SAN FRANCISCO—In a presentation on advances in the treatment of systemic lupus erythematosus (SLE) at the California Rheumatology Alliance 2016 Medical & Scientific Meeting in May, Maria Dall’Era, MD, director of the Lupus Clinic and Rheumatology Clinical Research Center at the University of California, San Francisco, discussed the range of treatments that have been identified over the years for lupus. These include anti-metabolic and alkylating agents, in addition to two cornerstone drugs in use since the 1950s—hydroxychloroquine, an anti-malarial drug also used in rheumatoid arthritis, and glucocorticoids. However, advances in licensed treatments for lupus have lagged behind other rheumatic diseases and only one treatment has been approved for lupus since the 1950s. Belimumab, a human monoclonal antibody that inhibits B cell activating factor (BAFF), was approved by the Food and Drug Administration in 2011.
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Many Phase II/III trials of lupus drugs have not met their primary endpoints, Dr. Dall’Era said. Demonstrating efficacy in these trials is a challenging proposition for a number of reasons. “We don’t know which are the best end points to measure. Which manifestations, because this disease is so heterogeneous? When to start, and for how long? Are we going to treat active patients in the early stages of disease, or do we treat in a maintenance phase? Should we eventually withdraw an effective therapy?” she posed. Which concomitant immunosuppressive agents and which dose of prednisone should be allowed in a study?
However, the future is bright, with more than 500 clinical trials of lupus therapies targeting a variety of innate and adaptive immune pathways listed at ClinicalTrials.gov. “What I’d like to emphasize regarding the reality of where we are in 2016, is that historically, there has never been more lupus clinical trial activity,” Dr. Dall’Era added in a follow-up interview with The Rheumatologist. “We are learning lessons from every negative trial. We can continue to improve trial design and increase the likelihood that we will be able to demonstrate efficacy of novel experimental agents.”
Promising Treatment Targets
In her presentation, Dr. Dall’Era explored two of the more promising treatment targets from all of this new research, BAFF blockade and blockade of interferon-alpha, a family of signaling glycoproteins from the larger class of cytokines secreted by immune system cells.
Regarding B cell targets, she said, “Let’s take a step back. We know that B cells are very important in the pathogenesis of lupus, and there are different ways to intervene in the B cells compartment, starting with belimumab.” Which patients are most likely to respond to belimumab? Patients with higher degrees of disease, reflected by higher SLEDAI (systemic lupus erythematosus disease activity index) scores and increased serologic activity, tend to have a better response, she said. Other predictors of response include low complement; positive anti-double-stranded DNA; and use of steroids.1
Other strategies for B cell interventions target B cell surface receptors, soluble modulators that lead to B cell proliferation and differentiation, and B cell signaling mechanisms downstream of the B cell receptor, Dr. Dall’Era noted. Drugs recently under investigation for BAFF-blockade include blisibimod, tabalumab and atacicept, which is unique in that it targets both BAFF and APRIL (a proliferation-inducing ligand).
Evidence for the role of type 1 interferons in SLE includes the fact that treatment with interferon-alpha leads to a lupus-like disease, risk polymorphisms for lupus are present in interferon-regulated genes, interferon signature is present in peripheral blood mononuclear cells and in tissues from lupus patients, and the level of expression of interferon-inducible genes correlates with disease activity. Drugs that have been studied include rontalizumab and sifalimumab, whose development have been discontinued; and anifrolumab, which is continuing in Phase III trials.
More than 500 current clinical trials of lupus therapies point toward a bright future, increasing the likelihood of demonstrating efficacy of novel experimental agents. —Dr. Dall’Era
Advances in Treating Lupus Nephritis
A major manifestation of SLE, lupus nephritis, is also being targeted with new treatment strategies, Dr. Dall’Era reported. Conventional induction treatment involves high doses of glucocorticoids, along with such drugs as mycophenolate mofetil or cyclophosphamide. An emerging strategy is multi-target therapy, she said, “already standard of care in the treatment of patients who have undergone organ transplant.” One recent small trial demonstrated the efficacy of the combination of tacrolimus and mycophenolate mofetil when compared with intravenous cyclophosphamide for induction treatment of lupus nephritis. Another trial in progress is studying the combination of voclosporin (a next generation calcineurin inhibitor) in combination with mycophenolate mofetil.
Another active area of research involves novel ways to use rituximab for the treatment of lupus nephritis. The Rituxilup trial, with European and American collaborators, is assessing the use of rituximab instead of, rather than as add-on therapy to, oral steroids. Rituximab is being given in combination with two doses of intravenous steroids and followed by mycophenolate mofetil. In the CALIBRATE trial, patients with lupus nephritis are undergoing an induction regimen of rituximab and two doses of intravenous cyclophosphamide, followed by belimumab maintenance.
Larry Beresford is an Oakland, Calif.-based freelance medical journalist.
- Van Vollenhoven RF, Petri MA, Cervera R, et al. Belimumab in the treatment of systemic lupus erythematosus: High disease activity predictors of response. Ann Rheum Dis. 2012 Aug;71(8):1343–1349.