Our understanding of the immune system and how it functions improves by the day and this knowledge is reflected on how we deal with disorders of the immune system and how we recruit our immune systems to fight infections and cancers. Many drugs have been developed based on those concepts and are proven successful in the management of many diseases through clinical trials. This branch of drugs is termed “immunotherapy” and arguably, the most successful of this group is rituximab.
What is rituximab and how does it work?
Rituximab is a drug developed by Biogen pharmaceuticals in the 90s and was approved by the FDA in 1997 for the treatment of B cell non-Hodgkin’s lymphoma, previously one of the most challenging lymphomas in its treatment. It was sold under the generic name Rituxan and is considered a DMARD (Disease Modifying Anti-Rheumatic Drug) and an anticancer drug. Like all drugs, its patent expires after 10 years, which makes its mass production easier and its price lower. Since its patent expired in 2016, it has become an essential drug in all healthcare systems across the globe
Rituximab is a monoclonal antibody, which means that it is an antibody targeted towards a specific protein. In this case, the protein is a surface antigen found on the surface of B lymphocytes called CD20 (Cluster of Differentiation).
Cluster of differentiation is a man-made system to classify cells depending on surface molecules after antibodies are found to target them. When rituximab binds to the CD20 molecule on B-cells, the cell is destroyed via several mechanisms. These mechanisms include antibody destruction, complement mediated destruction or even cellular suicide (apoptosis). The benefit of such destruction varies, in cancers for example, the destruction of CD20 cells causes the destruction of all cancerous cells which have the antigen to allow other normal cells to populate the blood. In autoimmune disorders, the destruction of such cells causes a remission of the autoimmune flare of symptoms as will be explained later in the article.
Rituximab since its conception in 1997 has been used in many related and unrelated conditions whose mechanisms are centered around b-cells or any cell that manifests the CD20 antigen. Those diseases are usually cancer related or autoimmune in nature. The main uses of rituximab include:
- Non-Hodgin’s Lymphoma: Its first approved use, and it was considered a game-changer drug for many cases. The only needed requirement for its use is the proof that such cancer cells are CD20 positive, since this medication is considered as a targeted therapy, and won’t act unless its “target” is present on the surface of cells. It can be used alone or with another monoclonal antibody, ibritumomab. It is used both in early cases and in refractory cases to other medication or even relapsed ones.
- Chronic lymphocytic leukemia: CLL is considered as one of the most challenging leukemias to manage. It usually develops in old, frail individuals who cannot tolerate high doses of chemotherapy, making their drug choices limited. Rituximab is considered a good option for such patients as well as those whose disease has relapsed after remission. The main requisite for its administration is the same, which is the presence of CD20 on the surface of cancer cells. It is given always in combination with other drugs such as fludarabine -which prevents DNA formation in cancer cells- and cyclophosphamide -which damages the DNA-.
- Rheumatoid arthritis: Rheumatoid arthritis is an autoimmune condition that affects mostly the small joints of the hands and feet. It can also have multisystem involvement with the eyes, heart and lungs being severely affected in some cases. The disease involves the release of large amounts of chemical mediators and cytokines as well as antibodies which makes its treatment complex and many drugs usually have to be used in combination to control the condition. Rituximab is used in cases which show little response to the traditional tumor necrosis factor inhibitors (infliximab and adalimumab). It is almost always used with methotrexate, which is an essential drug in rheumatoid arthritis.
- Pemphigus: Pemphigus vulgaris is a rare autoimmune skin disease that manifests by the appearance of several blisters. It results from the formation of antibodies that attack the junctions that keep skin layers from separating. Its diagnosis was considered a death sentence in the past, but thanks to corticosteroids and other new drugs, its mortality rate dropped considerably. Rituximab is usually used in severe cases along with corticosteroids. It functions to destroy B-cells which eventually form plasma cells that produce the antibodies that attack those skin junctions.
- Wegener’s granulomatosis (granulomatosis with polyangiitis): Wegener’s is a systemic inflammatory reaction that causes the formation of an immune complex called a granuloma in the wall of blood vessels causing their inflammation. This renders blood vessels weak causing easy bleeding through the nose or into the eye. The treatment of Wegener’s granulomatosis involves the use of extensive immunosuppression including high doses of glucocorticoids with rituximab. Other medications that can be used in the combination include cyclophosphamide and Mesna – a drug used with cyclophosphamide to decrease its risk of complications to the urinary bladder-.
