Treatment of Lupus Nephritis With Abatacept: The Abatacept and Cyclophosphamide Combination Efficacy and Safety Study

Abstract

Objective To assess the efficacy and safety of a 24-week course of abatacept in the treatment of active lupus nephritis. An additional exploratory objective was to assess the potential of abatacept to induce ‘clinical tolerance’, defined as sustained clinical quiescence of lupus nephritis after discontinuation of immunosuppressive therapy. Methods Patients (n=134) with active lupus nephritis were studied in a randomized, double-blind phase II add-on trial in which they received either abatacept or placebo in conjunction with the Euro-Lupus regimen of low-dose cyclophosphamide followed by azathioprine. The primary efficacy outcome was the frequency of complete response (CR) at week 24. Thereafter, patients who met either complete or partial response criteria continued blinded treatment through week 52. During this phase of the study, subjects in the abatacept treatment group who had achieved CR status at week 24 discontinued immunosuppressive therapy other than prednisone (10 mg/d). Results There were no statistically significant differences between groups with respect to the primary outcome or any of the secondary outcomes, including measures of safety. Thirty-three percent of subjects in the treatment group and 31% of subjects in the control group achieved CR status at week 24. Fifty percent of subjects in the treatment group who met CR criteria and therefore discontinued immunosuppressive therapy at week 24 maintained their CR status through week 52. Conclusion The addition of abatacept to a regimen of cyclophosphamide followed by azathioprine did not improve the outcome of lupus nephritis at either 24 or 52 weeks. No worrisome safety signals were encountered.

Another Piece of the Puzzle of Podocyte B7-1 Expression: Lupus Nephritis

“…In this study, complete response rates (defined as estimated glomerular filtration rate ≥90% of screening level, urinary protein-to-creatinine ratio (P/C) <0.26 g/g and inactive urinary sediment) were comparable between abatacept and placebo groups. These findings were confirmed by the subsequent ACCESS trial [33], in which the add-on abatacept therapy on a background of cyclophosphamide and azathioprine plus steroid treatment did not induce clinical benefit in LN patients, as revealed by the similar complete response rates (urinary P/C <0.5, serum creatinine level of ≤1.2 mg/dl or ≤125% of baseline, and possibility to taper prednisone therapy) among the study groups [33]. Moreover, in both trials, secondary end points were not met.…”

“…Moreover, in both trials, secondary end points were not met. Although Furie et al [32] reported improvements from baseline in anti-dsDNA antibodies and complement levels, no statistical comparisons were made for the biomarker analyses, and these results were not confirmed by the ACCESS study [33]. …”

Update on the treatment of focal segmental glomerulosclerosis in renal transplantation

“…The therapeutic role of co-stimulatory molecule blockades is emerging for some glomerulonephritis on native kidneys (e.g., lupus nephritis) [125] . Recently, abatacept was associated with interesting results in proteinuria reduction in a small case series of FSGS recurrent patients [103] .…”

Lupus Nephritis: A Different Disease in European Patients?

“…It was repeatedly stressed that it still remains to be demonstrated that a low-dose CYC regimen can be safely used also in patients with LN of other ethnicities including African Americans, Hispanics and Asian patients [65]. A recent trial of abatacept for LN (ACCESS [66]) demonstrated a surprisingly high response rate to low-dose CYC (which was used as a background treatment) in a mostly black (37%) and Hispanic (41%) population. The rate of complete remission (more than 30% in both arms treated with low-dose CYC) was higher than in recent trials of LN (ALMS [67] and LUNAR [68]).…”

“…The rate of complete remission (more than 30% in both arms treated with low-dose CYC) was higher than in recent trials of LN (ALMS [67] and LUNAR [68]). Even after using the same criteria for complete response (proteinuria ≤0.5 g/ 24 h and no worsening of serum creatinine compared to baseline), low-dose CYC in the ACCESS trial [66] was similarly effective as high-dose CYC in the ALMS trial [67] and low-dose CYC in the ELNT trial [63], with complete response achieved in 22, 24 and 23% in the ALMS, ELNT and ACCESS trials, respectively [69]. Although there were some differences in the severity of LN among these trials [the proportion of patients with proteinuria ≥3 g/24 h was lower in the low-dose CYC ELNT trial (42%) and in the low-dose CYC ACCESS trial (52%) compared to the high-dose CYC ALMS trial (60%)], these data suggest that at least the short-term (6-month) efficacy of low-dose CYC may be similar in African Americans and Hispanics as in Caucasian patients [69], especially when high-dose corticosteroids are given concomitantly.…”