Abstract
Background. Renal involvement is one of the major determinants of the outcome in patients with systemic lupus erythematosus. Renal involvement contributes to both morbidity and mortality of the patients as well as indirectly through side effects of therapy directed at the renal lesions. The aim of the study was to evaluate the efficacy of mycophenolate mofetil (MMF) and azathioprine (AZA) in the maintenance therapy of lupus nephritis. Methods. Thirty-two patients from our center with diagnosed lupus nephritis World Health Organization Class III, IV, V were treated with IVC (0.75–1g/month) for six months in addition to steroid therapy, and then with AZA (n = 15) or MMF (n = 17) as a maintenance therapy. The efficacy of two drugs was compared with changes in serum creatinine, creatinine clearance, 24 hour urine protein excretion, cholesterol, anti-dsDNA antibody, and urine sediment. Results. Mean follow-up time was 41.5 + 7 months. The total remission occurred in 84% of patients (82% with MMF and 87% with AZA), with a complete remission rate of 59.3% (58% with MMF and 60% with AZA) and a partial remission rate of 25% (22% with MMF and 27% with AZA). The urinary protein excretion before MMF treatment was 1.9 + 1 g/dL and decreased significantly to 0.91 + 0.6 g/dL (p = 0.028) after treatment, and decreased from 1.58 + 0.7g/dL to 0.4 + 0.23g/dL in the AZA group (p = 0.04). The serum creatinine level decreased from 1.32 + 0.7 mg/dL to 1.12 + 0.68 mg/dL in the MMF group (p = 0.23), and decreased from 0.91 + 0.23mg/dL to 0.88 + 0.23 mg/dL in the AZA group (p = 0.49). There was no significant change between two groups (p = 0.1). The serum cholesterol decreased from 229 + 57 mg/dL to 171 + 9 mg/dL (p = 0.002), and serum triglyceride level decreased from 228 + 116 mg/dL to 98 + 35 mg/dL (p = 0.004) in the MMF treatment, but no significant change was seen in AZA group. There was no significant difference between the two groups considering the rates of doubling of serum creatinine, progression to end-stage renal failure, relapses, and documented side effects, as well. Conclusion. Both therapeutic approaches with MMF or AZA, in combination with corticosteroids, are effective as a maintenance therapy for lupus nephritis.
INTRODUCTION
Renal involvement is one of the major determinants of the outcome in patients with systemic lupus erythematosus (SLE). Renal involvement contributes both directly to morbidity and mortality of the patients, as well as indirectly through drug-related severe adverse effects and toxicities.
Patient and renal survival of SLE patients has improved considerably over the past few decades, due in part to earlier recognition of renal disease, aggressive immunosuppression, and the prevention of complications of therapies.Citation[1–3] Although long-term cyclophosphamide (CY) regimens are efficacious in the treatment of proliferative lupus nephritis and has improved the prognosis of disease in these patients, the safety of the regimen still limits the success of therapy. There has been increasing attention on developing alternate therapies that promptly and effectively induce remission, prevent relapse, and maximize patient and renal survival while incurring the least toxicity. Nephrologists are now focusing on the concept of induction treatment with vigorous initial therapies, followed by maintenance treatment with lower doses of less toxic regimens.
In the last decade, sequential regimens of short-term CY induction followed by either mycophenolate mofetil (MMF) or azathioprine (AZA) maintenance have shown to be efficacious and safe in terms of reducing the long-term exposure to CY.
Azathioprine is a safe drug, and many argued that it was safer than and probably as effective as cyclophosphamide in the management of lupus nephritis. A randomized controlled trial comparing prednisolone, azathioprine with prednisolone, and intravenous cyclophosphamide in patients with mostly proliferative lupus nephritis observed that cyclophosphamide treatment is more effective in maintaining remission than azathioprine.Citation[4]
Recently, MMF has emerged as a promising alternative therapy for both induction and maintenance treatment for lupus nephritis (LN). Extensively used in organ transplantation, MMF has also been used in a variety of immune- and non-immune-mediated renal diseases. Mycophenolic acid (MPA), the active metabolite of MMF, is an inhibitor of the crucial enzyme involved in the de novo synthesis of guanosine nucleotides.Citation[5],Citation[6] As lymphocytes do not possess a salvage pathway for the generation of these nucleotides, MMF results in selective blockade of B- and T-cell proliferation. Unlike CYC, MPA has little impact on other tissues with high proliferative activity, which possess a salvage pathway for nucleotide synthesis. This accounts for its more favorable toxicity profile. In addition, MMF appears to have a variety of anti-inflammatory actions that are independent of its effect on cell-mediated immunity.Citation[7–11] Despite the successful induction of proliferative GN, relapses are common, ranging from 10 to 65%.Citation[12],Citation[13] Continued renal damage can adversely affect long-term renal survival with each relapse,Citation[14] and the treatment of these relapses is burdened by the toxicity. Consequently, optimal treatment and duration of maintenance therapy remains a challenge. The aim of the study was to evaluate the efficacy of MMF and AZA in the maintenance therapy of lupus nephritis
METHODS
In this retrospective study, we analyzed the patients with biopsy-proven lupus nephritis followed at our center from January 1999 to October 2006. The patients, who were equal to or older than 16 years of age and had a creatinine clearance > 25 mL/min, were enrolled this retrospective clinical observation. All patients underwent renal biopsies and had biopsy-proven lupus nephritis conducted in immunofluorescence and light microscopic examinations within the previous year.
