, adverse events occurred. Incidence of adverse events and severe adverse events such as respiratory and pulmonary infection and sepsis were comparable between the two groups. (details on adverse event reporting were in the Table 5 ). Table 5 Adverse events during the treatment period LEE group(n = 59) (n, %) Prednisone group(n = 49) (n, %) P value Respiratory and pulmonary infection 4(7) 9(18) 0.122 Urinary tract infection 0(0) 1(2) 0.926 Diarrhea 2(3) 0(0) 0.559 Slightly elevated liver enzyme 4(7) 4(8) 0.924 Rash 1(2) 4(8) 0.257 Elevated blood pressure 1(2) 1(2) 0.559 Fever 2(3) 1(2) 0.870 Sepsis 0(0) 1(2) 0.926 Itching 2(3) 0(0) 0.559 Nausea 1(2) 0(0) 0.926 Agrypnia 1(2) 0(0) 0.926 Paraesthesia 1(2) 0(0) 0.926 Insanity 1(2) 0(0) 0.926 Lipsotrichia 1(2) 0(0) 0.926 Herpes zoster 0(0) 2(4) 0.396 Toothache 0(0) 1(2) 0.926 Fatigue 0(0) 1(2) 0.926 Menstrual disorder 0(0) 1(2) 0.926 Insomnia 0(0) 1(2) 0.926 Obesity or weight gain 0(0) 0(0) 1.000 Impaired glucose tolerance or diabetes 0(0) 0(0) 1.000 Cataract 0(0) 0(0) 1.000 Acne 0(0) 0(0) 1.000 Avascular necrosis of hips 0(0) 0(0) 1.000 Total(n) 21(36) 27(55) 0.066 Table 6 The daily prednisone dose in LEF group and prednisone group Treatment time LEF group (mg/day) Prednisone group (mg/day) P value Baseline 40.4 ± 5.5 55.7 ± 9.5 < 0.001 Month 3 30.4 ± 9.2 43.5 ± 9.2 < 0.001 Month 6 15.9 ± 8.3 21.9 ± 7.8 1 g/day) and reduced eGFR, are at high risk of progression to ESRD. To our knowledge, this study was the first multicenter RCT study to compare the efficacy and safety of LEF plus prednisone to conventionally accepted-dose prednisone in patients with progressive IgAN. We observed that LEF plus low-dose prednisone is as effective as conventionally accepted-dose prednisone for treatment of progressive IgAN, with decreased 24 h UPE, increased sALB, stable renal function. Upon completion of the 12-month treatment, after cessation of trial medications, the mean percentage reduction in 24 h UPE was sustained in both groups during the 12-month follow-up period, which was consistent with changes in sALB, Scr and eGFR. In addition, patients treated with LEF plus low-dose prednisone have comparable overall response rate, relapsing rate and incidence of adverse events, as compared with that in conventionally accepted-dose prednisone group. Our single-center study in investigation of the efficacy and safety of LEF plus low-dose prednisone, showed that a greater reduction of proteinuria during long-term follow-up and fewer severe adverse events were observed in LEF group[ 11 ]. In another single-center study, Buardle FW et al. also confirmed corticosteroids or combined with immunosuppressive therapy can reduce proteinuria and loss of renal function in patients with progressive IgAN[ 16 ]. Corresponding to these findings, the present study demonstrated that LEF plus low-dose prednisone has similar effect in reduction of 24 h UPE versus conventionally accepted-dose prednisone. In addition, the reduction of 24 h UPE sustains throughout the treatment and follow-up periods. Evidence showed that a reduction in proteinuria is associated with a reduced risk of progression to ESRD in patients with IgAN[ 17 ]. Le W et al. showed that the rate of decline of renal function was associated with higher levels of time-averaged proteinuria, which was the most important risk factor of progression to renal failure in Chinese adult patients with IgAN[ 18 ]. A meta-analysis of trials for IgAN suggested that proteinuria reduction was significantly associated with outcomes in ESRD, with each 30% reduction in proteinuria, the risk of ESRD(non-significantly) decreased comparably[ 19 , 20 ]. Recently, Lou et al. compared IgAN patients treated with LEF with those treated only with ACEI, and found that the overall efficacy of the two groups was comparable[ 21 ]. At the time of biopsy, hypoproteinemia and eGFR < 60 mL/min/1.73 m2 were the independent risk factors for progression to ESRD in patients with IgAN[ 18 ]. We previously reported that the time-averaged serum albumin might serve as a marker of the long-term renal prognosis of IgAN patients who have achieved remission[ 22 ]. The present study showed that after treatment with LEF plus low-dose prednisone or conventionally accepted-dose prednisone, sALB significantly increase in both group, which is in accordance with our previous findings[ 22 ]. What’s more, the Scr and eGFR and changes in Scr and eGFR remain stable through the treatment and follow-up periods between the two group, indicating the renal function is better preserved during the treatment and follow-up periods. The stabilization in Scr and eGFR illustrates that this patient population is at low risk of disease progression, the interventions in this trial for patients with progressive IgAN and overt proteinuria are at least sufficient[ 23 – 25 ]. Remission rate is similar between the LEF and prednisone groups. Consistent with our findings, Hou JH, et al. found that mycophenolate mofetil plus prednisone versus full-dose prednisone did not differ in CR rate in patients with IgAN with active proliferative lesions[ 10 ]. High-dose systemic corticosteroids and immunosuppressive treatments cause considerable side effects[ 26 ]. Increase of adverse events such as serious infections, hypertension, osteoporosis, weight gain, and diabetes are associated with high-dose systemic corticosteroids[ 6 , 7 ]. Elevated liver enzymes, digestive symptoms, and alopecia are related to LEF[ 9 , 27 ]. In the present study, the total amount of prednisone was lower in the LEF group than that in the prednisone group (Table 6 ). Further, the LEF dosage in our study was also less than that in the previously reported LEF monotherapy trials in patients with IgAN[ 21 ]. In addition to effect of the LEF regimen, the lower dosage of immunosuppression may minimize drug adverse effects. Our results suggested that LEF plus low-dose prednisone is probably an alternative option for treatment of progressive IgAN, especially in those patients who was not tolerated to high-dose prednisone. Certain limitations in this trial were relatively small sample size, short follow-up time and ethnic difference, with non-Asian patients with progressive IgAN. Conclusion In conclusion, this study suggests that LEF plus low-dose prednisone did not differ in reducing proteinuria, increasing sALB and stabilising Scr and eGFR, and had comparable adverse events in patients with progressive IgAN. The observed effect was additive to optimised ACEIs or ARBs and supported LEF plus low-dose prednisone might be an effective therapy in patients with IgAN at high risk of progression. Abbreviations IgAN: IgA nephropathy; LEF: Leflunomide; UPE: 24h urine protein excretion; sALB: serum albumin; Scr: serum creatinine; eGFR: estimated glomerular filtration rate; ESRD: end-stage renal failure; ACEIs: angiotensin-converting enzyme inhibitors; ARBs: angiotensin receptor blockers; RAS: renin-angiotensin system; RCT: randomized controlled trial; CR: Complete remission; PR: partial remission; NR: No response. Declarations Acknowledgements Drugs were provided by Cinkate Pharmaceutical Company. Other members participated in this clinical trial: nephrologists from Huashan Hospital; Shanghai Changzheng Hospital; Zhongshan Hospital; Shanghai General Hospital; Shanghai Ninth People's Hospital; Xinhua Hospital; Huadong Hospital; Shuguang Hospital; Longhua Hospital. Author Contributions ZN designed and supervised the experiment. ZN, FL, CM, XD, WY, WZ, GJ, MS, LH, and YD participated in patients enrollment and data collection. ZZ, ZY analyzed the data and wrote the paper. ZN and HP modified the paper. All authors read and approved the final manuscript. Funding There was no funding to this work. Availability of data and materials The datasets used and/or analyzed during this study are available from the corresponding author on reasonable request. Ethics Approval and Consent to Participate This study was approved by the ethical review board of Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University. The work presented in that manuscript complies with guidelines for human studies and all patients provided written informed consent before enrollment. Consent for publication Not applicable. Competing Interests The authors of this manuscript have no conflicts of interest to disclose. References Donadio JV GJ: IgA nephropathy. N Engl J Med 2002, 347 :738-748. Li LS, Liu ZH: Epidemiologic data of renal diseases from a single unit in China: analysis based on 13,519 renal biopsies . Kidney Int 2004, 66 (3):920-923. 