| Background Systemic lupus erythematosus(SLE)is an autoimmune disease that can involve various systems and organs.Kidney is one of the most common and refractory organ involved,and is still the strongest predictor of morbidity and mortality in patients with SLE.Lupus nephritis(LN)in SLE patients appear persistent proteinuria > 0.5 g per day or greater than 3+ by dipstick,and/or cellular casts including red cell,hemoglobin,granular,tubular or mixed.Several studies showed significant differences in the incidence of LN among different races,especially in non-Caucasian race,the SLE patients with a higher incidence of LN,which in China,the cumulative incidence of lupus nephritis after diagnosis of SLE was 60%[1].LN incidence is high in China,up to 50-80 / 10 million people,and LN is also a common secondary glomerularnephritis in China.Many treatments are ineffective for 14%-33% of patients with LN,patients with effective treatments still have 27%-66% recurrence,while 5%-20% of patients eventually develop to end-stage renal disease,uremia.Although most of LN can successfully induce remission,its recurrence rate is as high as 27% to 66%,and China is also suffering a high incidence of LN,in this regard,how to rational use immunosuppressive drugs to control the minimum side effects under the premise of long-term remission of LN to reduce relapse has become a hotspot in rheumatology.Multiple pathogenic factors may invade the kidneys through multiple pathways to cause LN,and immune system disorders are the most basic pathogenesis of LN,hence immunosuppressive therapy is the most basic treatment of LN.2012 American College of Rheumatology(ACR)guidelines for LN recommended [2] that combined small dose of prednisone with mycophenolate mofetil(MMF)or azathioprine(AZA)as maintenance regimens after LN induction treatment achieved remission.In clinical practice work,we also use the above immunosuppressive drugs treat LN,however,the efficacy of using a single immunosuppressive agent is not satisfied,mainly for the dose is too large,long maintenance time,increased side effects or high renal flare rate.Because there are many mechanisms led to kidney disease,therefore,we study the efficacy and safety of MMF combined with leflunomide(LEF)as multi-target therapy to refractory LN(including type ?/?+?,?/?+?,?LN).Objective The maintenance therapy of LN is very important to prevent renal flare,but it is still a challenge for us,such as poor control disease progress in LN,high renal flare rate.Our study aims to compare the efficacy and safety of multi-target therapy to single drug in treating refractory LN(type?/?+?,?/?+?,?LN).Methods A total of 44 patients with LN achieved complete remission(CR)or partial remission(PR)after induction therapy were randomly assigned to multi-target group [MMF(0.5g per day)plus LEF(10mg per day),n=21)] and monotherapy group [MMF(0.5g twice per day),n=23],both groups were taking prednisone 10 mg per day or it's equivalent,irbesartan 150 mg per day,hydroxychloroquine 200 mg twice per day.The total follow-up time was 18 months.The primary end point was treatment failure,including renal flare,death,end-stage renal disease,doubling increase of serum creatinine level,or need rescue therapy for LN [such as high dose of predinsone,Cyclophosphamide(CTX)or immunoglobulin].Other assesssments included CR rate and adverse events.Results 1.Comparison of Renal Flare Rate Multi-target group(MMF+LEF)was superior to monotherapy group(MMF)respect to being free of renal flare rate(95.2% vs 69.6%,P = 0.031).The renal flare rate in multi-target group was lower than in monotherapy group,but without statistically significane((4.8% vs 30.4%,P = 0.070).2.Comparison of Renal Flare Rate in Different Renal Pathological Types Type ?/?+? LN had the highest renal flare rate in different types of LN in bothgroups,there was a rate of 12.5%(1/8)in multi-target group,and 41.7%(5/12)in MMF group,multi-target group was lower than MMF group,but with no statistically significant(P = 0.370).In type ? LN,the multi-target group did not appear renal flare,in MMF group showed 33.3% of renal flare(2/6),but also with no statistically significant(P=0.192).There was no renal flare in both groups in type ?/?+? LN.3.Comparison of Complete Remission Rate The cumulative complete remission rate of multi-target group was 81%(17/21),while in MMF group was 43.5%(10/23),but without statistical significance(P=0.082).The complete remission rate increased more in multi-target group than monotherapy group(57.2% vs 8.7%,P=0.001).The total remission rate(CR + PR)in the multi-target group was significantly higher than in MMF group(95.2% vs 69.6%,P = 0.031).4.Complete Remission Rate Compare in Different Renal Pathological Types Complete remission rate were highest in the type ?/?+? LN of both groups,Multi-target group was 100%(6/6),MMF group was 60%(3/5),with no significant difference(P = 0.182).The complete remission rate of type ?/?+? LN in multi-target group was 75%(6/8),MMF group was 33.3%(4/12),also with no significant difference(P = 0.171).Type ? LN in multi-target group was 71.4%(5/7),MMF single drug group was 50.0%(3/6),with no significant difference(P = 0.826).5.Comparison of Adverse Events The rate of adverse events were both more than 70%,the most common drug-related adverse events were infection and gastrointestinal symptoms.The incidence of adverse events in the multi-target group was 81%(17/21),with the highest incidence of infection,followed by gastrointestinal discomfort,reached by 42.9%(9/21)and 28.6%(6/21),respectively.One case of drug-related leukopenia,one case of alopecia,one case of elevated liver enzyme,two case of menstrual disorders in multi-target group.The incidence of adverse events in the MMF group was 73.9%(17/23),and the highest incidence of adverse events was still infection,followed by gastrointestinal discomfort,reached by 39.1%(9/23)and 30.3%(7/23),respectively.Two case of drug-related leukopenia,two case of elevated liver enzyme,one case of menstrual disorders and no alopecia occurred in MMF group.The incidence of adverse events between two groups was not statistically significance.ConclusionsMycophenolate mofetil plus leflunomide was superior to mycophenolate mofeti alone in preventing renal relapse and in maintaining a renal response to treatment in patients with refractory lupus nephritis who had a response to induction therapy. |
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