CYCLONES - CYClophosphamide LOw Dose and No Extra Steroid

The use of glucocorticoids (GC) greatly increased the survival of patients with SLE, particularly in cases of nephritis and a more significant improvement to 80% with the introduction of therapy combined with immunosuppressants in the late 1960s. This therapeutic regimen, however, results in a very high incidence of irreversible damage to the patient that is associated in more than 70% of the cases to GC use and in a smaller proportion to the use of a high dose of cyclophosphamide. In the last years, some less toxic schemes have been proposed. The use of low-dose cyclophosphamide has been shown to have equal efficacy as high dose for the induction of remission of lupus nephritis with a fifteen-year follow-up. Regarding GC, lower doses of methylprednisolone (MP) pulse have been shown to have similar efficacy and lower risk of infection. In addition, retrospective studies have found that high doses of oral GC during the induction period are associated with a higher incidence of side effects without a corresponding increase in efficacy . But it was only in 2013 that the first study was published that did not use oral GC in the treatment of lupus nephritis induction with excellent results. In transplantation area, there are already several trials minimizing the use of GC proposing in the first days after transplantation the use the methylprednisolone (MP) IV pulse (day 1, 500mg, day 2, 250mg and day 3, 125mg) followed by oral GC for 4 days (60mg, 40mg, 30mg and 20mg). In this study, the same incidence of acute rejection occurred when compared to patients who were treated with oral GC for a prolonged period. Regarding the route of administration of GC, it is important to emphasize that MP is three times more active through non-genomic pathway than through genomic pathway, which, in theory, results in a higher efficiency and lower collateral effect, when compared to the GC oral route that has similar potency through the two pathways. In addition, MP has a simpler and dose-proportional pharmacokinetics, whereas for oral prednisolone this kinetics is more complex and difficult to predict the dose required to achieve a specific concentration. Therefore, the present study intends to evaluate the efficacy and adverse effects of cyclophosphamide (EUROLUPUS scheme) associated to usual GC dose compared with EUROLUPUS with no extra oral GC regimen. The estimated number of patients was 116 patients for each arm (considering an error α = 0.05 and a power (1-β) of 80%). In moderate flares, due to other systemic manifestations, the use of a maximum of 20mg / day of prednisone for 1 month and a progressive reduction of 5mg every 15 days until withdrawal is allowed. Other immunosuppressive, biological, intravenous immunoglobulin or plasmapheresis will be prohibited. Regarding statistics, an Intention-To-Treat (ITT) analysis will be performed for the randomized patients, so that patients presenting side effects or low adherence to treatment will remain in the randomized group and will be evaluated at week 24. The proportion of patients achieving complete and partial remission at week 24 will be compared by the chi-square test or the Fisher's exact test, as appropriate. The same statistical methodology will be applied to compare the number of events listed as secondary endpoints.