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Moving East: the Euro–Lupus Nephritis regimen in Asia

2016; Elsevier BV; Volume: 89; Issue: 1 Linguagem: Inglês

10.1016/j.kint.2015.11.003

1523-1755

Frédéric Houssiau,

Inflammatory Bowel Disease

Treatment of lupus nephritis is more evidenced-based than ever. Yet many areas of uncertainty persist. The article by Rathi et al. brings a piece to the puzzle by comparing, in a group of Indian patients, the Euro-Lupus low-dose i.v. cyclophosphamide regimen with mycophenolate mofetil. Although some caveats must be raised, the results suggest that, after crossing the Atlantic, the Euro-Lupus regimen may well be moving East. Treatment of lupus nephritis is more evidenced-based than ever. Yet many areas of uncertainty persist. The article by Rathi et al. brings a piece to the puzzle by comparing, in a group of Indian patients, the Euro-Lupus low-dose i.v. cyclophosphamide regimen with mycophenolate mofetil. Although some caveats must be raised, the results suggest that, after crossing the Atlantic, the Euro-Lupus regimen may well be moving East. Renal involvement remains a major challenge for patients suffering from systemic lupus erythematosus. Lupus nephritis (LN) is frequent (30%–60% of cases) and leads to end-stage renal disease in 5%–30% of these patients, depending on the length of follow-up. Poor response to initial immunosuppression, nonadherence to therapy, and non-Caucasian ethnicity are among the most influential determinants of poor prognosis. Management of LN is by far the most standardized therapeutic area in systemic lupus erythematosus. Thus, quite comparable treatment recommendations have been issued on both sides of the Atlantic.1Bertsias G.K. Tektonidou M. Amoura Z. et al.Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis.Ann Rheum Dis. 2012; 71: 1771-1782Crossref PubMed Scopus (745) Google Scholar, 2Hahn B.H. McMahon M.A. Wilkinson A. et al.American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis.Arthritis Care Res (Hoboken). 2012; 64: 797-808Crossref PubMed Scopus (942) Google Scholar For induction of a response, the choice is between i.v. cyclophosphamide (CYC) and mycophenolate mofetil (MMF), both on top of glucocorticoids (GCs), prescribed i.v. (pulse methylprednisolone) and orally; for maintenance, the choice is between azathioprine and MMF, with minimal chronic use of GCs. Despite these advances, many uncertainties persist. First, very few studies have addressed the initial dose of GCs that should be prescribed, a pivotal issue given their role in damage accrual. The possibility that oral GCs are not needed is suggested by the results of a protocol (RITUXILUP) in which patients treated with pulse i.v. methylprednisolone, MMF, and rituximab performed well, without receiving any oral GC therapy. Second, we lack undisputed short-term predictors of long-term outcome. In this respect, we recently demonstrated, in 2 distinct LN cohorts, that (i) a proteinuria cutoff value of 0.7–0.8 g/d measured at 12 months maximizes sensitivity and specificity for the prediction of good long-term renal outcome, with a very high positive predictive value (88% and 94% in the 2 cohorts); and (ii) inclusion of the results of urinalysis in the response criteria set at 12 months undermined early identification of patients with good long-term renal outcome based on proteinuria decrease alone.3Dall’Era M. Cisternas M.G. Smilek D.E. et al.Predictors of long-term renal outcome in lupus nephritis trials: lessons learned from the Euro-Lupus Nephritis cohort.Arthritis Rheumatol. 2015; 67: 1305-1313Crossref Scopus (171) Google Scholar, 4Tamirou F. Lauwerys B.R. Dall’Era M. et al.A proteinuria cut-off level of 0.7 g/day after 12 months of treatment best predicts long-term renal outcome in lupus nephritis: data from the MAINTAIN Nephritis Trial.Lupus Sci Med. 2015; 2: e000123https://doi.org/10.1136/lupus-2015-000123Crossref Scopus (105) Google Scholar Third, no trial has addressed which treatment switch (if any) should be proposed to patients not achieving a sufficient response. Whether (and when) another cytotoxic drug should be tried or whether RTX should be prescribed in these cases, a hypothesis currently addressed by the RING (Rituximab in Lupus Nephritis with Remission as a Goal) trial, is currently unknown. Lastly, the question of the ideal duration of maintenance therapy has been ignored. The article by Rathi et al.5Rathi M. Goyal A. Jaryal A. et al.Comparison of low-dose intravenous cyclophosphamide with oral mycophenolate mofetil in the treatment of lupus nephritis.Kidney Int. 2016; 89: 235-242Abstract Full Text Full Text PDF Scopus (71) Google Scholar (2016) fills specific gaps concerning the low-dose i.v. CYC induction regimen, known as the Euro-Lupus (EL) protocol. This regimen, consisting of 6 biweekly pulses of a fixed 500-mg dose of i.v. CYC followed by azathioprine, was developed in the early 1990s at St Thomas’ Hospital (London, UK) and subsequently tested in a prospective trial, the Euro–Lupus Nephritis Trial (ELNT),6Houssiau F.A. Vasconcelos C. D’Cruz D. et al.Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide.Arthritis Rheum. 