Immunosuppressive Agents for the Treatment of Lupus Nephritis
Abstract
Abstract
Lupus nephritis (LN) is one of the most serious complications in patients with systemic lupus erythematosus (SLE). Initial clinical presentation with renal involvement is associated with more frequent exacerbations of lupus and lower survival.1 Although LN continues to be associated with high morbidity and mortality, even partial remission with treatment improves patient and renal survival significantly at 10 years.2,3 The first National Institutes of Health (NIH) trials for LN were initiated in the late 1970s; there are currently 30 ongoing clinical trials listed under clinicaltrials.gov. Although the NIH trials were instrumental in establishing cyclophosphamide (CYC) as the standard-of-care immunosuppressive agent for LN, the cumulative rate of relapse in an observational study was 25% at five years and 46% at 10 years in patients treated with this agent.4
With recent insights into the pathogenesis of SLE and with the design of biologic agents, the search for a safer and more effective ‘gold standard’ in LN treatment has led to several clinical trials in the last decade, some with promising and some with disappointing results. In this article we will present an overview of the treatment options currently available for patients with LN and provide a brief glimpse into what the future holds with respect to other immunosuppressive agents, including biologics.
Cyclophosphamide
In 1986, Austin et al. published the results of the five treatment arms of the NIH LN trial. They found that prednisone (PDN) alone increased the risk for renal flares compared with high-dose intravenous (IV) CYC. Oral CYC showed a marginal advantage in maintaining renal function and preventing end-stage renal disease (ESRD) over PDN alone.5–7 However, the use of CYC is limited by its side-effect profile, which includes hemorrhagic cystitis, bone marrow suppression, opportunistic infections, and premature gonadal failure.8
To address the issue of toxicity related to high cumulative doses of CYC, Houssiau et al. compared high-dose with low-dose CYC in the Euro-Lupus Nephritis trial. Ninety SLE patients were randomized to either the NIH regimen of 0.75–1g/m2 body surface area (high-dose) or CYC IV 500mg every two weeks for six doses for induction followed by oral azathioprine (AZA) for maintenance treatment (low-dose). The cumulative probability of renal remission and treatment failure was comparable between the two groups. Even the risk for renal flares was similar between the two regimens, although the rate of infections was lower in the low-dose group. Of note, however, the patients in this trial had less severe LN than the patients in the NIH trials.9,10
A recent meta-analysis of 25 articles on randomized controlled trials found that CYC in combination with steroids reduced the risk for doubling of serum creatinine compared with steroids alone (relative risk [RR] 0.59), but had no impact on overall mortality. 11
In a prospective study from 1988 to 2000 of 38 biopsy-proven LN patients treated with pulse methylprednisolone (MP) and CYC, the mean time to remission was 10±15 months, with 47% patients going into complete remission (CR) or partial remission (PR) during the study. About one-quarter of the patients still had proteinuria >1g/24 hours with normal renal function after two years of treatment. Repeat renal biopsies showed an increase in features of chronicity, including marked glomerular sclerosis and tubulointerstitial fibrosis. About 85% of relapses occurred within the first five years of treatment, with 13% of patients progressing to ESRD.12 Although CYC remains the recommended treatment for patients with severe LN, according to the 2008 European League Against Rheumatism(EULAR) task force report it is far from the perfect medication for LN.13
Mycophenolate Mofetil
Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid, was approved for prevention of renal transplant rejection in 1995 and, one year later, for other solid-tumor transplants. Within two years, case reports were published regarding its successful use as rescue therapy for LN refractory to other immunosuppressive agents. In 1999, Dooley et al. reported on 13 patients treated with MMF after failing treatment with CYC. A significant decrease in proteinuria as measured by urine protein-to-creatinine ratio, as well as an improvement in the baseline serum creatinine, was noted.14 The first randomized controlled trial comparing MMF with oral CYC was reported by Chan et al. Forty-two LN patients were treated with MMF in combination with prednisone for 12 months, and the CR and PR rates were compared with those of CYC plus prednisone for six months followed by azathioprine. Although there were no differences in remission rates between the two groups, the very high remission rates published in this study—81% in the MMF-treated group and 76% in the patients treated with CYC—have not been reproducible in subsequent trials.15
In another randomized controlled trial comparing MMF with IV CYC in 46 patients, Hu at al. demonstrated that there was more effective inhibition of autoantibody formation and fewer chronicity changes on repeat renal biopsies in the MMF group.16 Twenty patients with renal biopsy changes associated with poor prognosis—such as non-inflammatory necrotizing vasculopathy, thrombotic microangiopathy, and vasculitis—had a CR rate of 44.4% in MMF patients compared with 0% in the CYC arm of the study (p=0.026). Fifty-five percent of patients in the MMF group improved to proteinuria in the normal range versus 9% in the IV CYC group (p=0.05).17 Infections occurred in 30.4% of the patients in the CYC group versus only 17.4% of those in the MMF group.16 A 10-fold decrease in amenorrhea was also noted in women treated with MMF versus CYC. 18
