There is evidence from animal models of lupus nephritis that the combination of CTLA4-immunoglobulin (Ig)G plus cyclophosphamide can reverse this disease. The multicenter, double-blind, phase 2 ACCESS trial was undertaken to examine the value of abatacept (a fusion protein of IgG-Fc plus CTLA4 that binds to CD80 to block the costimulatory signal to T-cells) in patients with lupus nephritis. Wofsy and colleagues presented the 24-week and 52-week data from the ACCESS trial at the 2013 annual meeting of the American College of Rheumatology held in San Diego, California from October 25-30 (Abstract 884).
Patients with biopsy-proven class III or IV lupus nephritis and a urine protein:creatinine ratio of >1 received low-dose intravenous cyclophosphamide (500 mg every 2 weeks for 6 cycles) followed by azathioprine (2 mg/kg daily) per the Euro-Lupus nephritis regimen. Patients were then randomized in a double-blind fashion to receive saline or abatacept intravenously at weeks 0, 2, and 4, and then every 4 weeks. All patients also received oral prednisone at a starting dose of 60 mg daily, which was tapered to 10 mg daily within 12 weeks.
The primary clinical outcome of the ACCESS trial was a complete response at 24 weeks, defined as a urine protein:creatinine ratio of <0.5, serum creatinine level that was either normal or within 25% of baseline, and an ability to taper prednisone to 10 mg daily by week 12..
At 24 weeks, the results showed a complete response rate of 33% in the abatacept group compared with 31% in the control group (P = .85). The partial response rates were 59% in both groups. Adverse events were comparable in the abatacept and the control groups. There was a trend toward a higher complete response rate among African-American patients receiving abatacept (33%) versus saline control (16%), but these data did not reach statistical significance (P = .20). There were no significant differences between the groups at week 24 in mean urine protein:creatinine ratio, anti–ds-DNA and complement levels, British Isles Lupus Assessment Group score, 36-Item Short Form Health Survey scores, or frequency of serious adverse events. However, the Patient’s Global Assessment score in the abatacept group improved by 74% compared with by 38% in the control group (P = .051).
The ACCESS trial did not achieve its primary clinical end point of demonstrating a benefit of adding abatacept to the Euro-Lupus nephritis regimen in patients with lupus nephritis. However, the trial did validate the Euro-Lupus nephritis regimen in a racially and ethnically diverse North American population, demonstrating a >30% complete response rate within 24 weeks, which is significantly higher than that reported in previous trials involving patients with lupus nephritis.
In the second phase of the ACCESS trial, patients who showed complete response s at 24 weeks were randomized to abatacept plus azathioprine or to azathioprine alone, as a control. At week 52, complete responses were observed in 50% of the patients in the abatacept plus azathioprine and 62% in the controls, with partial responses observed in 5% of patients in each group.
These results demonstrated that 50% of the complete responses achieved at week 24 with abatacept were sustained for an additional 6 months, without the need for aggressive immunosuppressive therapy.