On November 19th, I went to the local hospital outpatient infusion clinic to receive the first dose of Rituxan® (rituximab). This Thursday I go back for the second dose which will complete one round of treatment. Rituxan in combination with methotrexate is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies (such as Humira, Enbrel, or Remicade).
Those of us living with multiple sclerosis CANNOT use one of the anti-TNF disease-modifying anti-rheumatic drugs (DMARDs) which are commonly used in the treatment of RA or other rheumatic diseases. This is because the anti-TNF drugs are known to increase disease activity in patients who have a demyelinating disease such as MS. Although I am officially using Rituxan as a treatment for RA, it is the hope of my rheumatologist, neurologist, and myself that Rituxan may be effective in slowing down my experience with MS relapses.
What is Rituximab?
Rituximab is a chimeric (mouse/human) monoclonal antibody directed at the antigen protein CD20, which is found on only pre-B and mature B cells. CD20 is not found on plasma cells, stem cells, or pro-B cells, and therefore eliminating the CD20 positive population does not prevent recovery of mature B cells or immunoglobulin production. B cells are a type of white blood cell, specifically a lymphocyte, which is responsible for producing immunoglobulins. Rituximab was initially FDA approved for the treatment of B cell lymphoma in 1997 and received approval for RA in 2006. It is NOT approved for use in multiple sclerosis.
Rituxan is administered as two 1000mg intravenous (IV) infusions separated by 2 weeks, a process which is repeated every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks. Premedication with an antihistamine (such as Benadryl®) and acetaminophen (Tylenol®) is recommended to reduce the incidence and severity of infusion-related reactions. For RA patients, glucocorticoids such as methylprednisolone (Solumedrol) 100mg IV or its equivalent are administered 30 minutes prior to each infusion.
Rituximab and Multiple Sclerosis
Rituxan has been tested in clinical trials for the treatment of primary progressive multiple sclerosis (PPMS) and relapsing-remitting multiple sclerosis (RRMS). It is with great interest that I have followed the presentations given at various neurological events in reference to B-cell therapy and MS. Oftentimes, we can learn what the results of the trials were many months before the results are published in journals.
Regarding the PPMS trial, it was a great disappointment to learn that the results were a statistical failure, although further analysis shows that rituximab was effective in a select group of patients. Trial results were recently published in the Annals of Neurology.
Regarding the Phase II trial of rituximab in RRMS, trials were much more encouraging as can be seen by the results which were published in the New England Journal of Medicine in February 2008. It is interesting to learn that about a quarter of the trial participants developed antibodies against rituximab, a chimeric (human/mouse) molecule that retains some murine (mouse) elements. Genetech doesn’t plan to conduct any more trials of Rituxan in MS patients, instead they are looking ahead to study ocrelizumab, a humanized anti-CD20 antibody.
In fact clinical trials are enrolling which will study the effects of ocrelizumab and ofatumumab in patients with RRMS. Ofatumumab is a fully humanized monoclonal antibody which targets CD20+ B-cells. The benefit of a fully humanized monoclonal antibody is that it should strongly decrease severe side-effects and infusion-related reactions.
Rituximab has also been studied in the treatment of Neuromyelitis Optica (NMO or Devic’s Disease) and has been found to be effective in reducing the frequency of attacks with subsequent stabilization or improvement in disability.
What is an Acute Infusion Reaction (ie. cytokine-release syndrome)?
Rituxan can cause severe, including fatal, infusion reactions. Severe reactions typically occurred during the first infusion within the first 30−120 minutes. During clinical trials, acute infusion reactions (manifested by fever, chills, rigors, pruritus, urticaria/rash, angioedema, sneezing, throat irritation, cough, and/or bronchospasm, with or without associated hypotension or hypertension) were experienced by 27% of Rituxan-treated patients following their first infusion, compared to 19% of placebo-treated patients receiving their first placebo infusion. The incidence of these acute infusion reactions following the second infusion of Rituxan or placebo decreased to 9% and 11%, respectively.
Since infusion reactions are more common during the first infusion, the initial infusion is started at a slow rate of 50 mg/hr. In the absence of infusion toxicity, the infusion rate is increased by 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr. Subsequent infusions can begin at a rate of 100 mg/hr and increased by 100 mg/hr increments at 30-minute intervals in the absence of infusion-related reactions. Acute infusion reactions during clinical trials which required dose modification (stopping, slowing, or interruption of the infusion) occurred in 10% and 2% of patients receiving Rituxan or placebo, respectively, after the first course.
Signs and symptoms of an acute infusion reaction include:
- Neurologic: Dizziness, headache, weakness, syncope, seizure
- Psychiatric: Anxiety, “sense of impending doom”
- Respiratory: Nasal congestion, rhinitis, sneezing, oropharyn- geal or laryngeal edema, bronchospasm, tachypnea, cyanosis, respiratory arrest
- Cardiovascular: Tachycardia, hypotension, arrhythmia, chest pain, ischemia or infarction, cardiac arrest
- Cutaneous: Flushing, erythema, pruritus, urticaria, angioedema, maculopapular rash
- Gastrointestinal: Nausea, vomiting, cramping, diarrhea
During clinical trials of Rituxan, acute infusion reactions were primarily of the Grade 1 or Grade 2 type. I wondered - what exactly does that mean? Below is a breakdown of how reactions are graded.