Thirty-two patients with diagnosed lupus nephritis World Health Organization class III, IV, V were treated with IVC (0.75–1 g/month) for six months in addition to steroid therapy, and then with AZA (2 mg/kg/day, n = 15) or MMF (1500–2000 mg/day, n = 17) as a maintenance therapy. All patients received either angiotensin-converting enzyme inhibitor (ACEI) and/or angiotensin II receptor blocker (ARB) therapy, and patients were advised regarding dietary restriction, including low sodium (2 g/day) and 0.8 g/kg protein-restricted diet. For proteinuria, a complete remission was defined as a reduction in proteinuria to < 0.2g per day with normal serum creatinine; partial remission was defined as a reduction of proteinuria from a nephrotic range to a range between 0.21 and 2 g per day with normal serum creatinine. Treatment failure was evaluated at week 12 and was defined as doubling the baseline serum creatinine. A relapse could occur after week 12 and was defined as doubling the lowest obtained serum creatinine so far and/or development of either a nephrotic syndrome (proteinuria > 3.5 g/day and serum albumin < 30 g/L), while the lowest protein excretion so far had been ≤ 2.0 g/day repeatedly, or proteinuria > 1.5 g/day without other causes, in a previously non-proteinuric patient.
The efficacy of two drugs was compared with changes in serum creatinine, 24 hr urine protein excretion rate, serum cholesterol level, anti-dsDNA antibody titers, and urine sediment.
Wilcoxon signed-ranks test was used as appropriate to compare data from the start and end of the treatment period. In all analyses, a two-tailed type error rate of 0.05 was used. Analysis was performed using SPSS Base 7.5 (SPSS, Inc, Cary, North Carolina, USA).
RESULTS
The baseline characteristics of the 32 patients are shown in . Seventeen of the patients were included in the MMF group and 15 in the AZA group. Of the 32 patients, 15 (47%) presented with renal impairment (estimated creatinine clearance according to MDRD < 60 mL/min), 13 (41%) were nephrotic (proteinuria > 3.5 g/24 h), and in 19 patients (59%), nephritis was the presenting symptom of SLE. The baseline parameters between the two treatment arms were similar except for higher creatinine level in the MMF group.
Table 1 Baseline characteristics of patients with lupus nephritis
The total remission occurred in 84% of patients (82% with MMF and 87% with AZA), complete remission rate of 59.3% (58% with MMF and 60% with AZA), and a partial remission rate of 25% (22% with MMF and 27% with AZA) over 41.5 + 7 months.
The urinary protein before MMF treatment was 1.9 + 1 g/dL and decreased significantly to 0.91+0.6g/dL (p = 0.028), and decreased from 1.58 + 0.7g/dL to 0.4 + 0.23g/dL in AZA group (p = 0.04). The serum creatinine level decreased from 1.32 + 0.7 mg/dL to 1.12 + 0.68 mg/dL in the MMF group (p = 0.23) and decreased from 0.91 + 0.23mg/dL to 0.88 + 0.23 mg/dL in the AZA group (p = 0.49).The comparison between two groups in changes of serum creatinine levels and protein excretion rates were non-significant (p = 0.1). The creatinine clearance at 24 months was similar in both groups (MMF group: 79 mL/min, AZA group: 83 mL/min; p = 0.4). The serum cholesterol levels decreased from 229 + 57 mg/dL to 171 + 9 mg/dL (p = 0.002), and serum triglyceride levels decreased from 228 + 116mg/dL to 98 + 35 mg/dL (p = 0.004) in the MMF treatment, but no significant changes were seen in either in the AZA group (see and ). There was no significant difference in the rates of doubling of serum creatinine, progression to end-stage renal failure, and relapses (see ). No deaths were reported.
Table 2 Baseline laboratory characteristics of the patients before the maintenance treatment regimen
Table 3 Last laboratory parameters (MMF group)
Table 4 Last laboratory parameters (AZA group)
In general, MMF and AZA were well tolerated (see ). Most of adverse events with MMF were gastrointestinal complications; in five patients diarrhea was seen, and in three patients hepatotoxicity (reversible increase in serum transaminase levels) developed. Two patients with MMF and four patients with AZA developed reversible bone marrow suppression during the treatment. Complications of therapy, including hospitalization, amenorrhea, and infections, were similar with MMF and AZA.
