Treatment Advances
On a positive note, two medications have recently been approved by the FDA for the treatment of lupus nephritis: belimumab and voclosporin.
Belimumab is a fully humanized IgG1γ monoclonal antibody directed against soluble B lymphocyte stimulator (BLyS). In the BLISS-LN study, 448 patients with biopsy-proven, active lupus nephritis were randomized to receive 10 mg/kg of intravenous belimumab or matching placebo in addition to standard therapy (i.e., either induction with high-dose steroids and intravenous cyclophosphamide using the Euro-Lupus protocol, and maintenance with low-dose steroids and 2 mg/kg of azathioprine per day; or induction with high-dose steroids and mycophenolate mofetil 3 g/day and maintenance with low-dose steroids and mycophenolate mofetil 1–3 g/day). The primary endpoint at week 104 was a primary efficacy renal response, defined as a ratio of urinary protein to creatinine of less than 0.7, an estimated glomerular filtration rate of no worse than 20% below the pre-flare value or greater than 60 mL/minute/1.73 m2 of body-surface area and no use of rescue therapy. 3
In the study, 43% of belimumab-treated patients achieved the primary endpoint, compared with 32% of placebo-treated patients. The risk of a renal-related event or death was lower among patients who received belimumab than among those who received placebo, with a hazard ratio of 0.51.3 Given these data, belimumab may be a useful adjunctive therapy when added to standard care for treating lupus nephritis.
In the AURORA 3 study, 357 patients with active lupus nephritis were randomized to receive the calcineurin inhibitor voclosporin at a dose of 23.7 mg twice per day or placebo in combination with 2 g per day of mycophenolate mofetil and rapidly tapered oral steroids. Patients could receive intravenous methylprednisolone up to 1 g on day 1 and 2, with tapering of oral corticosteroids to 2.5 mg per day by week 16. The study’s primary endpoint was renal response at 52 weeks, defined as urine protein to creatinine ratio of less than 0.5 mg/mg, estimated glomerular filtration rate (eGFR) greater than 60 mL/min or no confirmed decrease from baseline in eGFR of greater than 20%, presence of sustained, low-dose steroids and no administration of rescue medication.4
In this trial, 40.8% of voclosporin-treated patients achieved the primary endpoint vs. 22.5% of placebo-treated patients. Proteinuria reduction in the voclosporin group was twice as fast compared with standard of care alone, and the group receiving voclosporin demonstrated significantly greater renal response vs. controls as early as week 24.4
Thus, voclosporin in addition to mycophenolate mofetil appears to be helpful to treat patients with lupus nephritis. Of particular interest, ethnicity subgroup analysis in the AURORA 3 study indicates voclosporin is effective in Hispanic/Latino patients, a group that has traditionally had difficult to treat disease. This finding, coupled with the lower toxicity and side effect profile of voclosporin vs. the older calcineurin inhibitors, such as cyclosporine and tacrolimus, make this medication a potentially appealing option in many clinical scenarios.
Dr. Sheikh ended her presentation with several thought-provoking questions: Could belimumab and voclosporin become part of the standard of care to treat lupus nephritis? What is the role of cyclophosphamide in the treatment of patients with SLE in the modern era? What parameters, such as adherence, pregnancy considerations and renal function, should guide the selection of medications in the treatment of each patient with SLE?
As this lecture clearly demonstrated, the future of lupus management is both complex and exciting, and the rheumatology community will have to ask these and other important questions while seeking to help patients in the years ahead.