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Rauen T, Eitner F, Fitzner C, Sommerer C, Zeier M, Otte B, Panzer U, Peters H, Benck U, Mertens PR et al : Intensive Supportive Care plus Immunosuppression in IgA Nephropathy . N Engl J Med 2015, 373 (23):2225-2236. Hou JH, Le WB, Chen N, Wang WM, Liu ZS, Liu D, Chen JH, Tian J, Fu P, Hu ZX et al : Mycophenolate Mofetil Combined With Prednisone Versus Full-Dose Prednisone in IgA Nephropathy With Active Proliferative Lesions: A Randomized Controlled Trial . Am J Kidney Dis 2017, 69 (6):788-795. Min L WQ, Cao L, Zhou W, Yuan J, Zhang M, Che X, Mou S, Fang W, Gu L, Zhu M, Wang L, Yu Z, Qian J, Ni Z: Comparison of combined leflunomide and low-dose corticosteroid therapy with full-dose corticosteroid monotherapy for progressive IgA nephropathy. Oncotarget 2017, 8 :48375-48384. . Saag KG, Teng GG, Patkar NM, Anuntiyo J, Finney C, Curtis JR, Paulus HE, Mudano A, Pisu M, Elkins-Melton M et al : American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis . Arthritis Rheum 2008, 59 (6):762-784. Wang HY CT, Hou FF, Ni ZH, Chen XM, Lu FM, Xu FF, Yu XQ, Zhang FS, Zhao XZ, Zhao MH, Wang GB, Qian JQ, Cai GY, Zhu TY, Wang YH, Jiang ZP, Li YN, Mei CL, Zou WZ: Induction treatment of proliferative lupus nephritis with leflunomide combined with prednisone-a prospective multi-centre observational study. Lupus 2008, 17 :638-644. Kim JK, Kim JH, Lee SC, Kang EW, Chang TI, Moon SJ, Yoon SY, Yoo TH, Kang SW, Choi KH et al : Clinical features and outcomes of IgA nephropathy with nephrotic syndrome . Clin J Am Soc Nephrol 2012, 7 (3):427-436. Moon SJ, Park HS, Kwok SK, Ju J, Choi BS, Park KS, Min JK, Kim HY, Park SH: Predictors of renal relapse in Korean patients with lupus nephritis who achieved remission six months following induction therapy . Lupus 2013, 22 (5):527-537. Ballardie FW RI: Controlled Prospective Trial of Prednisolone and Cytotoxics in Progressive IgA Nephropathy. J Am Soe Nephrol 2002, 13 :142–148. Reich HN, Troyanov S, Scholey JW, Cattran DC, Toronto Glomerulonephritis R: Remission of proteinuria improves prognosis in IgA nephropathy . J Am Soc Nephrol 2007, 18 (12):3177-3183. Le W, Liang S, Hu Y, Deng K, Bao H, Zeng C, Liu Z: Long-term renal survival and related risk factors in patients with IgA nephropathy: results from a cohort of 1155 cases in a Chinese adult population . Nephrol Dial Transplant 2012, 27 (4):1479-1485. Inker LA, Mondal H, Greene T, Masaschi T, Locatelli F, Schena FP, Katafuchi R, Appel GB, Maes BD, Li PK et al : Early Change in Urine Protein as a Surrogate End Point in Studies of IgA Nephropathy: An Individual-Patient Meta-analysis . Am J Kidney Dis 2016, 68 (3):392-401. Lambers Heerspink HJ, Tighiouart H, Sang Y, Ballew S, Mondal H, Matsushita K, Coresh J, Levey AS, Inker LA: GFR decline and subsequent risk of established kidney outcomes: a meta-analysis of 37 randomized controlled trials . Am J Kidney Dis 2014, 64 (6):860-866. Lou T, Wang C, Chen Z, Shi C, Tang H, Liu X, Yin P, Yu X: Randomised controlled trial of leflunomide in the treatment of immunoglobulin A nephropathy . Nephrology (Carlton) 2006, 11 (2):113-116. Ni Z YY, Wang Q, Cao L, Che X, Zhang M, Xie Y, Qi C, Mou S: Time-averaged albumin predicts the long-term prognosis of IgA nephropathy patients who achieved remission. J Transl Med 2014, 12 :194. Rasche FM, Keller F, Rasche WG, Schiekofer S, Boldt A, Sack U, Fahnert J: Why, when and how should immunosuppressive therapy considered in patients with immunoglobulin A nephropathy? Clin Exp Immunol 2016, 186 (2):115-133. Rasche FM, Keller F, Rasche WG, Schiekofer S, Kahn T, Fahnert J: Sequential therapy with cyclophosphamide and mycophenolic acid in patients with progressive immunoglobulin A nephropathy: a long-term follow-up . Clin Exp Immunol 2016, 183 (2):307-316. Tesar V, Troyanov S, Bellur S, Verhave JC, Cook HT, Feehally J, Roberts IS, Cattran D, Coppo R, Group VsotE-EIW: Corticosteroids in IgA Nephropathy: A Retrospective Analysis from the VALIGA Study . J Am Soc Nephrol 2015, 26 (9):2248-2258. Floege J, Eitner F: Current therapy for IgA nephropathy . J Am Soc Nephrol 2011, 22 (10):1785-1794. Liu Y, Xiao J, Shi X, Hao G, Chen Q, Zhou J, Wei X: Immunosuppressive agents versus steroids in the treatment of IgA nephropathy-induced proteinuria: A meta-analysis . Exp Ther Med 2016, 11 (1):49-56. Supplementary Files CONSORT2010Checklist.doc Cite Share Download PDF Status: Published Journal Publication published 01 Jan, 2021 Read the published version in Renal Failure → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-99015","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research article","associatedPublications":[],"authors":[{"id":4054375,"identity":"702e237e-4bf8-4004-95d1-23d8c843d506","order_by":0,"name":"Zhaohui Ni","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2UlEQVRIiWNgGAWjYDACZgY2IHkARLIxfDCwkSNNC+OMgjRjYuyBaAExmHk+HE4kqN6cnf3Zgx8VdxL7GNifPbYxYE5gYD98dAM+LZbNDOmGPWeeJbYx8Jgb5xiw5THwpKXdwKfF4DDDMQnetsMgLWzSOQY8xQwSPGYEtDC2Sf4Fa2F/Jm1hIJHYQFgLM5s0xBYGM2kGAwNitLCxScucOWwMdJiZZI9BgjEbQb+cP/5M8k3FYdn5DezPJH78+S/Hz374GF4tCCD/AEKzEad8FIyCUTAKRgE+AADGxEMcHQtoPQAAAABJRU5ErkJggg==","orcid":"","institution":"Ren Ji Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Zhaohui","middleName":"","lastName":"Ni","suffix":""},{"id":4054376,"identity":"3f481a56-b3eb-4d4a-a8bf-69de8ef71e52","order_by":1,"name":"Zhen Zhang","email":"","orcid":"","institution":"Ren Ji 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16:08:34","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-99015/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-99015/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1080/0886022X.2021.1963775","type":"published","date":"2021-01-01T08:06:12+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":3294369,"identity":"1036630c-890e-4258-8379-d3a92c4401b4","added_by":"auto","created_at":"2020-10-30 14:53:25","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":65163,"visible":true,"origin":"","legend":"Patient enrollment and follow-up.\nAbbreviations: LEF: leflunomide.","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-99015/v1/4ca48d6870082d8bb8697e06.jpg"},{"id":3294370,"identity":"0319faea-79e7-4de4-88b1-55329b40870c","added_by":"auto","created_at":"2020-10-30 14:53:25","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":100596,"visible":true,"origin":"","legend":"The dosage of prednisone in LEF group was much lower than that in prednisone group\n***P\u003c0.001 versus prednisone group","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-99015/v1/113e35750fdad2e33832bbfe.jpg"},{"id":13608015,"identity":"d28a181b-882c-4fc9-811a-bf7527815353","added_by":"auto","created_at":"2021-09-17 06:14:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1212152,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-99015/v1/c2c1d154-6253-4544-aaf2-320c20651f02.pdf"},{"id":3294371,"identity":"284b6b62-12a6-42f0-b02d-f1cfefeae66c","added_by":"auto","created_at":"2020-10-30 14:53:25","extension":"doc","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":222208,"visible":true,"origin":"","legend":"","description":"","filename":"CONSORT2010Checklist.doc","url":"https://assets-eu.researchsquare.com/files/rs-99015/v1/54b247caa01d0fed63aaeb76.doc"}],"financialInterests":"","formattedTitle":"\u003cp\u003eLeflunomide Plus Low-dose Prednisone in Patients with Progressive IgA Nephropathy: A Multicenter, Prospective, Randomized, Open-labelled and Controlled Trial\u003c/p\u003e","fulltext":[{"header":"Background","content":" \u003cp\u003eIgA nephropathy (IgAN) is the most common type of primary glomerular disease[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], accounting for about 40% of primary glomerular diseases in our country[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Patients with IgAN have a variety of clinical presentations, ranging from isolated hematuria to rapidly progressive kidney failure. Evidence shows that nearly 50% of IgAN is progressive and eventually develops into end-stage renal failure (ESRD) in 10\u0026ndash;20 years[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Persistent proteinuria, hypertension, and reduced estimated glomerular filtration rate (eGFR) are major risk factor for IgAN progression to ESRD[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Thus, patients with progressive IgAN should be treated aggressively.\u003c/p\u003e \u003cp\u003eKidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) as first-line treatment for patients with IgAN with proteinuria of more than 1\u0026nbsp;g/day (recommendation level 1B)[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. For patients with overt proteinuria of more than 1\u0026nbsp;g/day and eGFR\u0026thinsp;\u0026gt;\u0026thinsp;50\u0026nbsp;mL/min/1\u0026middot;73 m\u0026sup2;, 6 months\u0026rsquo; treatment with high-dose systemic corticosteroids is recommended (recommendation level 2C)[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. However, high-dose systemic corticosteroids are associated with increase of adverse events such as serious infections, hypertension, osteoporosis, weight gain, and diabetes[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Accordingly, Therapeutic Evaluation of Steriods in IgA Nephropathy Global (TESTING) trial was forced to stop early after recruitment, with significantly higher risk of serious, fatal adverse events in the high-dose corticosteroid group[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Thus, the chosen dose of corticosteroids for treatment of IgAN is extremely important.