Two important studies of rituximab (brand name Rituxan) have demonstrated its benefits in treating people with SLE. In both of these studies, side effects were minimal, and benefits started within one to three months.
Rituximab, previously approved by the US Food and Drug Administration (FDA) for the treatment of non-Hodgkin’s lymphoma, is a genetically engineered antibody that targets B cells and eliminates them from the blood. B cells are a type of white blood cell that plays a central role in the development of lupus. Therefore, these studies explored the possibility that B cell depletion could reduce or eliminate SLE disease activity.
John Looney, MD, and his colleagues at the University of Rochester School of Medicine and Dentistry, Rochester, NY, began evaluating rituximab for treatment of SLE in 2000. One of their recent publications in Arthritis & Rheumatism (August 2004), reported on their Phase I/II dose-escalation study using rituximab. The purpose of this study was to evaluate the effects of administering varying doses of rituximab on disease activity.
The 17 participants were divided into low-, intermediate- and high-dose groups. Those in the low-dose group received a single infusion; those in the intermediate dose group also received a single infusion but of a higher dose. The high-dose group received weekly infusions of the same dose as that given to the intermediate group for 4 weeks. The high dose group received the same overall dose given to those with lymphoma. People taking most other medications prescribed for lupus that reduce damage to the body caused by autoimmune disease were able to join the study if their dose had been stable for one month.
Participants were evaluated using the SLAM index – a global lupus activity index that evaluates how you feel and the impact of the disease on various organ systems. In addition, laboratory measures were taken to determine the level of B cell depletion.
So how did they do? B cell depletion was achieved at varying levels within all the groups. “Interestingly, some participants on the lowest dose felt great, while some on the highest dose did not respond,” reported Dr. Looney. “The difference was whether they depleted their B cells.” A majority of participants – 11 of 17 – had profound B cell depletion, and their SLAM score was significantly improved within three months. At the end of a year, those who had gotten better continued to stay well with no difference in how they felt. Even after participants’ official year-long observation period ended, researchers continued to keep in touch with them. Three of the 17 participants went into remission and remained on no medications three years after their original month of rituximab treatment.
What dose level turned out to be best? The highest dose level provided the most significant benefit. However, even at that level, some did not respond. Although additional data will be required to address this issue, those less likely to respond included African Americans and people who made a certain kind of antibody (HACA) in response to the drug.
Of course, the depletion of B cells is not permanent, and the body gradually regenerates a new supply. So the Rochester group also examined the fate of discrete B cell subsets, well known to have certain abnormalities in SLE, to see what happened to them during this B cell recovery phase.
“In people treated with rituximab who completely deplete their B cells, those abnormalities do not return after the B cell recovery phase,” reported Jennifer Anolik, MD, a co-investigator on this study and colleague of Dr. Looney’s at the University of Rochester . In other words, the immune system seems to be reset back to normal, which may account for the long-term remission.
“We don’t know what complicated interplay of genetic and environmental factors contributes to getting lupus in the first place, so we don’t know what will make it come back if we induce remission,” said Dr. Anolik. “The B cells look like normal B cells by all measures that we have, and three participants have stayed well for over three years. So when it works, it seems to wipe the slate clean and let the immune system start again.”
Petros P. Sfikakis, MD, and his colleagues at the Athens University Medical School in Greece, recently conducted an open-label trial to determine the efficacy of rituximab in the treatment of lupus nephritis and explore the mechanisms by which B cell depletion promoted remission. The results of this study were published in Arthritis & Rheumatism (November 2004).
In a standard randomized, controlled clinical trial, the researcher and participants are not made aware of which group is receiving the investigated drug and which group is receiving a placebo. In an open-label study, the researchers and participants know the drug being administered and no one receives a placebo. In the study conducted by Dr. Sfikakis, 10 people with lupus nephritis received four weekly infusions of rituximab at the same dose as given to people with lymphoma. These infusions were given together with high levels of prednisolone, although the doses were tapered over time.
For participants in this study, B cell depletion lasted from one to seven months. In eight of the 10 participants, there was a 50% improvement in markers of kidney function: serum creatinine and albumin levels, urine sediment, and 24-hour urinary protein measures. In five cases, complete remission, defined as normal serum creatinine and albumin levels, inactive urine sediment, and 24-hour urinary protein under 500 mg., was achieved. On average, complete remission occurred within three months from the start of the study; for four of these five participants, complete remission was sustained at month 12. Of these four, two continued to sustain complete remission 2 ½ years from the outset.
Although not universally accepted, many believe that T cells play a major role in the pathogenesis of SLE. It is suggested that T cells provide a helper cell that stimulates B cells to make antibodies that lead to SLE disease activity. Dr. Sfikakis’ team also reviewed the effects of B cell depletion on T cells. It was concluded that the production of T helper cells was decreased by fourfold. In addition, expression of markers in the blood indicating that T cells are being activated -- thus potentially contributing to autoimmune problems -- was significantly decreased even when only partial remission was observed.
“Interestingly, the period of B cell depletion did not directly correspond to remission,” said Dr. Sfikakis. “Two participants who never achieved even partial remission did deplete their B cells – but their T cells were still activated.” Based on this information, Dr. Sfikakis concluded that B cell depletion is not enough to achieve remission; the action of T cells must also be down regulated. Therefore, Dr. Sfikakis proposed that in future studies, his group would like to examine how the T cells behave in the presence of the regenerated B cells and how sustained remission or relapse correlates with the activity of these cells.
What it means for people with lupus: All three physicians agree that rituximab is a promising agent that appears to be a safe and effective treatment, at least for the majority of people who experienced profound B cell depletion. However, they caution that randomized, controlled trials assessing rituximab are urgently needed to prove that it works and to determine the most effective treatment methods. In some people it may produce permanent remission; in others it may only induce a remission that must be sustained with other drugs, albeit much milder ones that would otherwise be needed. “This is a bright light in the treatment of lupus,” said Dr. Looney. “We have biologics that have dramatically changed how we deal with rheumatoid arthritis, and this is the first one that really looks good in lupus. We need to get rituximab into clinical trials and, if it proves out, get it approved.”
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