Treatment of lupus nephritis-the advantages of a flexible approach

DiVuse proliferative glomerulonephritis (class IV of combined small doses of corticosteroids with immunothe WHO classification) is the most frequent and severe suppressive agents, namely cyclophosphamide and/or form of renal involvement in systemic lupus eryth- azathioprine. A number of controlled trials compared ematosus (SLE ). The prognosis of this disease was the eVects of immunosuppressive agents with those of ominous until the early sixties but it has considerably corticosteroids alone. The results have been controverimproved over the years. Several factors have contrib- sial. Some studies failed to show any benefit of uted to this: earlier diagnosis of SLE, detection of immunosuppressive drug [4,5], while others found that milder forms of SLE nephritis, and more appropriate these agents could favourably influence the outcome prevention and management of extrarenal complica- of diVuse lupus nephritis [6,7]. A bias of those trials tions. There are few doubts, however, that the tremend- was the small number of patients enrolled, which ous improvement in the prognosis of lupus nephritis weakened the statistical power. However, when the is mainly due to the refinement of the specific data of the available trials were collected in a pooled treatment. analysis, it clearly appeared that the risk of renal death was significantly lower for patients assigned to receive immunosuppressive agents than for those given sterHigh-dose versus low-dose steroids oids alone [8 ]. In 1986 the group of the National Institutes of DiVerent therapeutic approaches have been adopted Health ( NIH) in Bethesda reported the long-term over the years: corticosteroids were the first eVective results of a controlled trial in which patients with lupus agents used in lupus nephritis and still are of vital nephritis were randomized to be given high-dose predimportance for the management of this disease. It was nisone alone or moderate doses of prednisone in associPollak et al. [1 ] who showed that small doses of ation with oral cyclophosphamide or with azathioprine corticosteroids could not modify the relentless outcome or with azathioprine plus oral cyclophosphamide or of diVuse lupus nephritis, while higher dosages could with intravenous pulses of high-dose cyclophosphamsignificantly improve the prognosis. Since then, most ide [9 ]. While there was no diVerence between the five physicians treated class IV nephritis with prednisone, groups until the 5th year, the kidney survival was 1‐2 mg/per kg body-weight per day for 6 months or significantly worse at 10 years in patients who were until control of the disease is obtained, followed by given corticosteroids alone than in those given intraprogressive reduction of the doses. Such an approach venous cyclophosphamide. There was a trend to a is not completely satisfying, however. The use of high- better outcome for the group assigned to intravenous dose corticosteroids often leads to disabling and life- cyclophosphamide than for those given various types threatening complications; moreover, even high doses and combinations of oral immunosuppressive drugs, of oral prednisone cannot ever achieve a good control but this diVerence was marginal and not statistically of SLE. Finally, progressive glomerulosclerosis may significant. Even when the follow-up was extended to develop in patients treated with corticosteroids alone, 16 years no diVerence could be seen between intravenas shown by repeated biopsies [2 ]. Because of the poor ous and oral cyclophosphamide, either alone or comresults in the long term, even Pollak et al. [3 ] aban- bined with azathioprine, while patients treated with doned the use of large doses of prednisone. steroids alone or in association with azathioprine had a worse kidney survival than those assigned to cycloImmunosuppressive drugs versus steroids alone phosphamide [10 ]. The NIH group performed further controlled trials In order to reduce the doses of prednisone and to that showed the superiority of monthly intravenous reinforce the eYcacy of treatment many investigators pulses of cyclophosphamide over monthly intravenous pulses of methylprednisone ( MP) and the more pro