Update on Rituximab (Rituxan®) for Treating Lupus
The first studies of rituximab in lupus are under way. This treatment targets a type of white blood cell (B cell) that is central to the immune disorder of lupus. B cells are important to immune defense because they regulate the manufacture of protective antibodies to fight disease; however, in lupus patients, B cells sometimes produce harmful antibodies (autoantibodies) that cause inflammation. Rituximab depletes B cells that are circulating in the bloodstream, sometimes for six months or longer. Early forms of B cells (stem cells in the bone marrow) can eventually replace those B cells. Some of the more mature forms of B cells (those that reside in the spleen, producing antibodies) do not seem to be directly affected by rituximab. The exciting idea that is being studied is the possibility that temporary depletion of B cells could leave enough protective antibodies in place to protect the body while interrupting harmful communications between B cells and other cells in the circulation that lead to lupus flares.
The early studies reviewed here have suggested that rituximab might be well-tolerated by lupus patients, at least with short-term therapy. It is known, however, that, similar to many other treatments for autoimmune disease, infections can occur in patients receiving rituximab, some of which could be potentially serious. For these reasons, further careful studies are important in order to understand this treatment better and to find the best ways to use it. The LFA is very pleased to see that large multi-center trials of rituximab are currently under way for lupus patients. -Joan T. Merrill, M.D., LFA Medical Director
Advances in the understanding of the pathogenesis of lupus provide a rationale for B cell depletion as a potential therapeutic strategy. Simply put, if the B cells are overly active in this disease, then reducing their numbers might help.
Rituximab, a B cell depletion treatment, was originally developed to treat non-Hodgkin's lymphoma, a blood cancer. B cells are the white blood cells that stimulate the production of antibodies-special, targeted proteins that recognize and help eliminate foreign substances that enter the body. The complex process by which B cells recognize invaders in the body, and start the manufacturing process for antibodies that will seek these invaders out, bind to them and help to eliminate them, is a critical element of the body's immune defense.
Rituximab is an antibody that binds to CD20, a protein on the surface of both normal and malignant B cells. B cell depletion is an interesting strategy to pursue if B cells are malignant or, in the case of autoimmune diseases, if they are hyper-stimulated and causing inflammation. The treatment sounds draconian, but in fact, after interrupting the pathologic process, new, normal B cells can be regenerated later. This is because the cells in the bone marrow that give rise to B cells (stem cells) do not have CD20 protein that is recognized by rituximab. B cells are able to regenerate after treatment with rituximab and may return to normal levels within several months.
Research has shown that B cell depletion does not affect the levels of immune protective antibodies in the short term, even though levels of autoantibody might be decreased. This suggests that the body's requirements for producing protective antibody and autoantibody are different. Furthermore, some data suggest that B cell depletion might affect the activation of T cells, another form of white blood cell that is sometimes overly stimulated in lupus.
Safety and Efficacy for Lupus
In a small, early study conducted by a team led by Daniel Albert, M.D., seven patients were treated with rituximab, each with active lupus who had failed at least one immunosuppressive agent. After receiving four weekly infusions of rituximab, six of the seven patients seemed to get better after treatment. Three were thought to have a brief remission (six weeks to six months) and three seemed to achieve a more prolonged remission (six-nine months). All but one patient had more than 99 percent B cell depletion lasting more than three months. The one patient who exhibited only 95 percent B cell depletion was the one who had no clinical response. However, this is a very early report and it is not possible to be sure whether the small difference in B cell depletion had anything to do with the response.
B Cell Abnormalities
A study conducted by Jennifer Anolik, M.D. and co-workers found that, compared with people in good health, lupus patients had several abnormalities related to their B cells, including low overall lymphocyte counts (the larger group of white blood cells which include B and T cells) and an increase in the cells that give rise to plasma cells (antibody-producing cells). When patients were treated with rituximab, these abnormalities partially resolved, and this difference persisted even months later, after the stem cells had regenerated circulating B cells in these patients. The frequency of B cells which react in a manner that leads to autoimmunity (autoreactive B cells) also decreased one year following treatment, despite the fact that these cells were not perfectly depleted during the study treatments and the fact that there was evidence of persistent autoantibodies in most patients after treatment. What does all of this mean? Although much remains to be learned about how rituximab affects B cells, this study suggested the possibility that rituximab might lead to a longer term improvement in some of the abnormalities of the behavior of B cells that occur in lupus patients.