\u003c/p\u003e \u003cp\u003eIgAN is recognized as an autoimmune kidney, which is one of the rationales for the use of immunosuppression to IgAN treatment[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The evidence for immunosuppressive therapy in IgAN is still insufficient. The benefit of systemic immunosuppression in treating IgAN has been questioned in the STOP-IgAN trial, which showed no significant effect of using immunosuppression both in terms of change in eGFR after 3\u0026nbsp;years of follow-up or the development of ESRD in patients with IgAN and persistent proteinuria with protein excretion 0.75\u0026nbsp;g/day, despite supportive care including blockers of the renin-angiotensin system (RAS). Recently, it was showed that Mycophenolate mofetil plus prednisone could reduce adverse events in patients with IgAN, and the histopathologic lesions were taken into consideration in the study[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. However, clinical and laboratory indicators, such as 24\u0026nbsp;h urine protein excretion(UPE), eGFR, serum albumin(sALB), serum creatinine(Scr), were not taken into consideration in this study, and as such, it is impossible to determine whether its conclusions apply to patients with overt proteinuria and reduced eGFR. Moreover, our previous single-center study showed that leflunomide(LEF) combined with low-dose corticosteroid could reduce proteinuria and severe adverse events during long-term follow-up[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Thus, large-scale, multi-center randomized controlled trial (RCT) is needed to further evaluate the efficacy and safety of LEF for treatment of patients with IgAN who are at risk of progression to ESRD.\u003c/p\u003e \u003cp\u003eLEF is a new immunosuppressant and anti-inflammatory drugs, by blocking the de novo synthesis of pyrimidines which interfere with DNA synthesis; and inhibiting inflammatory cytokine mediated activation of Nuclear Factor κB and protein tyrosine phosphorylation. It is now widely applied in rheumatoid arthritis, systemic lupus erythematosus and organ transplant rejection, and achieves approval effects. However, the efficacy and safety of LEF in treatment of progressive IgAN is still unclear and large-scale, multi-center randomized controlled study of progressive IgAN is limited[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHence, a prospective, multicenter, open, randomized, parallel controlled study was conducted to observe the clinical efficacy and safety of LEF plus low-dose prednisone in the treatment of progressive IgAN.\u003c/p\u003e "},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003e1. Patients:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients were recruited from 12 renal units in Shanghai, China. They were aged 18-65 with biopsy-confirmed primary IgAN in recent 3 months, and with any one of the following cases: 24-UPE\u0026gt;1.0g/day; eGFR\u0026lt;60ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e(calculated by CKD-MDRD equation); and renal histological lesions defined as Lee\u0026rsquo;s IV, or glomerulus and/or segmental sclerosis \u0026ge; 40%. Patients with anyone of the following conditions were excluded: (a) rapidly progressive IgAN (IgAN with rapid renal function loss, characterized histopathologically by necrotizing capillaritis or active crescent formation\u0026gt;50%); (b) secondary IgAN such as Henoch-Schonlein purpura nephritis, hepatitis-associated glomerulonephritis, and lupus nephritis, diabetic nephropathy, etc.; (c) \u0026nbsp;receiving immunosuppressive and cytotoxic drugs for over 1 weeks or corticosteroid more than 20mg/day for more than 4 weeks within 6 months; (d) eGFR \u0026lt;30ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e; (e) malignancy, HIV infection, acute central nervous system diseases, serious gastrointestinal diseases; (f) pregnancy or lactation. This study was approved by local ethics committees and all patients provided written informed consent before enrollment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2. Procedures:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBefore randomly allocation, eligible patients were enrolled into a 3-month run-in phase, during which, RAS blockade was optimised by adjusting ACEIs and ARBs to a maximum recommended dose or maximum tolerated dose (in keeping with established clinical practice), to a target blood pressure of less than 130/80 mmHg. At the end of run-in, patients according to the inclusion criteria were randomly allocated to LEF plus low-dose prednisone (LEF group) or conventionally accepted-dose prednisone group (prednisone group). All patients continued optimised ACEIs or ARBs treatment throughout the trial. Patients in LEF group received LEF 40mg/day for 3 days, after which the dose was reduced to 20 mg/day and administered for 12 months, combined with oral prednisone 0.5-0.8mg/kg/day for 8-12 weeks with a maximum daily dose of 40mg. Then prednisone was tapered by 5mg, 2.5mg to a maintenance dose of 10mg per day. Patients in prednisone group received oral prednisone 1mg/kg/day for 8-12 weeks, which was tapered by 5mg, 2.5mg to a maintenance dose of 10mg per day. The maximum daily dose of prednisone was 60mg. \u0026nbsp;The followed-up is 12 months. During the treatment, when the disease relapsed, it is allowed to maintain the prednisone unchanged for 4 weeks, or increase to the dose before relapsing for 2-4 weeks and, if necessary, a temporary methylprednisolone was allowed (\u0026lt;1g). During the follow-up period, the patients were retreated with the original regimen when the disease relapsed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3. Allocation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients will be randomly assigned to either the LEF group or the prednisone group at a 1:1 allocation ratio, using a computer generated randomisation schedule of permuted blocks of random sizes ranging from 4 to 10. The creation of the randomisation sequentially numbered will be performed by persons not else involved in the trial. The final enrolment and subsequent allocation of participants will be conducted by investigators not taking part in any outcome assessment, who will be blinded to the randomisation sequence at all times during the intervention period. Outcome assessors will not take part in any of the processes related to allocation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4.\u0026nbsp;Outcome\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients were randomized to LEF group or prednisone group using a computer algorithm method of permuted blocks. Demographics and baseline characteristics were collected at month 0. When recording clinical and laboratory characteristics at month 3, month 6, month 9, month12, month 24, the medications and adverse events were recorded at the same time. Standardised questionnaires at each visit were used to ask patients about the presence of specific LEF-related and corticosteroid-related adverse events.\u003c/p\u003e\n\u003cp\u003eThe primary outcome is 24h UPE and secondary outcomes were sALB, Scr, and eGFR.\u003c/p\u003e\n\u003cp\u003eComplete remission (CR) was defined as 24h UPE\u0026lt;0.3g/d, with stable Scr (changes in Scr \u0026pound;15% of baseline values) and sALB \u0026ge; 35g/L; partial remission (PR) was defined as 24h UPE decreased by 50% of the baseline value and\u0026nbsp;\u0026ge; 0.3g/d, with stable Scr and sALB\u0026nbsp;\u0026ge; 30g/L; No response (NR) was defined as a 24h UPE \u0026gt; 3.5 g/d, or \u0026lt; 50% reduction in baseline value, or Scr doubled. Relapse was defined as the reappearance of overt proteinuria, defined as \u0026gt; 1.0 g/d or an increase of \u0026gt; 50% from the lowest level of proteinuria after remission[14, 15].