On December 17, 2006, the FDA issued a warning to physicians using rituximab (Rituxan-TM) that two fatal cases of progressive multifocal leukoencephalopathy (PML) were reported in patients receiving this drug for the off-label treatment of SLE. [The term “off-label” refers to a treatment that was not initially intended to treat the condition in question.]
Even though rituximab is not indicated for the treatment of SLE, the manufacturer (Genentech) estimates that approximately 10,000 patients with SLE have been treated with this drug.
In order to put this report into perspective and explain why a physician would consider the use of an unapproved medication like rituximab in a patient with SLE, a few definitions and explanations are needed.
Systemic lupus erythematosus (SLE) is a complex, systemic, autoimmune disorder that varies greatly from mild to severe and life-threatening. Those who have severe renal, nervous system, heart, blood, or lung diseases commonly will need immunosuppressive drugs, including combinations of steroids in high doses with medications such as azathioprine, methotrexate, mycophenolate mofetil, or cyclophosphamide, all of which are currently and commonly used off-label for the treatment of SLE.
As if their disease was not bad enough, these patients have to contend with drug-related, severe or life-threatening side effects such as infections, malignancy, sterility, or osteonecrosis. Practical, cost-benefit decisions are made every day, understanding the complicated tradeoffs that patients must make in partnership with their physician. A life-threatening disease with limited therapeutic options often demands complicated decisions that one would not have made at another time. There is a constant search for “kinder, gentler” medications that can bring a more acceptable balance of disease control and adverse drug effects. Mycophenolate mofetil is a recent example.
It is for that reason that rituximab has been used, off label, in patients with severe manifestations of SLE who are unresponsive to the other medications noted above. In many such cases when patients and physicians have run out of options, rituximab has been quite effective and safe - at least in the short run.
JC virus and PML
JC virus, first described in 1971, was named with the initials of a patient with PML and has been identified in many areas of the body, including the brain, This virus commonly causes harmless infections in children with normal immune systems and remains dormant forever in the 80% of normal people who carry it. Unfortunately, immunosuppression due to AIDS or medications may lead to reactivation of the virus and a rare infection of the brain and spinal cord called progressive multifocal leukoencephalopathy (PML).
PML is a progressive neurologic disease resulting in irreversible neurologic deterioration and death; unfortunately, there is no known effective treatment. [It is of note that in 2005, cases of PML were reported in patients receiving a Biogen product, natalizumab (Tysabri-TM) for the treatment of multiple sclerosis. This biologic was initially voluntarily suspended by the manufacturer, but subsequently reintroduced with new guidelines for its use.]
Rituximab action and the PML incidence in cancer and autoimmune disorders
Rituximab targets CD20-positive B lymphocytes, cells that can become cancerous or exhibit autoimmune effects resulting in the development of diseases like RA and SLE. Reports of serious viral illness have included 23 confirmed cases of PML in patients with non-Hodgkin’s lymphoma (NHL), either during treatment or as long as one year after the last dose.
The drug label for rituximab carries a warning about the possible development of PML in NHL patients. PML has also been reported in patients who were treated with other immunosuppressive drugs, and prior to the development and use of rituximab. No cases of PML have been reported in rituximab-treated patients with rheumatoid arthritis.
Can we test for JC virus and, if positive, will this predict the chances of development of PML?
While there are sophisticated tests that can tell you whether or not you have been infected with the virus, no test can predict whether or not you may get PML. Certainly, if you have been treated with rituximab or any other immunosuppressant medication such as steroids or cyclophosphamide, any new neurologic symptoms should be reported to your physician immediately.
Two cases of PML in Rituximab-treated SLE Patients
According to a report by the FDA, the first death occurred in March 2006 in a 70-year old woman with a history of lupus nephritis. She had received prior treatment with cyclophosphamide, azathioprine, and long-term corticosteroid therapy. After receiving multiple infusions of rituximab (four in 2004 and two in 2005) for the treatment of refractory hemolytic anemia, she developed vertigo, tongue biting, and difficulty walking. Magnetic resonance imaging (MRI) revealed multiple brain lesions, and brain autopsy showed characteristics of PML.
The second death occurred in July 2006 in a 45 year old woman with a 24-year history of SLE and prior treatment with cyclophosphamide and intravenous methylprednisolone. After receiving three courses of rituximab from 2002 to 2005 for the treatment of refractory thrombocytopenia, she developed neurologic signs and symptoms. MRI revealed multiple brain lesions, and tests of cerebrospinal fluid were positive for JC virus.
The HSS Perspective On These Cases of PML
Here are the facts: SLE is often a life-altering - and can be a life-threatening - disease that also can have serious consequences from many of the medications used to treat it, such as corticosteroids and other immunosuppressive agents. Patients, in consultation with their physician, commonly must make very difficult risk-benefit decisions factoring in the knowns and unknowns relating to their disease and the medications available. What one patient may find unacceptable with a given set of facts, another may find reasonable and worthy of consideration.