2002; 46: 2121-2131Crossref PubMed Scopus (814) Google Scholar a head-to-head comparison with the so-called NIH regimen, consisting of 6 monthly high-dose (0.75–1 g/m2) i.v. CYC pulses followed by quarterly pulses. After 10 years of follow-up, rates of end-stage renal disease and renal impairment were similar.7Houssiau F.A. Vasconcelos C. D’Cruz D. et al.The 10-year follow-up data of the Euro-Lupus Nephritis Trial comparing low-dose and high-dose intravenous cyclophosphamide.Ann Rheum Dis. 2010; 69: 61-64Crossref PubMed Scopus (371) Google Scholar The major caveat raised against an indiscriminate use of the EL regimen is that the ELNT was performed with a mainly Caucasian European population and that its efficacy should not be extrapolated to LN populations with different ethnic backgrounds. This uncertainty was recently waived for patients of Afro-American or Hispanic descent by the results of ACCESS (Abatacept and Cyclophosphamide Combination Efficacy and Safety Study), in which the add-on value of abatacept was tested on top of the EL regimen used as standard of care in an ethnically mixed group of LN patients (39% Afro-American and 40% Hispanic or Mestizo). While abatacept was not found superior to standard of care, the EL regimen achieved, on its own, a 25% complete response rate at 6 months, similar to that observed in both arms (MMF and high-dose i.v. CYC) of ALMS (Aspreva Lupus Management Study),8Appel G.B. Contreras G. Dooley M.A. et al.Mycophenolate mofetil versus cyclosphosphamide for induction treatment of lupus nephritis.J Am Soc Nephrol. 2009; 20: 1103-1112Crossref PubMed Scopus (779) Google Scholar, 9Wofsy D. Diamond B. Houssiau F.A. Crossing the Atlantic: the Euro-Lupus Nephritis regimen in North America.Arthritis Rheumatol. 2015; 67: 1144-1146Crossref Scopus (19) Google Scholar thereby demonstrating the efficacy of the EL regimen in an ethnically diverse LN population. After having crossed the Atlantic, the EL regimen is now moving East (Figure 1). The article by Rathi et al.5Rathi M. Goyal A. Jaryal A. et al.Comparison of low-dose intravenous cyclophosphamide with oral mycophenolate mofetil in the treatment of lupus nephritis.Kidney Int. 2016; 89: 235-242Abstract Full Text Full Text PDF Scopus (71) Google Scholar indeed describes the first randomized trial using the EL regimen in India, with good short-term results, in terms of both efficacy and safety. Rathi et al.5Rathi M. Goyal A. Jaryal A. et al.Comparison of low-dose intravenous cyclophosphamide with oral mycophenolate mofetil in the treatment of lupus nephritis.Kidney Int. 2016; 89: 235-242Abstract Full Text Full Text PDF Scopus (71) Google Scholar fill another gap, namely a head-to-head comparison of the EL regimen and MMF. While the latter immunosuppressant was found equally efficacious compared with high-dose i.v. CYC in at least 4 randomized trials, including ALMS,9Wofsy D. Diamond B. Houssiau F.A. Crossing the Atlantic: the Euro-Lupus Nephritis regimen in North America.Arthritis Rheumatol. 2015; 67: 1144-1146Crossref Scopus (19) Google Scholar it was never tested against the EL regimen. In a well-designed non-inferiority controlled randomized trial, the investigators included 100 LN patients, half of whom received MMF for 6 months (target dose between 1.5 and 3 g/d) and the other half 6 biweekly 500-mg i.v. CYC pulses followed by azathioprine (2 mg/kg/d) for 3 additional months. Notably, all patients received huge amounts of GCs (3 i.v. methylprednisolone pulses of 750 mg, followed by oral prednisolone at a dose of 1 mg/kg/d for 8 weeks). All patients were on hydroxychloroquine and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. After 6 months, half of the patients in both groups achieved complete response, defined by a proteinuria ≤0.5 g/d, return to normal serum creatinine, and inactive urine sediment. Side effects were comparable between groups, except for gastrointestinal adverse events, more common in the MMF group. Notably, very few patients experienced gastrointestinal symptoms in the EL group, which is consistent with our own experience. Several notes of caution should be made. First, the dose of GCs was very high, raising the possibility that the results at 6 months were mostly driven by GCs. The doses were indeed twice as high as in the ELNT and higher than in ALMS. Second, 26% of the patients suffered from pure class V LN (only 16% in ALMS and none in the ELNT). This said, a subset analysis excluding class V cases did not change the conclusions. Third, MMF was soundly introduced gradually, but this might have slightly disadvantaged this arm compared to the i.v. CYC group receiving a full dose from the start, the more so as the trial was very short-term. Fourth, the most severe cases of LN (crescentic and serum creatinine >250 μmol/l) were excluded, for which no conclusions can therefore be drawn. Fifth, the cost analysis, much in favor of the EL arm in this analysis (7 times less expensive than MMF), is obviously biased by the reimbursement system operating in this public-sector hospital that does not charge patients for infusion and day-care treatment. Mutatis mutandis, in Belgium, costs, over a period of 6 months, almost break even: €760 for 6 months of MMF treatment (2 g/d; brand or generic) and €708 for 6 months of EL treatment (€45 for six 500-mg doses of i.v. CYC, €630 for 6 hospital infusions per day, and €33 for azathioprine at 2 mg/kg/d during 3 months). Last but not least, follow-up is very short. Patients and lupologists eagerly await newer drugs, including targeted therapies, which may possibly replace GCs and cytotoxics. In between, trials aimed at fine-tuning how best to use currently available drugs are most welcome. In this respect, it should be stressed that the EL regimen ensures optimal compliance with treatment within the first months, with a rhythm of infusions well in line with the medical visits needed to secure optimal follow-up of these critically ill patients. FAH was the designer and coordinator of the ELNT, which supports the use of low-dose i.v. CYC—the so-called the EL regimen—as induction therapy of LN. The ELNT was an investigator-initiated study.