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e5. Statistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNormal distribution variables were expressed by means \u0026plusmn; SD and compared by t-test or ANOVA. Non-parametric variables were represented as median with range, and the either the Mann-Whitney U test or the Kruskal-Wallis test was used. The chi-square test was employed for the categorical variables. Statistical analyses were performed using SPSS 13.0, with p-values \u0026lt;0.05 considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n\u003cp\u003e\u003cstrong\u003e1. Baseline characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 108 patients were enrolled and eligible for randomization in this study during June 1,\u0026nbsp;2004 to June 30, 2010 (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). There were 59 cases in LEF group, including 32 males and 27 females, aged 35.7\u0026thinsp;\u0026plusmn;\u0026thinsp;11.2 years, and 49 cases in prednisone group, including 23 males and 26 females, with an age of 35.5\u0026thinsp;\u0026plusmn;\u0026thinsp;11.2\u0026nbsp;years. The baseline characteristics between the two groups were comparable (see Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eBaseline characteristics\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCharacteristics\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eLEF group\u003c/p\u003e\n\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;59)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ePrednisone group\u003c/p\u003e\n\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;49)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eMale(n)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e32(54%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e23(47%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.066\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eFemale(n)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27(46%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26(53%)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAge(years)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e35.7\u0026thinsp;\u0026plusmn;\u0026thinsp;11.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e35.5\u0026thinsp;\u0026plusmn;\u0026thinsp;11.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.185\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eDuration\u0026nbsp;of\u0026nbsp;disease\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(months)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19.4(4.1\u0026ndash;46.8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10.6(6.2\u0026ndash;40.1)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.184\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eUPE (g/24\u0026nbsp;h)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.8(1.3\u0026ndash;3.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.9(1.2\u0026ndash;2.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.420\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003esALB(g/L)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e37.7\u0026thinsp;\u0026plusmn;\u0026thinsp;5.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e37.2\u0026thinsp;\u0026plusmn;\u0026thinsp;5.1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.609\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBUN (mmol/L)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.6\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.0\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.159\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eScr (\u0026micro;mol/L)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e112.3\u0026thinsp;\u0026plusmn;\u0026thinsp;56.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e96.4\u0026thinsp;\u0026plusmn;\u0026thinsp;38.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.099\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eeGFR(ml/m)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e66.9\u0026thinsp;\u0026plusmn;\u0026thinsp;40.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e64.6\u0026thinsp;\u0026plusmn;\u0026thinsp;31.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.747\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eHb(g/L)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e132.0\u0026thinsp;\u0026plusmn;\u0026thinsp;16.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e131.1\u0026thinsp;\u0026plusmn;\u0026thinsp;19.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.797\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eALT(IU/L)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20.3\u0026thinsp;\u0026plusmn;\u0026thinsp;5.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21.5\u0026thinsp;\u0026plusmn;\u0026thinsp;11.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.470\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAST(IU/L)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20.7\u0026thinsp;\u0026plusmn;\u0026thinsp;11.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e23.6\u0026thinsp;\u0026plusmn;\u0026thinsp;20.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.352\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\"\u003eNote: Values for categorical variables are given as count; values for continuous variables, as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation or median [IQR].\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\"\u003eAbbreviations: UPE: urine protein excretion; sALB: Serum albumin; BUN: blood urea nitrogen; Scr: serum creatinine, eGFR: estimated glomerular filtration rate; Hb: hemoglobin; ALT: alanine transaminase; AST: aspartate aminotransferase; LEF: leflunomide.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cp class=\"gridtable\"\u003e\u003cstrong\u003e2. Efficacy\u003c/strong\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cp\u003e24\u0026nbsp;h UPE when patients with IgAN enrolled were 1.8(1.3\u0026ndash;3.5) and 1.9(1.2\u0026ndash;2.9) in LEF group and prednisone group, respectively. After 12 months treatment, 24\u0026nbsp;h UPE were significantly lower ([0.6(0.3\u0026ndash;1.4) vs 1.8(1.3\u0026ndash;3.5), p5\u0026lt;0.01] in LEF group, [0.6(0.3-1.0) vs 1.9(1.2\u0026ndash;2.9), p\u0026lt;0.01] in prednisone group) in both groups versus baseline value. At month 3, 6, 9 months, 24\u0026nbsp;h UPE were also significantly lower in both groups compared to baseline data (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). What\u0026rsquo;s more, the effect sustained during the 12-months follow-up period (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). At 12 months, sALB was significantly higher ([44.7\u0026thinsp;\u0026plusmn;\u0026thinsp;6.4 vs 37.7\u0026thinsp;\u0026plusmn;\u0026thinsp;5.0, p\u0026lt;0.01] in LEF group, [43.3\u0026thinsp;\u0026plusmn;\u0026thinsp;3.6 vs 37.2\u0026thinsp;\u0026plusmn;\u0026thinsp;5.1, p\u0026lt;0.01] in prednisone group) in both groups versus baseline data. At month 3, 6, 9 months, sALB were also much higher in both groups compared to baseline (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e), and the effect sustained during the 12-months follow-up (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Scr and eGFR did not change significantly throughout the treatment and follow-up periods (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e), indicating renal function was stable in both groups through the treatment period. Difference of the 24\u0026nbsp;h UPE, sALB, Scr and eGFR between the two groups was not significant at each visit (p\u0026gt;0.05). It suggested that LEF plus low-dose prednisone and conventionally accepted-dose prednisone had the same effect on treatment of progressive IgAN.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eOutcomes of Treatment\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCharacteristics\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth colspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eLEF group\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ePrednisone group\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"7\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eUPE(g/24h)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eBaseline\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e1.8(1.3\u0026ndash;3.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e1.9(1.2\u0026ndash;2.9)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.318\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMonth 3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e0.8(0.4\u0026ndash;1.9)**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e0.9(0.3\u0026ndash;1.3)**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMonth 6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e0.8(0.3\u0026ndash;1.9)**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e0.8(0.2\u0026ndash;1.6)**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMonth 9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e0.6(0.3\u0026ndash;1.8)**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e0.7(0.2-1.0)**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMonth 12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e0.6(0.3\u0026ndash;1.4)**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e0.6(0.3-1.0)**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMonth 18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e0.4(0.1\u0026ndash;0.9)**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e0.5(0.2\u0026ndash;1.1)**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMonth 24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e0.5(0.1\u0026ndash;1.1)**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e0.5(0.3-1.0)**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"7\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003esALB(g/L)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eBaseline\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e37.7\u0026thinsp;\u0026plusmn;\u0026thinsp;5.