Natalizumab PML
What is PML?
PML stands for progressive multifocal leukoencephalopathy and is a relatively rare potentially fatal disease of the brain caused by a viral infection. PML is characterised by progressive damage of the white matter of the brain typically in multiple different areas hence the descriptor multifocal. PML is caused by by the JC virus (JCV), which causes a persistent infection that is normally kept under control by your immune system. JC refers to John Cunningham the name of the index patient in whom PML was first described; please note the tradition of naming viruses after patients has stopped. In general the JC virus is harmless and only causes problems in people who are immunocompromised or have a weakened immune systems.
You can get infected with the virus when at any time. Infections start in childhood and increase gradually so that by the time you are an adult about 50-60% of the general population are infected with the virus. We estimated that about 0.5% of the population get infected with the virus every year. We think the virus is transmitted in urine and saliva. JCV cause an asymptomatic primary, or initial, infection; in other words you don't have any know ill effects when become infected with JCV. JCV then resides in the kidney, possibly the bone marrow and lymphoid tissue. Infected people intermittently shed the virus in their urine and saliva, which is why we think these two body fluids are responsible for spreading the infection.
When you are infected with the virus your immune system responds to it by making antibodies, i.e. you become JCV seropositive. We detect these antibodies with a simple blood test. We assume that all people who are JCV-seropositive are still infected with the virus.
How does JCV cause PML?
If you are immunocompetent your immune system keeps the virus in check. If you immune system is compromised JCV is allowed to replicate and as it replicates it mutates. Some of the mutants acquire the ability to infect glial cells in the brain, i.e. the oligodendrocyte that produces myelin and the astrocyte. Once the mutant JCV infects the glial cells it hijacks the cells machinery and reproduces itself. This causes the cell to burst releasing thousands of new viruses to infect adjacent cells. After a critical amount of glial cells are infected and killed you start to develop focal neurological symptoms. The symptoms you present with with PML depends on the areas of the brain that is infected with the virus. The symptoms of PML are very non-specific and can mimic and MS relapse. The latter is a problem as a large number of MSers have been misdiagnosed as having a relapse when they initially present with their first symptoms of PML. However, if the presenting symptoms are a change in cognition, personality and performance of complex motor tasks (apraxia) and are accompanied by seizures then this is more in keeping with PML.
Why is PML so common in MSers?
In fact PML is quite rare in MSers and until the era of immunosuppressive DMTs there was no reports of PML occuring in someone with MS. This may be an ascertainment bias in that someone with MS who developed PML in the past may have simply been misdiagnosed as having worsening, or malignant, MS. PML is particularly a problem with natalizumab. Natalizumab blocks trafficking of lymphocytes into the central nervous system (CNS) and thereby prevents the immune system surveying the brain and spinal cord for viruses. PML also occurs with other immunosuppressive therapies and has been described on both fingolimod and dimethyl fumarate that are unrelated to previous natalizumab treatment. There have also been MSers who have developed PML on alemtuzumab, teriflunomide, fingolimod, rituximab and ocrelizumab as a carry-over effect from previous natalizumab therapy. We assume that the PML was asymptomatic when they stopped natalizumab and only presented after they had switched to another DMT. PML is called carry-over PML if it occurs within 12 months of stopping natalizumab. However, I don't the risk from natalizumab ever goes away. The reason for this is that PML is a complex disease and takes time to develop. The JCV virus has to acquire several mutations to allow it to cause PML. These mutant strains may persist in the body long term and hence increase the your risk, or at least lower your threshold, for developing PML in the future if you remain on immunosuppression.
How do you diagnose PML?
PML is diagnosed clinically with the aid of the MRI scan and cerebrospinal fluid to detect the virus using a lab test called JCV-DNA PCR. Occasionally a brain biopsy is required to make the diagnosis, but this is required much less often nowadays.
Who is at risk of developing PML?
Everyone who is JCV-seropositive is at risk of PML. If you are JCV-seronegative you are at very low risk of PML, with the one caveat that you may become infected with the virus; anywhere between 0.5% and 2% of MSers who are JCV-seronegative become positive annually. If you are JCV seropositive your risk increases with duration of treatment; it is particularly low if you have been on natalizumab less than 12-24 months. The level of antibody against JCV also predicts risk; people with a raised anti-JCV index are at a higher risk. Please note that not all anti-JCV positive MSers shed virus; therefore a subset of MSers with antibodies to the virus may have cleared the virus from the body and hence be at low risk of PML. This may explain why a persistently low index of antibodies to JCV indicates a low risk of PML. This may simply indicate past infection and no active infection at present. In contrast those with a high level of antibody, or a rising level of antibodies, have ongoing active infection, which boosts the antibody response. This indicates the virus is active, possibly mutating, and hence the much higher risk of developing PML. MSers who have previously been on an immunosuppressive therapy, for example mitoxantrone, azathioprine, or any of other immunosuppressive DMTs, are also at high risk of developing PML. Immunosuppressive therapies, presumably allow the virus to escape immune surveillance and acquire the necessary PML-associated mutations and put you at higher risk. Immunosuppressive therapies also blunt the immune response to the virus and affect the JCV antibody index and make it unreliable; in other words a low-index in MSers previously exposed to immunosuppression are still at high risk of developing PML. Therefore you cannot use the anti-JCV antibody index in MSers previously exposed to an immunosuppressive therapy.
