Multiple sclerosis, natalizumab, and PML: Helping patients decide
ABSTRACTThe treatment benefits of natalizumab in patients with multiple sclerosis (MS) appear to exceed those of other disease-modifying drugs, but progressive multifocal leukoencephalopathy (PML) has been identified as a risk in patients receiving natalizumab. As of August 2011, a total of 150 cases of natalizumab-associated PML had been reported worldwide. The overall risk is estimated at approximately 1.66 in 1,000 patients. Independent risk factors for natalizumab-associated PML are number of infusions beyond 36 and prior use of immunosuppressive drugs. Classifying JC virus antibody status appears to be useful in treatment decision-making for individual MS patients. Patient tolerance for risk plays an important role in the selection of therapy, and the treating physician’s perception and tolerance of risk may differ markedly from the patient’s. Physicians can help patients make individual informed decisions regarding the use of natalizumab, given the known risk of PML.
DISCUSSION
Dr. Calabrese: Have you perceived growing concern over PML among the MS patient population over the past 2 to 3 years?
Dr. Rudick: I would say that it’s pretty stable. Patients who are risk intolerant select out of natalizumab. Some patients would just as soon take their chances with MS rather than deal with additional risk. Since we talk about the risk of PML with patients prior to treatment, the patients who choose natalizumab are able to deal with the risk. The difficult cases are those patients who will be severely disabled before long but choose not to go on natalizumab because they’re very risk averse. It gets even more complicated when the closest family member (parents or spouse) want their relative to use natalizumab but the patient is risk averse. This can become quite complicated—for example, I’ve seen situations where the patient is a minor, and one parent wants their child to use natalizumab but the other is risk-averse. Spouses often see risk differently, and this has led to interesting and difficult discussions. In the case of a child with MS, I listen to preferences from family members, but otherwise I empower the patient to drive the decision.
Dr. Major: Our data seem to suggest a higher percentage of individuals who are seropositive—about 56%. The issue, however, is a lack of a standard to define seropositive and seronegative. I suggested that the natalizumab manufacturer collect a bank of samples and allocate them to laboratories with no vested interest for polymerase chain reaction (PCR) assays, from which consensus definitions of seropositive and seronegative could be developed.
Dr. Calabrese: Why is there no confirmatory immunoassay for this virus? We don’t have false positives for hepatitis B or human immunodeficiency virus. We still seem to be relying on older technologies.
Dr. Major: To determine the level of antibody, an enzyme-linked immunosorbent assay is just fine.
Dr. Calabrese: That’s for sensitivity, but what about specificity?
Dr. Major: Specificity is quite good. Everybody now uses the same antigen, the polyoma capsid antigen, VP1, to detect productive viral infection, but there are no set standards for the cutpoints to classify as seropositive and seronegative. Certainly, there’s high sensitivity with PCR to detect JCV DNA in cerebrospinal fluid (CSF), because we’re able to detect very low copy levels of JCV DNA in the CSF.
Dr. Simpson: I would like to see a quantitative measure of risk versus benefit for all of the drugs used in MS, not just natalizumab. When you look at any clinical trial, you see a table of adverse events and you see efficacy measures, but you don’t see the two combined. This really is necessary to compare drug A with drug B. Instead, we end up making decisions based on risk tolerance and rather soft criteria. One could argue that we don’t want to be so algorithmic that we take the art out of medicine, but the criteria we use to make decisions are quite soft. I wonder whether you have any suggestions on a more quantitative approach.
Dr. Rudick: This is an important point, but a difficult problem. We have much more information about PML associated with natalizumab than we do about many serious adverse events. For example, there are rare adverse events with interferon beta—severe depression, liver injury, and so forth. But we don’t have precise quantitative data on most adverse drug effects, and in general adverse events are underreported in clinical practice.
The natalizumab-PML situation is somewhat unique. PML is a dramatic, often fatal, disease that is virtually never observed spontaneously in MS, and the strict reporting requirements have resulted in near-complete ascertainment and more precise risk estimates. This situation doesn’t apply to most adverse events associated with other therapies—even for some severe adverse events. But you are correct—focusing exclusively on the risk of PML seems somewhat simplistic because there are clear risks with other drugs, and these need to be factored into treatment decisions.
Dr. Molloy: Do you have good tools that predict how a patient with MS will do over time?
Dr. Fox: We have fair tools, not great tools.
Dr. Rudick: We’re diagnosing MS earlier, sometimes at the first symptom. We’re even beginning to recognize it in patients without symptoms who have MS observed as an incidental MRI finding. It is difficult at the earliest stage of MS to predict severity with any confidence. The best predictor we have is the severity of the disease by MRI criteria. This can provide a general guide to treatment decisions, but it is an imprecise predictor.