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e37.2\u0026thinsp;\u0026plusmn;\u0026thinsp;5.1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.073\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMonth 3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e40.4\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e40.2\u0026thinsp;\u0026plusmn;\u0026thinsp;3.4**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMonth 6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e41.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.6**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e42.9\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMonth 9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e43.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e42.6\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMonth 12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e44.7\u0026thinsp;\u0026plusmn;\u0026thinsp;6.4**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e43.3\u0026thinsp;\u0026plusmn;\u0026thinsp;3.6**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMonth 18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e44.9\u0026thinsp;\u0026plusmn;\u0026thinsp;2.8**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e42.5\u0026thinsp;\u0026plusmn;\u0026thinsp;5.2**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMonth 24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e44.3\u0026thinsp;\u0026plusmn;\u0026thinsp;3.0**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e43.3\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8**\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"7\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eScr(umol/L)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eBaseline\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e112.3\u0026thinsp;\u0026plusmn;\u0026thinsp;56.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e96.4\u0026thinsp;\u0026plusmn;\u0026thinsp;38.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.689\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMonth 3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e107.2\u0026thinsp;\u0026plusmn;\u0026thinsp;39.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e97.9\u0026thinsp;\u0026plusmn;\u0026thinsp;36.1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMonth 6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e106.5\u0026thinsp;\u0026plusmn;\u0026thinsp;45.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e94.4\u0026thinsp;\u0026plusmn;\u0026thinsp;32.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMonth 9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e107.6\u0026thinsp;\u0026plusmn;\u0026thinsp;36.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e92.3\u0026thinsp;\u0026plusmn;\u0026thinsp;32.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMonth 12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e111.4\u0026thinsp;\u0026plusmn;\u0026thinsp;43.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e97.9\u0026thinsp;\u0026plusmn;\u0026thinsp;42.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMonth 18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e101.3\u0026thinsp;\u0026plusmn;\u0026thinsp;34.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e98.6\u0026thinsp;\u0026plusmn;\u0026thinsp;28.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMonth 24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e108.3\u0026thinsp;\u0026plusmn;\u0026thinsp;26.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e109\u0026thinsp;\u0026plusmn;\u0026thinsp;65.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" rowspan=\"7\" align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eeGFR(ml/min/1.73\u0026nbsp;m\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003e)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eBaseline\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e66.9\u0026thinsp;\u0026plusmn;\u0026thinsp;40.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e64.6\u0026thinsp;\u0026plusmn;\u0026thinsp;31.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.891\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMonth 3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e73.4\u0026thinsp;\u0026plusmn;\u0026thinsp;28.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e68.1\u0026thinsp;\u0026plusmn;\u0026thinsp;26.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMonth 6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e74.6\u0026thinsp;\u0026plusmn;\u0026thinsp;29.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e73.6\u0026thinsp;\u0026plusmn;\u0026thinsp;27.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMonth 9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e70.3\u0026thinsp;\u0026plusmn;\u0026thinsp;26\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e70.7\u0026thinsp;\u0026plusmn;\u0026thinsp;23.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMonth 12\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e67.3\u0026thinsp;\u0026plusmn;\u0026thinsp;26.7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e72.8\u0026thinsp;\u0026plusmn;\u0026thinsp;30.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMonth 18\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e71.5\u0026thinsp;\u0026plusmn;\u0026thinsp;28.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e68.9\u0026thinsp;\u0026plusmn;\u0026thinsp;30.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eMonth 24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e66.4\u0026thinsp;\u0026plusmn;\u0026thinsp;18.7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e63.9\u0026thinsp;\u0026plusmn;\u0026thinsp;22.7\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"8\"\u003e**P\u0026thinsp;\u0026lt;\u0026thinsp;0.01 versus baseline value\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"8\"\u003eAbbreviations: UPE: urine protein excretion; sALB: Serum albumin; Scr: serum creatinine, eGFR: estimated glomerular filtration rate; LEF: leflunomide.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAt 12 months, 12 patents had complete remission, 13 patents had partial remission in LEF group; and 15 patients had complete remission, 10 patients had partial remission in prednisone group. Overall response rates were 69%(36 of 52 patients) in the LEF group and 67%(30 of 45 patients) in the prednisone group. There was no significant difference between the two groups (P\u0026thinsp;=\u0026thinsp;0.959) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eThe complete, partial and overall response between LEF group and prednisone group\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth colspan=\"3\" align=\"left\"\u003e\n\u003cp\u003eLEF group\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003ePrednisone group\u003c/p\u003e\n\u003c/th\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003ep value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003en/N\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eRate\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003en/N\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eRate\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eMonth 12\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eCR\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e17/52\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e33%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18/45\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e40%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.592\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003ePR\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e19/52\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e37%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12/45\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.411\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eOverall response\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e36/52\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e69%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30/45\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e67%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.959\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"7\"\u003e\u003csup\u003ec\u003c/sup\u003en/N: event number/total number\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"7\"\u003eAbbreviations: CR: complete remission; PR: partial remission\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAt 24 months, relapse rates were 3%(2 of 59 patients) in the LEF group and 10%(5 of 49 patients) in the prednisone group. There was no significant difference between the two groups (P\u0026thinsp;=\u0026thinsp;0.299) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab4\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eThe relapsing rate between LEF group and prednisone group\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eLEF group\u003c/p\u003e\n\u003c/th\u003e\n\u003cth colspan=\"2\" align=\"left\"\u003e\n\u003cp\u003ePrednisone group\u003c/p\u003e\n\u003c/th\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003ep value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003en/N\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eRate\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003en/N\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eRate\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eMonth 24\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eRelapsing\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2/59\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5/49\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10%\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.299\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"6\"\u003e\u003csup\u003ec\u003c/sup\u003en/N: event number/total number.