Crossing the Atlantic: the Euro-Lupus Nephritis regimen in North America.

More than a quarter century has passed since a landmark trial at the National Institutes of Health (NIH) established pulse intravenous (IV) cyclophosphamide (CYC) and high-dose glucocorticoids as the standard of care for active lupus nephritis (1). In the ensuing years, numerous other conventional and biologic therapies have been proposed and tested, most notably mycophenolate mofetil (MMF) (2) and rituximab (3), but none has been demonstrated to be superior to IV CYC during induction treatment of active disease. Until the emergence of new treatment strategies that are proven to be superior to IV CYC, there will be a need for evidence-based best practices to guide the use of CYC. For this reason, the Euro-Lupus Nephritis Trial (ELNT) compared 2 approaches to IV CYC therapy. One approach consisted of 44 weeks of IV CYC based on the NIH regimen, followed by maintenance therapy with azathioprine (AZA). The other approach consisted of just 6 biweekly infusions of IV CYC at lower doses (500 mg/infusion), followed by maintenance therapy with AZA (4,5). After 10 years of followup, efficacy was comparable in the 2 groups; the frequency of serious infectious complications was lower in the low-dose IV CYC group, but this advantage did not reach statistical significance. Despite the ELNT results, many lupus experts have been hesitant to adopt the modified regimen, citing concerns that the findings in a population of northern European, primarily Caucasian, subjects might not be generalizable to other populations that tend to have more severe and refractory nephritis (e.g., black and Hispanic patients). A recent trial of abatacept for lupus nephritis (NCT00774852) has provided new data that may allay concerns about the generalizability of the ELNT regimen (6). The Abatacept and Cyclophosphamide Combination: Efficacy and Safety Study (ACCESS) trial, in which all subjects received the ELNT regimen as background therapy, was conducted in a North American patient population that was 37% black and 41% Hispanic. Although the trial did not demonstrate a benefit of abatacept, the results were striking in that the rate of complete response in both treatment groups (with or without abatacept) was .30% at 6 months, which is higher than rates of complete response in other recent lupus nephritis trials (2,3). The high response rate was particularly surprising given the racial and ethnic diversity within the study population. We are keenly aware that it is hazardous to compare results from trials with different study designs and populations. Among other potential pitfalls, the studies do not all use the same criteria to define complete response. To address this problem, we applied the same response criteria to the raw data from the ELNT, the ACCESS trial, and the Aspreva Lupus Management Study (ALMS) (NCT00377637) (Table 1). To enable the use of data elements that were available from all 3 trials, we defined complete response at 6 months as proteinuria #0.5 gm/24 hours and no worsening of the serum creatinine level relative to baseline. According to this analysis, the rate of complete response was strikingly similar among all of the groups. The MMF standard-of-care regimen yielded a complete response rate of 21% in the ALMS trial. The high-dose IV CYC regimen yielded a complete response rate of 22% and 24% in the ALMS and ELNT trials, respectively, and the low-dose IV CYC regimen yielded a complete response rate of 23% and 25% in the ACCESS David Wofsy, MD: University of California, San Francisco; Betty Diamond, MD: Feinstein Institute for Medical Research, Manhasset, New York; Fr ed eric A. Houssiau, MD, PhD: Universit e Catholique de Louvain, Brussels, Belgium. Address correspondence to David Wofsy, MD, Division of Rheumatology (Box 0633), University of California San Francisco, 533 Parnassus Avenue, San Francisco, CA 94143. E-mail: wofsyd@ medsch.ucsf.edu. Submitted for publication November 11, 2014; accepted in revised form February 5, 2015.