Table 5 Outcome at last follow-up
CONCLUSION
Subsequent studies at the National Institutes of Health proved that concomitant i.v. methylprednisolone with monthly pulse i.v. CYCCitation[15],Citation[16] was more effective in the short term than either therapy alone. In longer follow-up of the same population, the combination regimen had no greater toxicity than CYC alone, but far superior renal outcomes. Although clearly effective, this regimen is associated with both short-term and long-term adverse effects, including increased risk of severe infections, gonadal damage,Citation[16–18] and malignancy.Citation[19] Many patients (up to 22%) fail to achieve remission with this regimen or relapse after treatment, and some patients still progress to end-stage renal disease.Citation[20]
The aim of the present study was to demonstrate the efficacy of mycophenolate mofetil (MMF) versus azathioprine (AZA) as a maintenance therapy for lupus nephritis. In the present study we achieved a total remission rate 84% (82% with MMF and 87% with AZA), complete remission rate of 59.3% (58% with MMF and 60% with AZA), and a partial remission rate of 25% (22% with MMF and 27% with AZA) over 41.5 + 7 months. There has been no uniformly accepted definition of remission. In most studies, remission is a composite of improvement in proteinuria, using 50% reduction in proteinuria for partial remission and proteinuria less than 0.5g/day for complete remission.
The Euro-Lupus Nephritis Trial, a European-based multi-center prospective trial, compared low-dose to high-dose i.v. CYC for severe active LN.Citation[21] The majority of patients was white and had class IV diffuse proliferative lupus nephritis (DPLN). At 41 months, there were no significant differences in the primary end point or cumulative probability of treatment failure between the high- and low-dose treatment arms (20 vs. 16%, respectively). There were also no differences in renal remissions (54 vs. 71%, respectively) or renal flares (29 vs. 27%, respectively). The shorter regimen had less toxicity with fewer and less severe infections. This study provides good support for a shorter duration and lower total dose of CYC for induction therapy for proliferative LN. The Euro-Lupus trial includes a population with relatively milder renal disease than in some other studies (mean creatinine 1–1.3 mg/dL; mean proteinuria 2.5–3.5 g/day for both groups). Moreover, almost 85% of the patients were Caucasian. Nevertheless, the Euro-Lupus regimen is an option for some patients with proliferative LN, particularly Caucasians with less severe renal injury. In addition, the study confirms that the sequential use of CYC and AZA is a viable strategy to reduce toxicity without compromising overall efficacy. In this cohort of patients who were on high dose CYC and AZA maintenance therapy, treatment failure rate was 13% and lower than Euro-Lupus trial. Most patients had milder renal disease (mean creatinine 0.91 + 0.23 mg/dL, mean proteinuria 1.58 + 0.7 g/day), like the Euro-Lupus trial, but fewer patients (54%) were class IV DPLN as compared to Euro-Lupus trial.
A recent trial by Contreras et al.Citation[22] sheds light on the relative efficacy of maintenance regimens using either MMF, AZA, or continued i.v. CYC in severe LN. The high-risk study population included 59 patients, predominantly African-Americans and Hispanics. The majority had diffuse proliferative disease with mean Scr 1.6 mg/dL and urine protein/creatinine ratio > 5. Fewer patients treated with AZA and MMF reached the primary endpoints of death and CRF compared to the CYC group. Relapse-free survival was higher with MMF (78%) and AZA (58%) compared to i.v. CYC (43%). Mortality was increased with i.v. CYC compared to both oral agents. They concluded that maintenance therapy with either MMF or AZA was superior to i.v. CYC. In the present study, we achieved a total remission rate 84% (82% with MMF and 87% with AZA), complete remission rate of 59.3% (58% with MMF and 60% with AZA), and a partial remission rate of 25% (22% with MMF and 27% with AZA) over 41.5 + 7 months. In the Conteras study, some patients did not achieve remission at the end of the induction phase with i.v. CYC, which may be attributable to the large percentage of Hispanics and Blacks in the study. Patients with rapidly progressive and crescentic disease were excluded.
In the present study, all patients were Caucasian. In comparison with the Conteras report, the lack of racial differences of our study group could explain the superiority of our total remission rate of AZA group (87% vs. 58%).
In the present study, creatinine levels are higher in the MMF group at the start, and proteinuria is higher after treatment in the MMF group. As proteinuria after treatment in the MMF group is higher compared to the AZA group, it could be possible that the AZA group has favored a better outcome for the AZA arm.
The adverse events experienced during our study were mostly unremarkable and were not severe enough to lead to the interruption of therapy. The patients' compliance to the therapy was similar in both groups. The adverse events profile of MMF and AZA were similar in our study patients. Most events were mild and reversible with dose reduction. The incidence of diarrhea increased with MMF. Complications of therapy, including hospitalizations, amenorrhea, infections, and gastrointestinal problems, were similar with MMF and AZA.
This retrospective study confirms favorable results for AZA and MMF in the maintenance treatment of lupus nephritis. In conclusion, after induction treatment with lower dosages CYC, AZA or MMF maintenance treatment is effective for patients with moderate to severe lupus nephritis.
DECLARATION OF INTEREST
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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