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBaseline daily oral prednisone dose in LEF group was much lower than that in prednisone group (40.4\u0026thinsp;\u0026plusmn;\u0026thinsp;5.5 vs 55.7\u0026thinsp;\u0026plusmn;\u0026thinsp;9.5, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). At 3 and 6 months, daily oral prednisone doses in LEF group were 30.4\u0026thinsp;\u0026plusmn;\u0026thinsp;9.2 and 15.9\u0026thinsp;\u0026plusmn;\u0026thinsp;8.3, respectively, and they ([30.4\u0026thinsp;\u0026plusmn;\u0026thinsp;9.2 vs 43.5\u0026thinsp;\u0026plusmn;\u0026thinsp;9.2, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001]; [15.9\u0026thinsp;\u0026plusmn;\u0026thinsp;8.3 vs 21.9\u0026thinsp;\u0026plusmn;\u0026thinsp;7.8, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001]) were significantly lower than that in prednisone group (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Further, the total amount of prednisone in LEF group was lower than that in prednisone group (21.5\u0026thinsp;\u0026plusmn;\u0026thinsp;13.41 vs 28.83\u0026thinsp;\u0026plusmn;\u0026thinsp;19.95, p\u0026thinsp;=\u0026thinsp;0.031) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3. Adverse events\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt the early induction stage, adverse events occurred. Incidence of adverse events and severe adverse events such as respiratory and pulmonary infection and sepsis were comparable between the two groups. (details on adverse event reporting were in the Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab6\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eAdverse events during the treatment period\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eLEE group(n\u0026thinsp;=\u0026thinsp;59)\u003c/p\u003e\n\u003cp\u003e(n, %)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ePrednisone group(n\u0026thinsp;=\u0026thinsp;49)\u003c/p\u003e\n\u003cp\u003e(n, %)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eRespiratory and pulmonary infection\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4(7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9(18)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.122\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eUrinary tract infection\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0(0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1(2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.926\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eDiarrhea\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2(3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0(0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.559\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eSlightly elevated liver enzyme\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4(7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4(8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.924\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eRash\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1(2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e4(8)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.257\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eElevated blood pressure\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1(2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1(2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.559\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eFever\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2(3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1(2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.870\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eSepsis\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0(0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1(2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.926\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eItching\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2(3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0(0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.559\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eNausea\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1(2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0(0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.926\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAgrypnia\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1(2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0(0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.926\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eParaesthesia\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1(2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0(0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.926\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eInsanity\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1(2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0(0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.926\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eLipsotrichia\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1(2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0(0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.926\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eHerpes zoster\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0(0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2(4)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.396\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eToothache\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0(0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1(2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.926\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eFatigue\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0(0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1(2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.926\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eMenstrual disorder\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0(0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1(2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.926\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eInsomnia\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0(0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1(2)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.926\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eObesity or weight gain\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0(0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0(0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eImpaired glucose tolerance or diabetes\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0(0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0(0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eCataract\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0(0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0(0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAcne\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0(0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0(0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eAvascular necrosis of hips\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0(0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0(0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.000\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eTotal(n)\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21(36)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27(55)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.066\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab5\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eThe daily prednisone dose in LEF group and prednisone group\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eTreatment time\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eLEF group\u003c/p\u003e\n\u003cp\u003e(mg/day)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003ePrednisone group\u003c/p\u003e\n\u003cp\u003e(mg/day)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eP value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e40.4\u0026thinsp;\u0026plusmn;\u0026thinsp;5.