National Cancer Institute Common Terminology Criteria for Adverse Events: Acute infusion reaction (cytokine-release syndrome)
- Grade 1 - Mild reaction: infusion interruption not indicated; intervention not indicated
- Grade 2 - Supportive therapy and/or infusion interruption; responds promptly to symptomatic treatment; prophylactic medication is indicated for > 24 hours
- Grade 3 - Prolonged (ie, not rapidly responsive to symptomatic medications and/or brief interruption of infusion) or recurrence of symptoms following initial improvement: hospitalization indicated for other clinical sequelae
- Grade 4 - Life-threatening reaction: pressor or ventilatory support indicated
- Grade 5 - Death
My Infusion Experience
I am making a point to mention possible infusion-related reactions with Rituxan because I experienced some during this first go around. About 45 minutes into the actual drip of rituximab, I noticed that my ears were a bit itchy. I was scratching them when I thought to myself that I really should have taken the extra time (although I was running late) to wash my ears carefully with a washcloth. When my scalp began to itch, I thought to myself - “hey! I washed my hair and my head should NOT be itching like this.”
Then my chest began to itch and broke out while my ears swelled so much that the skin was very firm and putting off heat. My tongue felt odd as my throat became scratchy. I started to cough a little (which was annoying as I had definitely gotten over a long case of bronchitis weeks prior). My face started itching (and apparently became rather flushed) while my lips noticeably swelled.
It was when the nurse came to check on me (the patient must be monitored every 30 minutes during the infusion) that I noticed I couldn’t hear through very stuffy ears (ie. swollen tissue blocked ears). I called a family member to inform them about the reaction and I had trouble talking as my voice was affected. It was about this time that I realized I was having some trouble breathing and was becoming anxious as the discomfort increased.
The nurse immediately stopped the infusion and contacted my rheumatologist for her treatment recommendation. I received an additional 100mg of steroids and more benadryl, this time by IV. The rate of the infusion was decreased and we waited to see if my symptoms would calm down. The response was not immediate and 30 minutes later, I still had some of the symptoms although diminished. Thus we had to keep the infusion rate at a slower pace until I was back to ‘almost’ normal.
About an hour later, we increased the infusion rate a bit and monitored how I did. At one point, I did begin to feel the same symptoms but the look on the nurse’s face was one of great disappointment (because they had already done what they could without stopping the process altogether) that I emphasized that the symptoms were still ‘tiny’ compared to what they had been. But, honestly, I did feel a need to downplay any symptoms after the nurse expressed concern for how long the infusion was going to take.
Eventually, I reached the end of the bag of medication and was released to go home. An infusion experience which would normally take about 6 hours (including time for premedication) took me 9 hours to complete. After looking for more detailed information regarding infusion reactions, I have determined that my reaction was definitely Grade 2 and perhaps bordered on the Grade 3 category.
Understanding monoclonal antibody infusion-related reactions
In the case of my experience, the acute infusion reaction was of the cytokine-release syndrome type. Cytokines function as important chemical messengers between cells and are proteins which are produced and secreted by cells in the body. There are several types of cytokines: interleukins (ILs), interferons (IFNs), tumor necrosis factors (TNFs), lymphokines, monokines, and chemokines. Cytokines mediate normal immune function by transmitting signals between cells. As such, cytokines are often involved in the body’s response to monoclonal antibody therapy.
What happens is that the monoclonal antibodies bind to the target cells. The subsequent immune response destroys the target cell and releases cytokines. As cytokines circulate throughout the body, they carry out their normal functions of mediating immunity, activating lymphocytes, triggering inflammation, and attracting leukocytes, which may lead to systemic symptoms. When the cytokines reach the brain, they can penetrate the blood-brain barrier and trigger the hypothalamus to raise core body temperature, eliciting a fever. Common infusion-related reaction symptoms include fever, nausea, chills, hypotension, tachycardia, asthenia, headache, rash, scratchy throat, and dyspnea.
Sources and References:
Infusion-Related and Hypersensitivity Reactions of Monoclonal Antibodies Used to Treat Colorectal Cancer—Identification, Prevention, and Management. Kang SP, Saif, MW. Supportive Oncology 2007, 5(9):451-457.
B cells as therapeutic targets in autoimmune neurological disorders. Dalakas MC. Nature Clinical Practice Neurology 2008 Oct;4(10):557-567.
Nuanced role of cytokines in three major human brain disorders. Steinman L. Journal of Clinical Investigation 2008 Nov;118(11):3557-3563.
Rituximab in patients with primary progressive multiple sclerosis: Results of a randomized double-blind placebo-controlled multicenter trial. Hawker K, O’Connor P, et al. Annals of Neurology 2009 Oct, 66(4):460-471.
Effect of Rituximab on the Peripheral Blood and Cerebrospinal Fluid B Cells in Patients With Primary Progressive Multiple Sclerosis. Monson NL, Cravens PD, et al. Archives of Neurology 2005;62:258-264.
B-Cell Depletion with Rituximab in Relapsing–Remitting Multiple Sclerosis. Hauser SL, Waubant E, et al. New England Journal of Medicine 2008 Feb 14;358(7):676-88.
Treatment of Neuromyelitis Optica With Rituximab: Retrospective Analysis of 25 Patients. Jacob A, Weinshenker BG, et al. Archives of Neurolology 2008;65(11):1443-1448.
Understanding monoclonal antibody infusion-related reactions. (Biogen Idec/Genetech)
Spotlight on Anti-CD20. Waubant E. The International MS Journal 2008; 15: 19–25
Full prescribing Information for Rituxan. (Biogen Idec/Genetech)