The results of the ACCESS study, “Abatacept and Cyclophosphamide Combination Therapy for Lupus Nephritis” sponsored by the Immune Tolerance Network (ITN) and led by Drs. Betty Diamond (The Feinstein Institute) and David Wofsy (University of California, San Francisco), were published this week in Arthritis and Rheumatology. Abatacept (ORENCIA®) in combination with low-dose cyclophosphamide (Cytoxan, Bristol-Myers Squibb) did not improve the proportion of lupus nephritis patients who achieved a complete response compared to low-dose cyclophosphamide alone.
The ACCESS study was a phase II randomized, double-blind, placebo-controlled trial which enrolled 134 lupus nephritis patients from the US and Mexico. Patients were randomized to monthly infusions of either abatacept or placebo, and both treatment groups received low-dose cyclophosphamide, followed by azathioprine and prednisone maintenance therapy. The primary endpoint compared the proportion of patients in each group who achieved a complete renal response at 24 weeks, as assessed by common clinical and laboratory measures of renal function.
Abatacept (CTLA4Ig), a biologic approved for rheumatoid arthritis, blocks the co-stimulatory signal that is required for the activation of effector T cells in the presence of an antigen. The investigators hypothesized that blocking co-stimulatory signals with abatacept while simultaneously quelling inflammation using cyclophosphamide might change the immune system in a durable way that stops the autoimmune attack on self-antigens in lupus nephritis.
At 24 weeks there was no difference in response rates between the treatment and control arms, where 33% (22/66) of patients in the treatment group and 31% (21/68) of the patients in the control group achieved a compete response. There was also no difference in the rate of lupus nephritis renal flare or significant adverse events between the two groups.
The study also included an exploratory phase to assess whether those who achieved a complete response in the abatacept group could be withdrawn from abatacept and azathioprine immunosuppression, and maintain disease remission at 52 weeks on low dose prednisone alone. Fifty percent (11/22) of complete responders in the abatacept group were able to withdraw from azathioprine and maintain remission at 52 weeks on prednisone alone, compared to 62% (13/21) of those in the control group who maintained remission while on azathioprine and prednisone. The results raise the possibility that individuals who respond to treatment for lupus nephritis might be carefully followed on low dose steroids alone, rather than treated indefinitely with full dose immunosuppression. The ITN will further investigate potential biomarkers that distinguish those who were able to maintain remission following immunosuppression withdrawal, to help predict who might benefit from shorter treatment duration in the future.
The control regimen in this study, low-dose cyclophosphamide and azathioprine (also referred to as the Euro-Lupus regimen), is commonly used in Caucasian populations to treat lupus nephritis but less frequently in Hispanic or Black populations who typically suffer from more severe and refractory forms of disease. The ACCESS study included an ethnically-diverse population (39% Black, 40% Hispanic or Mestizo) and was able to achieve a 31% complete response rate in the control group, demonstrating that this less-intensive low dose cyclophosphamide regimen can be potentially effective in this particular demographic.