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e55.7\u0026thinsp;\u0026plusmn;\u0026thinsp;9.5\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eMonth 3\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30.4\u0026thinsp;\u0026plusmn;\u0026thinsp;9.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e43.5\u0026thinsp;\u0026plusmn;\u0026thinsp;9.2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eMonth 6\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15.9\u0026thinsp;\u0026plusmn;\u0026thinsp;8.3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21.9\u0026thinsp;\u0026plusmn;\u0026thinsp;7.8\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eMonth 9\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12.0\u0026thinsp;\u0026plusmn;\u0026thinsp;5.6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13.5\u0026thinsp;\u0026plusmn;\u0026thinsp;5.9\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.181\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eMonth 12\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8.8\u0026thinsp;\u0026plusmn;\u0026thinsp;5.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.5\u0026thinsp;\u0026plusmn;\u0026thinsp;6.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.493\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eTotal\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21.5\u0026thinsp;\u0026plusmn;\u0026thinsp;13.4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e28.8\u0026thinsp;\u0026plusmn;\u0026thinsp;20.0\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e0.031\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003ePatients with IgAN, with overt proteinuria(\u0026gt;1\u0026nbsp;g/day) and reduced eGFR, are at high risk of progression to ESRD. To our knowledge, this study was the first multicenter RCT study to compare the efficacy and safety of LEF plus prednisone to conventionally accepted-dose prednisone in patients with progressive IgAN. We observed that LEF plus low-dose prednisone is as effective as conventionally accepted-dose prednisone for treatment of progressive IgAN, with decreased 24\u0026nbsp;h UPE, increased sALB, stable renal function. Upon completion of the 12-month treatment, after cessation of trial medications, the mean percentage reduction in 24\u0026nbsp;h UPE was sustained in both groups during the 12-month follow-up period, which was consistent with changes in sALB, Scr and eGFR. In addition, patients treated with LEF plus low-dose prednisone have comparable overall response rate, relapsing rate and incidence of adverse events, as compared with that in conventionally accepted-dose prednisone group.\u003c/p\u003e\n\u003cp\u003eOur single-center study in investigation of the efficacy and safety of LEF plus low-dose prednisone, showed that a greater reduction of proteinuria during long-term follow-up and fewer severe adverse events were observed in LEF group[\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e]. In another single-center study, Buardle FW et al. also confirmed corticosteroids or combined with immunosuppressive therapy can reduce proteinuria and loss of renal function in patients with progressive IgAN[\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e]. Corresponding to these findings, the present study demonstrated that LEF plus low-dose prednisone has similar effect in reduction of 24\u0026nbsp;h UPE versus conventionally accepted-dose prednisone. In addition, the reduction of 24\u0026nbsp;h UPE sustains throughout the treatment and follow-up periods. Evidence showed that a reduction in proteinuria is associated with a reduced risk of progression to ESRD in patients with IgAN[\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e]. Le W et al. showed that the rate of decline of renal function was associated with higher levels of time-averaged proteinuria, which was the most important risk factor of progression to renal failure in Chinese adult patients with IgAN[\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e]. A meta-analysis of trials for IgAN suggested that proteinuria reduction was significantly associated with outcomes in ESRD, with each 30% reduction in proteinuria, the risk of ESRD(non-significantly) decreased comparably[\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e]. Recently, Lou et al. compared IgAN patients treated with LEF with those treated only with ACEI, and found that the overall efficacy of the two groups was comparable[\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eAt the time of biopsy, hypoproteinemia and eGFR\u0026thinsp;\u0026lt;\u0026thinsp;60\u0026nbsp;mL/min/1.73\u0026nbsp;m2 were the independent risk factors for progression to ESRD in patients with IgAN[\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e]. We previously reported that the time-averaged serum albumin might serve as a marker of the long-term renal prognosis of IgAN patients who have achieved remission[\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e]. The present study showed that after treatment with LEF plus low-dose prednisone or conventionally accepted-dose prednisone, sALB significantly increase in both group, which is in accordance with our previous findings[\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e]. What\u0026rsquo;s more, the Scr and eGFR and changes in Scr and eGFR remain stable through the treatment and follow-up periods between the two group, indicating the renal function is better preserved during the treatment and follow-up periods. The stabilization in Scr and eGFR illustrates that this patient population is at low risk of disease progression, the interventions in this trial for patients with progressive IgAN and overt proteinuria are at least sufficient[\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e]. Remission rate is similar between the LEF and prednisone groups. Consistent with our findings, Hou JH, et al. found that mycophenolate mofetil plus prednisone versus full-dose prednisone did not differ in CR rate in patients with IgAN with active proliferative lesions[\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eHigh-dose systemic corticosteroids and immunosuppressive treatments cause considerable side effects[\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e]. Increase of adverse events such as serious infections, hypertension, osteoporosis, weight gain, and diabetes are associated with high-dose systemic corticosteroids[\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e]. Elevated liver enzymes, digestive symptoms, and alopecia are related to LEF[\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e]. In the present study, the total amount of prednisone was lower in the LEF group than that in the prednisone group (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003e). Further, the LEF dosage in our study was also less than that in the previously reported LEF monotherapy trials in patients with IgAN[\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e]. In addition to effect of the LEF regimen, the lower dosage of immunosuppression may minimize drug adverse effects. Our results suggested that LEF plus low-dose prednisone is probably an alternative option for treatment of progressive IgAN, especially in those patients who was not tolerated to high-dose prednisone. Certain limitations in this trial were relatively small sample size, short follow-up time and ethnic difference, with non-Asian patients with progressive IgAN.\u003c/p\u003e"},{"header":"Conclusion","content":" \u003cp\u003eIn conclusion, this study suggests that LEF plus low-dose prednisone did not differ in reducing proteinuria, increasing sALB and stabilising Scr and eGFR, and had comparable adverse events in patients with progressive IgAN. The observed effect was additive to optimised ACEIs or ARBs and supported LEF plus low-dose prednisone might be an effective therapy in patients with IgAN at high risk of progression.\u003c/p\u003e "},{"header":"Abbreviations","content":"\u003cp\u003eIgAN: IgA nephropathy; LEF: Leflunomide; UPE: 24h urine protein excretion; sALB: serum albumin; Scr: serum creatinine; eGFR: estimated glomerular filtration rate; ESRD: end-stage renal failure; ACEIs: angiotensin-converting enzyme inhibitors; ARBs: angiotensin receptor blockers; RAS: renin-angiotensin system; RCT: randomized controlled trial; CR: Complete remission; PR: partial remission; NR: No response.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDrugs were provided by Cinkate Pharmaceutical Company. Other members participated in this clinical trial: nephrologists from Huashan Hospital; Shanghai Changzheng Hospital; Zhongshan Hospital; Shanghai General Hospital; Shanghai Ninth People's Hospital; Xinhua Hospital; Huadong Hospital; Shuguang Hospital; Longhua Hospital.