- Other autoimmune conditions: The mechanism of action of rituximab made it possible for it to be used in many autoimmune conditions with varying degrees of safety depending on the extent of its side effects in each condition. Its approved uses until the date and time of writing this article include:
- Autoimmune hemolytic anemia
- Idiopathic thrombocytopenic purpura: Which is an immune-mediated destruction of blood platelets causing easy bruising and spontaneous bleeding.
- Thrombotic thrombocytopenic purpura
- Post organ transplantation: Although the use of rituximab hasn’t yet been adequately confirmed in the prevention of organ rejection after transplantation. It is used in cases of acute rejection where it can help salvage the transplanted body organ like the kidney.
How is it administered?
Rituximab is administered via an IV slow infusion or slow injection.
The side effects of rituximab play a major role in its uses. As great as its potential is, the development of some side effects can cause the drug to be contraindicated in some conditions. The most common side effects of rituximab include:
- Generalized side effects including: Weakness, headache, dizziness, muscle pain especially at the back, abdominal pain and diarrhea.
- Infusion reactions: Many drugs that are administered intravenously can have an infusion reaction. The severity of such reaction depends on the drug injected as well as the individual themselves. Some individuals can experience the following with rituximab:
- Bronchospasm with short breath
- Edema of the face and lips
- Itchiness and redness of the skin at the site of injection
Infusion reactions are always anticipated and managed in specialized centers. Bronchodilators and even adrenaline can be given depending on the severity of the condition and the rate of infusion can be decreased.
- Increased risk of infections: Rituximab targets B-cells which are the cells that differentiate to plasma cells and produce antibodies. Antibodies are essential to a functioning immunity and a sharp drop of B-cell count will invariably weaken the immunity. A common manifestation of immunodeficiency in patients receiving rituximab is the activation of dormant infections like hepatitis B and papilloma viruses. It is usually not severe, however, in some cases of viral activation, severe side effects to the central nervous system can occur including progressive multifocal leukoencephalopathy which can be life threatening.
- Tumor lysis syndrome: A common side effect with all medications that kill cancer cells. If cells are destroyed in excess, the chemical substances sequestered with the cell will be released freely into the circulation causing some side effects. Common manifestations of tumor lysis syndrome include:
- Kidney damage: Our kidney is designed like a filter with pores that drain water and some electrolytes, when larger molecules are present like proteins, they don’t pass through such filters. When tumor lysis syndrome affects muscle fibers however, large quantities of the protein myoglobin are released into the circulation and are filtered through the kidney, but this protein is altered by the acidity of urine and can precipitate in the “filters” of the kidney, obstructing them and causing reversible or irreversible kidney damage.
- Increased potassium level: Potassium is an electrolyte that is almost exclusively found within cells, but when excess cells release it, its level in the blood rises causing side effects especially to the heart electrical system which, in severe cases, can cause cardiac arrest.
- Increased level of uric acid and gout: Uric acid is a byproduct of the metabolism of purines, a key component of our DNA. Normal level of uric acid can be excreted by the kidney, but excess levels can form crystals either in the joint lining, causing gouty arthritis, or in the kidney or ureters causing kidney stones. In severe cases, it can cause renal failure.
- Cytokine storm: Cytokine storm is a complex medical condition that results from many causes including severe bacterial or viral infections or in case of chemotherapy of cancer. Many white cells contain chemical substances called cytokines which function to attract other immune cells and activate many immune mechanisms. The destruction of large numbers of white blood cells over a short period of time can cause the level of cytokines to rise rapidly. Cytokine storm presents with varying severity. Fever, diarrhea and rashes are common findings, but in few severe cases, alterations to the body’s coagulation system can occur leading to the formation of blood clots in some areas and bleeding from other.
There is no absolute contraindication to rituximab in many diseases, but in patients with viral infections, extreme caution should be exercised for fear of their activation and severe flares.
Is rituximab safe in pregnancy?
Monoclonal antibodies can pass through the placenta and affect fetuses, however, it is unlikely that miscarriage or severe malformations will occur and most cases can pass without significant anomalies, but a fall in the level of white cells of the newborn is expected. With that said, fertile females receiving rituximab should be advised to use contraception during the duration of therapy and a year afterwards.