The two lupus cases reported by the FDA, in patients previously immunosuppressed, do not seem to provide a high enough level of concern to eliminate the off-label use of Rituxan in systemic lupus erythematosus, in view of the limited options and the risks associated with those options. In rheumatoid arthritis patients (who are generally less desperately ill than the most severely affected lupus patients) no cases of PML have been reported in patients taking Rituxan.
Physicians should maintain a very high level of suspicion for any Rituxan-treated patient with new neurologic symptoms, such as disorientation, difficulty with balance, walking or speaking, or new visual difficulty. Published literature on follow-up of patients treated with Rituxan, along with cases reported to the FDA, will determine the risk/benefit of Rituxan in autoimmune disease.
At this time, we feel that Rituxan continues to be a reasonable option in patients with active rheumatoid arthritis and lupus where their level of disease justifies the use of this medication, after consideration of the risks and benefits of available alternatives.
Physicians should evaluate all patients who have received rituximab for signs or symptoms suggestive of PML. Any suspect cases of PML should be reported immediately to Genentech, Biogen Idec, or to the FDA MedWatch program.
Patients with SLE who have been, or are being, treated with rituximab have a few options, each of which should be discussed carefully with their physician:
1. In those who have previously been treated with rituximab successfully, some may not need retreatment, and all factors, including this report of PML, will need to be considered in the decision to use rituximab again. A patient who has taken rituximab should contact their physician immediately if they develop new neurologic symptoms.
2. In those patients who are currently being treated successfully with rituximab for an active SLE problem, and if all other therapies have previously failed, the decision regarding continued use of the drug and/or retreatment will need to be made employing the new information about the rare potential development of PML. Other therapies can be considered. As new information arises regarding JC virus, its measurement, and the ability to predict who might develop PML after rituximab use becomes available, it will need to be considered in the decision process. A patient with new neurologic symptoms during their treatment with rituximab should contact their physician immediately.
3. In those who are currently considering the off-label use of rituximab, it is vital to incorporate this new PML data into the decision-making process. If other drugs have failed to help, and rituximab offers a high likelihood of improvement, it should be discussed carefully with a physician.
4. In those who are thinking of joining a study that is focused on determining whether rituximab is effective in the treatment of renal or non-renal lupus, remember that the FDA has not stopped those studies in the face of the two patients described above. That is because rituximab has good potential to be important new drug in the fight against SLE, and the FDA believes that such a study continues to be reasonable and important. The FDA may change the protocols in the setting of this PML information to assure greater safety, oversight, and long-term surveillance.
FDA Public Health Advisory
The following is the official advisory distributed by the FDA on the subject of Rituxan and PML in SLE patients:
FDA Public Health Advisory
Life-threatening Brain Infection in Patients with Systemic Lupus Erythematosus After Rituxan (Rituximab) Treatment
FDA has received reports of the death of two patients who were treated with Rituxan for systemic lupus erythematosus (SLE). Both patients developed a life-threatening viral infection of the brain. This infection is called progressive multifocal leukoencephalopathy (PML). PML is caused by the JC virus and is usually fatal. There are no known effective treatments for PML.
The signs of PML include confusion, dizziness or loss of balance, difficulty talking or walking, and vision problems. Recognition of these warning signs of PML may be obscured by the fact that they are also associated with the underlying diseases for which Rituxan may be prescribed.
• Patients who have been treated with Rituxan should contact their doctor if they experience any warning signs like those listed above--to find out the exact cause of their warning signs and to be checked for PML.
• Physicians who are thinking about treating a patient with Rituxan for any condition should inform their patient about the chance of PML with Rituxan treatment because there is no known effective treatment for PML.
• Patients who are taking or are considering taking Rituxan should be aware of the chance of developing PML and discuss it with their doctor.
Rituxan is a powerful medication that is used to suppress the immune system. It works by blocking the effect of specific immune cells in the blood, known as B cells, for up to six to nine months. Rituxan is approved for use only in patients with certain types of cancer called non-Hodgkin’s lymphoma and for rheumatoid arthritis when other treatments have failed. Rituxan is not approved for the treatment of SLE. The sponsor estimates that approximately 10,000 patients with SLE have been treated with Rituxan.
In February 2006, the labeling for Rituxan was updated to include information about reports of several different types of viral infections, including PML, that had become active again or worsened in cancer patients taking Rituxan. FDA is working to gather more information about Rituxan and PML and to strengthen the Warnings about PML in the Rituxan product label.
More details about Rituxan and PML can be found in FDA’s Information for Healthcare Professionals at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm126519.htm
The FDA asks health care professionals and patients to report possible cases of PML to the FDA through the MedWatch program by phone (1-800-FDA-1088) or by the Internet at http://www.fda.gov/medwatch.