Induction phase treatment of proliferative LN
Most clinicians initially treat active proliferative LN with high doses of corticosteroids in conjunction with other immunosuppressive medications. High dose oral regimens include starting doses of predisone or prednisolone 1 mg/kg/day or 60 mg/day and/or “pulse” intravenous (IV) methylprednisolone infusions (0.5-1.0 g daily for one to three days followed by lower doses of oral corticosteroids.
Steroid doses have usually been tapered to 0.5mg/kg/day or less by the third month of treatment to avoid such adverse effects as cosmetic alterations, gastrointestinal ulceration, hypertension, psychoses, and enhanced risk of infectious complications.
Cytotoxic agents in conjunction with corticosteroids have long been a mainstay of many induction regimens for the treatment of LN.11-14 While it remains uncertain whether oral therapy or IV pulses of cyclophosphamide is more effective,15 clearly IV therapy involves a lower cumulative dose with the likelihood of fewer side effects and problems with adherence.
Through a series of trials at the National Institute of Health (NIH), IV monthly pulses of cyclophosphamide ( 0.5-1 g/m2) for six consecutive months followed by pulses every third month were established as an effective therapy that is superior to corticosteroids in preventing renal failure.33 Subsequent studies have focused on achieving equal efficacy but less long-term morbidity through use of shorter or modified induction and maintenance regimens.13,14
A trial by the EuroLupus Group14 randomized 90 patients with diffuse or focal proliferative LN or membranous plus proliferative disease to receive either the standard six monthly pulses of cyclophosphamide (0.5-1 g/m2/month) followed by infusions every third month or to a shorter treatment course consisting of 500 mg of IV cyclophosphamide every two weeks for six doses (total dose 3g) and then switching to azathioprine maintenance therapy (2mg/kg/day). Both regimens were equally effective in achieving various renal and extra-renal outcomes.
The shorter regimen had less toxicity with significantly fewer severe and total infections. This trial was largely performed in Caucasians and may not be applicable to other populations. Reports after five and 10 years continued to find no differences in the risk of renal failure between treatment groups15 and no differences in serum creatinine values and 24-hour urinary protein excretion at 10 years. The cumulative dose of cyclophosphamide using the older NIH regimen was almost double that of the newer low-dose regimen.
Although there are limitations to the Euro-Lupus data (small numbers of patients, mainly Caucasian subjects, and exclusion of patients with severe renal insufficiency), this regimen has largely replaced the older NIH regimen and is widely accepted as a first-line induction therapy for severe LN.
Controlled trials, and subsequent meta-analyses, have also examined the role of mycophenolate mofetil (MMF) as a first-line induction agent for severe LN12-14,16 One Chinese study randomized 42 patients to receive either 12 months of oral MMF (2g/d for six months followed by 1 g daily for six months) or six months of oral cyclophosphamide (2.5 mg/kg/day) followed by oral azathioprine (1.5 mg/kg/day) for six months,17 both along with concomitant corticosteroids.
At 12 months, the number of complete or partial remissions and relapses was similar in both treatment arms, but with fewer infections and deaths in the MMF arm. Longer follow-up confirmed these benefits.18 A second Chinese trial also compared treatment with pulse IV cyclophosphamide to MMF and found that MMF -treated patients had greater reductions in proteinuria and hematuria and improved histology on repeat biopsy.1
A U.S. induction trial including 140 patients mostly with proliferative lupus nephritis compared the results of six IV cyclophosphamide monthly pulses to oral MMF up to 3 g daily with a similar tapering dose of corticosteroids.19 In both treatment arms, more than 50% of subjects were African American.
At six months, complete remissions and complete and partial remission combined were significantly more common in the MMF arm. Moreover, adverse effects were less severe with MMF, with no significant differences at three years in the numbers of patients with renal failure, end-stage renal disease (ESRD), or mortality.
The Aspreva Lupus Management Study (ALMS), a 370-patient international multicenter trial of induction therapy with either MMF, 3g/day, or monthly IV cyclophosphamide showed equivalent complete and partial remissions at six months as well as resolution or stability of all renal and extra-renal parameters in both study arms.20 In the small subgroup of patients with initial GFR less than 30mL/min/1.73 m2, there was no indication that MMF was less effective than cyclophosphamide.21
The adverse effects of each regimen were as expected, with diarrhea the most common adverse effect with MMF and nausea/vomiting and alopecia the most common adverse effects with cyclophosphamide therapy. Mortality in both treatment arms was similar, with only 14 deaths, mostly infection-related, out of the 370 patients. With the results of these two large randomized trials, MMF has become well accepted as a first-line induction therapy for severe LN.
Other induction agents
Other agents studied as induction therapy for severe LN include azathioprine, cyclosporine, tacrolimus, plasmapheresis, IV gamma globulin, rituximab, and CTLA4IG, a co-stimulatory blocker. None has achieved the success of the EuroLupus or MMF regimens. Although a trial comparing azathioprine to cyclophosphamide found no difference in eventual outcome, there were more relapses and more doublings of serum creatinine values with azathioprine.22