(Please see Update posted in June of 2015)
By A. G. Moore
Researchers have known for some time that B cells (immune system agents produced in bone marrow and released into the blood stream) play an active role in SLE disease activity. Based on this understanding, a number of therapies have been designed, or are being contemplated, which target B cells specifically. Rituximab is one of these B cell depleters.
B cell depletion has proven to be a successful strategy in other diseases, such as non-Hodgkin’s lymphoma and rheumatoid arthritis. So hopes were high, when Rituximab was introduced, that this strategy would offer doctors and patients another option for inducing remissions in systemic lupus.
Unfortunately, clinical trials did not meet the high expectations–at least not for Rituximab. The trials failed to show any advantage of Rituximab therapy over placebo. Both Rituximab and placebo were given in conjunction with other powerful drugs and outcomes for patients in control and non control groups were the same.
Not only did Rituximab fail to live up to expectations, but evidence was growing that a small but serious risk of infection increased with the use of Rituximab. Two potentially fatal infections that were observed in patients receiving Rituximab therapy were activation of latent hepatitis B and JC viruses. Activation of hepatitis B sometimes resulted in liver failure and death and the JC activation sometimes resulted in a brain disorder called PML (progressive multifocal leukoencephalopathy). Since both of these viruses are fairly widespread in the population (in the case of PML, the virus generally does not cause symptoms unless the patient is immune compromised), some researchers have suggested that anyone contemplating Rituximab therapy should first be tested for the presence of latent hepatitis B and JC viruses.
Although Rituximab failed to live up to expectations, there are doctors who still believe it is useful to their patients, especially in cases of refractory lupus (lupus that resists treatment). In these cases, Rituximab has been used as a “rescue” medicine. I came across one case discussed in the Saudi Journal of Kidney Diseases and Transplantation (March 2012). The Saudi Journal article describes a patient who had reached end stage renal disease; both cyclophosphamide and mycophenolate had been used to treat her disease. Finally, doctors tried Rituximab in conjunction with cyclophosphamide. Within months the patient regained kidney function and for at least nine months after that continued to show good kidney function.
Although Rituximab has proven to be disappointing in the treatment of systemic lupus, researchers continue to explore the role of B cells in this disease and look for ways of curbing B cells’ disease-inducing actions. Some scientists believe that the key to the success of B cell targeting is to be very specific about what kind of B cells are the focus of depletion efforts. It turns out there are “good” (helper) B cells and “bad” (pathogenic) B cells. Some B cells induce or exacerbate inflammation and some work against inflammation. Complicating this dual nature of B cells is the variability with which the “bad” B cells express themselves in different lupus patients. It’s hard to design one B cell therapy when B cell profiles vary from patient to patient.
Although the therapies that have so far come out of B cell depletion drugs are at best moderately effective (Benlysta is one of these) in treating SLE, researchers are confident that with B cell targeting they may yet develop successful interventions. Work continues as scientists discover more about the nature of B cells. When this very important part of the immune system is more clearly understood, it is likely that effective and targeted treatments for different manifestations of lupus will follow.