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZN designed and supervised the experiment. ZN, FL, CM, XD, WY, WZ, GJ, MS, LH, and YD participated in patients enrollment and data collection. ZZ, ZY analyzed the data and wrote the paper. ZN and HP modified the paper. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere was no funding to this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during this study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval and Consent to Participate \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the ethical review board of Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University. The work presented in that manuscript complies with guidelines for human studies and all patients provided written informed consent before enrollment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors of this manuscript have no conflicts of interest to disclose.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eDonadio JV GJ: \u003cstrong\u003eIgA nephropathy.\u003c/strong\u003e \u003cem\u003eN Engl J Med \u003c/em\u003e2002, \u003cstrong\u003e347\u003c/strong\u003e:738-748.\u003c/li\u003e\n\u003cli\u003eLi LS, Liu ZH: \u003cstrong\u003eEpidemiologic data of renal diseases from a single unit in China: analysis based on 13,519 renal biopsies\u003c/strong\u003e. \u003cem\u003eKidney Int \u003c/em\u003e2004, 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\u003cstrong\u003e17\u003c/strong\u003e:638-644.\u003c/li\u003e\n\u003cli\u003eKim JK, Kim JH, Lee SC, Kang EW, Chang TI, Moon SJ, Yoon SY, Yoo TH, Kang SW, Choi KH\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eClinical features and outcomes of IgA nephropathy with nephrotic syndrome\u003c/strong\u003e. \u003cem\u003eClin J Am Soc Nephrol \u003c/em\u003e2012, \u003cstrong\u003e7\u003c/strong\u003e(3):427-436.\u003c/li\u003e\n\u003cli\u003eMoon SJ, Park HS, Kwok SK, Ju J, Choi BS, Park KS, Min JK, Kim HY, Park SH: \u003cstrong\u003ePredictors of renal relapse in Korean patients with lupus nephritis who achieved remission six months following induction therapy\u003c/strong\u003e. \u003cem\u003eLupus \u003c/em\u003e2013, \u003cstrong\u003e22\u003c/strong\u003e(5):527-537.\u003c/li\u003e\n\u003cli\u003eBallardie FW RI: \u003cstrong\u003eControlled Prospective Trial of Prednisolone and Cytotoxics in Progressive IgA Nephropathy.\u003c/strong\u003e \u003cem\u003eJ Am Soe Nephrol 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Surrogate End Point in Studies of IgA Nephropathy: An Individual-Patient Meta-analysis\u003c/strong\u003e. \u003cem\u003eAm J Kidney Dis \u003c/em\u003e2016, \u003cstrong\u003e68\u003c/strong\u003e(3):392-401.\u003c/li\u003e\n\u003cli\u003eLambers Heerspink HJ, Tighiouart H, Sang Y, Ballew S, Mondal H, Matsushita K, Coresh J, Levey AS, Inker LA: \u003cstrong\u003eGFR decline and subsequent risk of established kidney outcomes: a meta-analysis of 37 randomized controlled trials\u003c/strong\u003e. \u003cem\u003eAm J Kidney Dis \u003c/em\u003e2014, \u003cstrong\u003e64\u003c/strong\u003e(6):860-866.\u003c/li\u003e\n\u003cli\u003eLou T, Wang C, Chen Z, Shi C, Tang H, Liu X, Yin P, Yu X: \u003cstrong\u003eRandomised controlled trial of leflunomide in the treatment of immunoglobulin A nephropathy\u003c/strong\u003e. \u003cem\u003eNephrology (Carlton) \u003c/em\u003e2006, \u003cstrong\u003e11\u003c/strong\u003e(2):113-116.\u003c/li\u003e\n\u003cli\u003eNi Z YY, Wang Q, Cao L, Che X, Zhang M, Xie Y, Qi C, Mou S: \u003cstrong\u003eTime-averaged albumin predicts the long-term prognosis of IgA nephropathy patients who achieved remission.\u003c/strong\u003e \u003cem\u003eJ Transl Med \u003c/em\u003e2014, \u003cstrong\u003e12\u003c/strong\u003e:194.\u003c/li\u003e\n\u003cli\u003eRasche FM, Keller F, Rasche WG, Schiekofer S, Boldt A, Sack U, Fahnert J: \u003cstrong\u003eWhy, when and how should immunosuppressive therapy considered in patients with immunoglobulin A nephropathy?\u003c/strong\u003e \u003cem\u003eClin Exp Immunol \u003c/em\u003e2016, \u003cstrong\u003e186\u003c/strong\u003e(2):115-133.\u003c/li\u003e\n\u003cli\u003eRasche FM, Keller F, Rasche WG, Schiekofer S, Kahn T, Fahnert J: \u003cstrong\u003eSequential therapy with cyclophosphamide and mycophenolic acid in patients with progressive immunoglobulin A nephropathy: a long-term follow-up\u003c/strong\u003e. \u003cem\u003eClin Exp Immunol \u003c/em\u003e2016, \u003cstrong\u003e183\u003c/strong\u003e(2):307-316.\u003c/li\u003e\n\u003cli\u003eTesar V, Troyanov S, Bellur S, Verhave JC, Cook HT, Feehally J, Roberts IS, Cattran D, Coppo R, Group VsotE-EIW: \u003cstrong\u003eCorticosteroids in IgA Nephropathy: A Retrospective Analysis from the VALIGA Study\u003c/strong\u003e. \u003cem\u003eJ Am Soc Nephrol \u003c/em\u003e2015, \u003cstrong\u003e26\u003c/strong\u003e(9):2248-2258.\u003c/li\u003e\n\u003cli\u003eFloege J, Eitner F: \u003cstrong\u003eCurrent therapy for IgA nephropathy\u003c/strong\u003e. \u003cem\u003eJ Am Soc Nephrol \u003c/em\u003e2011, \u003cstrong\u003e22\u003c/strong\u003e(10):1785-1794.\u003c/li\u003e\n\u003cli\u003eLiu Y, Xiao J, Shi X, Hao G, Chen Q, Zhou J, Wei X: \u003cstrong\u003eImmunosuppressive agents versus steroids in the treatment of IgA nephropathy-induced proteinuria: A meta-analysis\u003c/strong\u003e. \u003cem\u003eExp Ther Med \u003c/em\u003e2016, \u003cstrong\u003e11\u003c/strong\u003e(1):49-56.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"IgA nephropathy, leflunomide, prednisone ","lastPublishedDoi":"10.21203/rs.3.rs-99015/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-99015/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e This trial was designed to assess the efficacy and safety of Leflunomide (LEF) plus low-dose prednisone for the treatment of progressive IgA nephropathy (IgAN). \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eWe did a prospective, randomized, open-labelled, multicenter, controlled trial, comprised of 3-month run-in, 12-month treatment and 12-month follow-up phases. After 3-month run-in phase, patients with biopsy-confirmed IgAN at a risk of progression were randomly allocated to LEF plus low-dose prednisone (LEF group) or conventionally accepted-dose prednisone (prednisone group). Our primary outcome was 24h urine protein excretion(UPE) and secondary outcomes were serum albumin(sALB), serum creatinine(Scr), and eGFR. Safety was evaluated in all patients who received the trial medications. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e108 patients (59 in LEF group, 49 in prednisone group) were enrolled and finished their treatment and follow-up periods. The difference in baseline data between the two groups was comparable. Compared with baseline, both groups showed significant decrease in 24h UPE(p\u0026lt;0.01) and increase in sALB (p\u0026lt;0.01), with stable Scr and eGFR throughout the 12-month treatment period. What’s more, these effects sustained through the 12-month follow-up period. However, there was no difference in 24h UPE, sALB, Scr and eGFR between the two groups (P\u0026gt;0.05). At 12 months, difference of overall response rate, relapsing rate and incidence of adverse events between the two groups was not significant.\u003cstrong\u003e \u003c/strong\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eThe efficacy and safety of LEF plus low-dose prednisone and conventionally accepted-dose prednisone in treatment of progressive IgAN are comparable. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eTrial registration: \u003c/strong\u003eThe trial is registered at isrctn.org with the ISRCTN97636235 on July 28, 2006. \u003c/p\u003e","manuscriptTitle":"Leflunomide Plus Low-dose Prednisone in Patients with Progressive IgA Nephropathy: A Multicenter, Prospective, Randomized, Open-labelled and Controlled Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-10-30 14:53:23","doi":"10.21203/rs.3.rs-99015/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9f6db16a-9d35-4fb0-9541-77cde26107e7","owner":[],"postedDate":"October 30th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":932836,"name":"Urology \u0026 Nephrology"}],"tags":[],"updatedAt":"2021-08-16T08:06:12+00:00","versionOfRecord":{"articleIdentity":"rs-99015","link":"https://doi.org/10.1080/0886022X.2021.1963775","journal":{"identity":"renal-failure","isVorOnly":true,"title":"Renal Failure"},"publishedOn":"2021-01-01 08:06:12","publishedOnDateReadable":"January 1st, 2021"},"versionCreatedAt":"2020-10-30 14:53:23","video":"","vorDoi":"10.1080/0886022X.2021.1963775","vorDoiUrl":"https://doi.org/10.1080/0886022X.2021.1963775","workflowStages":[]},"version":"v1","identity":"rs-99015","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-99015","identity":"rs-99015","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}