Rituximab and Apheresis: novel dual therapy in use at Braverman Reproductive Immunology to prevent antibody-mediated inflammation during pregnancy

Posted By Dr. Braverman || 6-Feb-2015

Pregnancy is marked by profound changes to the maternal immune system to allow the semi-allogeneic fetus to implant and grow within the uterus.

Among immune cells, B lymphocytes (B cells) are key players in the maternal immune adaptation towards fetal implantation. There are several subsets of B cells, each with different functions and potential roles to play in pregnancy. Some B cell subsets appear to play a protective role in pregnancy by secreting the immunomodulatory cytokine IL-10 which regulates T cell function, while other B cells function in protective immunity to prevent infections (production of antibodies against microbial agents) in the maternal reproductive tract. On the other hand, some B cell subsets are capable of producing antibodies against normal cellular components (autoantibodies) which can contribute to autoimmune disease, or antibodies that target components of the embryo/fetus encoded by the paternal genetics – most notably paternally derived HLA molecules. These antibodies (autoantibodies and antibodies against paternal components such as HLA) can be harmful to pregnancy maintenance by inducing miscarriage, or later complications as preeclampsia, intrauterine growth restriction, or stillbirth.

Maternal B cells play also a crucial role in neonatal health by protecting the new born from infections and providing him with antibody-mediated protective immunity.

Thus, B cells play a crucial role during pregnancy, and targeting of B cells with specific therapies such asRituximab may be beneficial to maintaining pregnancy.

  1. What is Rituximab?

Rituximab (Rituxan®, Genentech) is a chimeric (mouse-human) monoclonal antibody that targets CD-20 antigen on the surface of B cells. It is currently classified as FDA category C.

Rituximab binds to CD20 and induces B cells destruction by inducing antibody-mediated cell lysis. It leads to rapid (within 72 hours) and sustained depletion of B cells that could remain suppressed for several months with repetitive injections as seen in kidney transplant recipients. Its half-life in the blood is 35.9 days and can be detected in the serum for up to 6 months.
Rituximab eliminates multiple B cell subsets as CD20 antigen is expressed early in B lymphocyte ontogeny, from immature bone marrow resident pre-B cells (precursors) up to the point of initiation of plasma cell differentiation in secondary lymphoid tissues where CD20 disappears from the cell surface.
Rituximab induces an immunological "reset" of most of the B cells residing in the spleen and the secondary lymph nodes.
It is interesting to note that anti-HLA antibodies that are produced by plasma cells cannot be eliminated by Rituximab (they don't express CD20 anymore), but eliminating B cell proliferation as well as depletion of precursors of mature plasma cells may prevent anti-HLA antibody production.

  1. When is it used?

Rituximab has been first approved in 1997 in USA for the treatment of refractory or relapsed B cell lymphomas and in several hematological conditions in adults. More recently, it has been increasingly used to treat various autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, particularly in cases when anti-TNFα therapy has failed.

In children, Rituximab has been used in a variety of off-label indications such as chronic immune thrombocytopenic purpura (ITP) with promising results. Rituximab is also of great interest in solid organ transplantation where clinical studies show its beneficial role in the prevention and treatment of acute and chronic organ rejections.

  1. Is it Safe?

​The most common adverse events seen with the use of Rituximab are transient flu-like symptoms during the first infusion that resolved completely in less than 3 hours, spontaneously or with diphenhydramine (antihistamine) and/or paracetamol administration. In some cases, the flu-like symptoms during the first infusion (high dose used generally to treat patients with lymphomas) were accompanied by broncho- spasm, hypotension or severe cytokine release syndrome but patients were able to complete treatment after these symptoms resolved. Cytokine release syndrome is a systemic and transient release of cytokines caused by B-cell depletion that can result in T-cell activation and increase the risk of embryo rejection if administrated during pregnancy. This syndrome occurs at the first infusion and its severity is proportional to the dose of Rituximab (a low dose will have a minimal impact on cytokine release). Corticosteroid treatment prior to Rituximab injection may prevent the adverse effects cause by the inflammatory storm and decrease the risks by 30%.

The incidence of infections is not increased but complications due to infection have been reported although data are controversial.

  1. Rituximab: a preventing therapy to autoantibody- and anti-paternal HLA antibody mediated inflammation during pregnancy

Besides clinical studies on lymphomas where Rituximab is generally used in combination with chemotherapy, most of the literature on its use comes from clinical trials on patients undergoing organ transplantation. Since embryos are essentially semi-allografts (they contain maternal genetics as well as paternal genetics that are "foreign" to the maternal immune system), data from the organ transplant field are of prime interest in the study and application of reproductive immunology.

Rituximab is largely used in organ transplantation as a preventive therapy in organ rejection, but is also used as a treatment for acute or chronic rejection. In the context of organ transplantation, Rituximab is infused several times (usually once a week for 4 weeks at a high dose 375 mg/m2) and has a strong and long lasting impact on B cell depletion and anti-HLA antibody production. This regimen is often used in combination with plasmapheresis and/or IVIG and confers outstanding outcomes on lowering transplant rejection and increasing patient longevity.

Is it safe for pregnant women or women planning to conceive?

Extensive information has been accumulated on Rituximab use during pregnancy, largely from pregnant patients suffering from autoimmune diseases such as RA or SLE, or patients suffering from lymphomas. Placental passage of Rituximab is known to be minimal in the first trimester, moderate in the second, and extensive in the third, and may affect fetal B cell development if administrated after the first trimester.

In animal studies, exposed offspring (rhesus monkey) did not exhibit any adverse genetic (teratogenic) effects but did have decreased lymphoid tissue B cells. Further studies conducted to assess effects of rituximab throughout pregnancy and postpartum revealed that the B-cell counts returned to normal levels, and immunologic function was restored within 6 months postpartum in the mother.

In women, the largest clinical study reported outcomes of 231 pregnancies with preconception or antepartum exposure to rituximab. Most pregnancies resulted in uncomplicated live births.

Several others studies reported healthy babies, born at term with normal B cells count, when Rituximab is administrated before conception or in the first few weeks of pregnancy. If administrated during the second trimester, babies could have a low B cell number (that will put them at higher risk for potential infections) that will restore within 3 months.

In the last few months, we have started developing a therapeutic plasma exchange protocol in partnership with the New York Blood Center. We are now happy to announce that plasma exchange therapy is available and in use at Braverman Reproductive Immunology.
This treatment option allows the removal of pathologic anti-paternal HLA antibodies or autoantibodies that can function to adversely affect pregnancy outcome.

Rituximab could be used at a low dose (150 mg/m2: sufficient immunosuppressant dose used in transplant recipients) before conception, as a therapy in patients trying to conceive and who have high levels of CD5+ B cells, autoantibodies or paternal-specific anti-HLA antibodies.

Rituximab in combination with therapeutic exchange plasma will suppress the generation and accumulation of antibodies with potentially harmful effects on the embryo/fetus and help to prevent antibody-mediated inflammation that could have harmful effects on the fetus and its development.

Besides its indisputable efficiency, this novel dual therapy will allow to minimize the use of IVIG (in term of dose and frequency) and will be the most cost effective therapy to prevent antibody-mediated inflammation and its dramatic effects on fetal health during pregnancy.

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