What is my risk of developing PML on natalizumab?
The following table and graph summarise these risk factors. Another bit of information that is missing is data on extended interval dosing of natalizumab. It looks as if receiving natalizumab every 5 or 6 weeks, i.e. extended interval dosing or EID, dramatically reduces your risk of getting PML.
What about switching from natalizumab to another DMT?
A switch is relatively straight forward if you are JC virus seronegative and are switching because of lack of efficacy, or for a lifestyle choice, for example if you are tired of monthly infusions, or you want to an IRT that offers you the freedom to fall pregnant without worrying about rebound activity, or you simply prefer the long-term potential that an IRT has to offer. In this situation switching without from natalizumab without a wash-out period, to prevent rebound disease activity after natalizumab, makes sense and should be relatively safe (option 1 below).
The situation if you are JC virus seropositive is much more problematic because of the risk of carry-over PML. With a maintenance agent such as fingolimod we simply exclude asymptomatic PML by doing a lumbar puncture to look for JCV DNA in the spinal fluid and an MRI; if these tests are clear we start fingolimod as soon as possible after the last natalizumab infusion with the knowledge that if PML should develop we can always stop fingolimod and it will be cleared from the body within in 4-6 weeks. This early switching strategy also prevents rebound activity when natalizumab wears after approximately 3-4 months.
With an IRT, such as alemtuzumab, things are more complicated because we can't reverse their action hence we have to be confident that there is no carry-over PML. Why am I so concerned? Simple, if you develop carry-over PML post-alemtuzumab, before reconstitution of your immune system your are likely to succumb to the PML. I am aware of one MSer who has died under these circumstances. The reason for this is that we have to rely on a functioning immune system, in particular a population of cells called CD8+ cytotoxic T-lymphocytes (CTLs), to clear the JC virus from the brain. CD8+ lymphocytes take many months to reconstitute post-alemtuzumab and other IRTs during which time the PML is unchecked.
A large number of you argue that by treating MS, a disabling disease, with immunosuppressive therapies we simply create another ticking time bomb and swap one disease, MS, for another disease, immunosuppression. The difference between these two diseases is that MS-related disability is in general irreversible and associated with loss of quality of life. Immunosuppression on the other hand can be derisked to some extent and its consequences, in particular the opportunistic infections, treated. For more information please read the sections on each DMT. However, the poster-child for derisking opportunistic infections must be natalizumab-associated PML. We now know that MSers who are JCV-seropositive either to need to come off natalizumab or switch to EID, because of the risk of PML. In the high-risk subjects who decide to stay on natalizumab we offer them 3-monthly MRI studies to look for asymptomatic PML, which has a better prognosis than symptomatic PML.
Can you treat PML?
The short answer is no. There have some potential treatments proposed for PML, but none have shown to work. In the MS context it is clear that you need immune reconstitution to clear the virus from the brain and herein lies the problem. When you wash out natalizumab with either plasma exchange, or by waiting for it to wash-out spontaneously, when your immune cells start re-trafficking into the brain you develop and encephalitis. This is called IRIS (immune reconstitution inflammatory syndrome). To achieve
IRIS in itself is very dangerous. Therefore in patients with a large PML burden, or PML in strategic brain areas such as the brainstem, we tend to give steroids to try and dampen down the damage associated with IRIS. Anecdotal experience suggests steroids work. Is there another strategy that we can try? There have been case reports describing the anti-HIV drug, maviroc, which blocks a particular chemokine receptor CCR5 on lymphocytes, may help prevent or dampen down IRIS. T-cells, including cytotoxic CD8+ T-cells, use the CCR5 receptor to cross the blood-brain-barrier. Blocking CCR5 seems to dampen down IRIS and appeared to prevent IRIS-related damage in these two cases. Clearly maviroc as a monotherapy is not enough to stop the immune system clearing the JC virus from the CNS. The question that arises is whether or not maraviroc is better than steroids in achieving this? The latter will require a clinical trial.
The mainstay of treating PML in the context of natalizumab treatment is reversal of the natalizumab effect. To speed this up you can do plasma exchange, i.e. to remove the plasma and hence the circulating natalizumab. As soon as the natalizumab levels in the peripheral blood drop low enough the receptors become active again an immune system re trafficking occurs and allows your own T cells to fight the infection. A problem arises when we can't reconstitute CNS immunosurveillance. This can happen after been treated with IRTs, in particular alemtuzumab and possibly cladribine, or in people with persistent lymphopaenia. This is where immunotherapies are needed. One strategy is to give unfortunate people with PML in this situation donor anti-JCV lymphocytes that are matched to their HLA (human leukocyte antigens) to fight the infection. In short this is a immune transplant, i.e. giving them donor-matched T-lymphocytes to fight JCV. This strategy has been shown to work; T-cells that were designed to attack BK virus that cross-reacts with JCV have helped several people recover from PML when they would have been expected to have died.
In reality I hope the number of cases of natalizumab-associated PML drops to become a very rare complication of this treatment. Now that we have derisking strategies, and other highly-effective DMTs which are safer do we really need to continue to put pwMS at such a high risk of PML?
Please note that until we get a drug that clears JCV from the body we will never derisk the PML problem completely. As you are aware PML is a complication of immunosuppression and therefore it will remain a rare complication of our MS treatments.