Risk of Developing an Immune Response Against the Treatment
John Looney, M.D., along with Dr. Anolik and other co-workers, also reported on the clinical effects of rituximab in a small study of patients with lupus. Gradually increasing doses of rituximab were added to ongoing lupus therapy in this protocol-a single infusion of 100 mg/m2 (low dose), a single infusion of 375 mg/m2 (intermediate dose), or four infusions (one week apart) of 375 mg/m2 (high dose).
The majority of patients (11 out of 17) had full B cell depletion. This depletion persisted for up to 12 months, despite the absence of a significant change in a major autoantibody that is associated with lupus (anti-dsDNA antibody) and complement levels (another laboratory marker of inflammation).
Unfortunately, six patients developed an antibody against the drug itself. This raises two concerns:
- anti-treatment antibodies might lead to excess inflammation just like lupus does, and
- even if that is not the case, the treatment might not be able to work if the drug is coated by anti-drug immune proteins.
In this study, those at higher risk to develop an immune response against the treatment were people of African-American ancestry, people with higher disease activity at the start of the study, those who seemed to achieve less B cell depletion with the treatment, and those found to have lower levels of circulating rituximab, when this was measured two months after the initial treatment.
Severe Refractory Lupus
Maria Leandro, M.D., and colleagues tested rituximab in 24 patients with severe lupus who had failed other immune-suppressing treatments. The patients (22 women and two men) were followed for a minimum of three months, and the majority (19 out of 24), were followed for six months.
Only one patient failed to achieve B lymphocyte depletion. Lupus disease activity was measured by an index called the BILAG which looks individually at eight different organs in the body. Improvement seemed to occur in each part of the body, even though the average amount of steroid (prednisolone or methylprednisolone) that patients were taking dropped slightly from 13.8 mg to 10 mg.
Stephen Marks, M.D., and colleagues conducted an open- label study of B cell depletion in seven children with refractory lupus. During a two-week period, patients received two 750-mg/m2 intravenous infusions of rituximab, with intravenous cyclophosphamide (if they had not previously received this treatment) and high-dose oral corticosteroids. Thus, they were all receiving aggressive treatment already, then rituximab was added in.
The patients were followed for a median of one year, with no serious side effects noted. In all patients, the flares that were present when rituximab therapy was given improved. Two patients with life-threatening disease who appeared to be unresponsive to aggressive standard treatments and were on dialysis at the start of the study eventually were able to stop the dialysis. Both of these patients continued to have improvement in their kidneys.
This was not a placebo-controlled study and rituximab was given along with other aggressive treatments. Nothing is proven. However, the good safety profile and the overall good responses in these patients support further studies of rituximab in children with lupus.
This is not to suggest that rituximab has always worked. Monika Edelbauer, M.D., and her team published a case report on a 14-year-old girl with severe lupus in the kidney (Class IV) who did not respond to conventional immune suppressing treatments. She was treated with six monthly rituximab doses at 375 mg/m2, oral mycophenolate (Cellcept), and prednisone, followed by more rituximab every three months. Although some of the aspects of this patient's lupus flare responded well, and although she did have complete B cell elimination, remission of her kidney disease was not achieved.
Active Proliferative Lupus Nephritis
In this study, Petros Sifikakis, M.D. and colleagues treated 10 patients with active lupus kidney disease with rituximab (four weekly infusions of 375 mg/m2) combined with steroids (oral prednisolone). The patients were followed for 12 months. B cell depletion lasted from one month to seven months in various patients and the treatment was well tolerated. Partial remission was achieved promptly in eight of 10 patients; complete remission was later established in five patients, and was sustained at 12 months in four patients.
There was no blinding in this study; that is, all patients received rituximab, and the doctors and the patients all knew what they were getting. On the other hand, the tests that are used to determine how the kidneys are doing are mostly lab tests, so the potential impact of wishful thinking might be a bit less in this kind of study.
Rituximab has been approved for use in lymphoma for more than seven years and more than 500,000 patients have been treated. Clinical research studies in rheumatoid arthritis have led to the recent approval of rituximab for that disease as well. Smaller studies have been performed for a number of different autoimmune diseases. This experience provides a large safety database so that the drug can be administered now in studies of lupus patients with relative confidence. As is true of many powerful drugs, however, rituximab can be associated with serious side effects, especially infections, and so it should be stressed that patients with B cell depletion require close monitoring.