Tag Archives: PML

DMTsDetail

Natalizumab

Summary

Natalizumab is a first-in-class selective adhesion molecule blocker that reduces the trafficking of lymphocytes into the central nervous system (CNS). It is a very high-efficacy DMT capable of achieving long-term NEIDA (no evident inflammatory disease activity) and limiting end-organ damage (brain volume loss) in most people with MS who receive it. Following rebaselining, average annual brain volume loss for patients treated with natalizumab is within the expected range for age-matched people without MS. Natalizumab has a rapid onset of action; when it is used early in the disease course, many people with MS report a reduction in symptoms of disability and fatigue.

One result of reduced lymphocyte trafficking in the brain is reduced immune surveillance. This puts patients receiving natalizumab at high risk of progressive multifocal leukoencephalopathy (PML) if infected with the JC virus that causes it. The risk of PML is variable and can be reduced by using extended interval dosing (EID), whereby natalizumab is given as a 6-weekly infusion and is very well tolerated. (Normally natalizumab is given every 4 weeks.) A small number of people with MS (<5%) may develop infusion reactions, which can be serious. Infusion reactions typically come on with the second, third or fourth natalizumab infusion and are associated with developing so-called neutralising antibodies (NAbs). 

Trade names

Tysabri.

Mode of action

Natalizumab is immunosuppressive, and it is associated with opportunistic infections, including PML, and possibly secondary malignancies of the CNS. Natalizumab is a monoclonal antibody that targets VLA-4 or α4β1 integrin on lymphocytes, preventing them from crossing the blood ̶̶ brain barrier. A lymphocyte must stick to the wall of a blood vessel before it can cross – like two surfaces of Velcro sticking together. Natalizumab blocks one of the surfaces so the lymphocytes cannot cross the blood vessel wall. People with MS on natalizumab treatment have more circulating white blood cells in their blood than normal. This is because the cells that normally adhere temporarily to blood vessel walls (marginating cells) are now found in the blood.

Efficacy

Very high, particularly in people with rapidly evolving severe MS.

Class

Maintenance, immunosuppressive.

Immunosuppression

Yes, but limited to the CNS.

Dosing

  • Tysabri 300 mg and Tyruko 300 mg are both administered by intravenous infusion once every 4 weeks. Tysabri is also available as a subcutaneous injection, given once every 4 weeks.
  • There is evidence that extended interval dosing (EID) of natalizumab – increasing the gap between infusions from 4 weeks to 5 or 6 weeks – may dramatically reduce the risk of PML.

Main adverse events of special interest

Infusion reactions

These tend to be mild and occur in about 20% of patients; they may be associated with headache, dizziness, nausea, urticaria and rigors.

Hypersensitivity reactions

These occur in approximately 5% of patients. In about a quarter of this 5% they can be anaphylactoid in nature and typically occur during the infusion or within an hour of completing the infusion. Hypersensitivity reactions are characterised by either a low or high blood pressure, chest pain, chest discomfort, shortness of breath, swelling of the throat, rash, urticaria, rigors, nausea, vomiting and flushing. Most hypersensitivity reactions occur on the second, third or fourth infusion and are associated with the development of anti-drug antibodies, i.e. your own body rejects natalizumab by making antibodies against it. Persistent anti-natalizumab antibodies develop in approximately 5 ̶ 6% of people with MS on natalizumab; they decrease the drug’s effectiveness and cause hypersensitivity reactions.

Infections

In general, natalizumab is not associated with systemic infections. As an immunosuppressive therapy, natalizumab has been associated with opportunistic infections, particularly PML. Other opportunistic infections include cryptosporidium diarrhoea and cryptococcal meningitis. Herpes infections (varicella zoster virus, herpes simplex virus) have occurred more frequently in patients receiving natalizumab than in those receiving a placebo. Serious life-threatening encephalitis and meningitis caused by herpes simplex or varicella zoster can occur on natalizumab. The presentation of these infections is atypical because reduced trafficking of cells into the CNS reduces the intensity of the inflammation. Rarely, these viruses may infect the retinae and lead to acute retinal necrosis and loss of vision.

PML and granule cell neuronopathy

JCV is the commonest opportunistic infection in seropositive natalizumab-treated people with MS. JCV can cause PML and granule cell neuronopathy (GCN). PML is the commonest complication of JCV, and its management is described separately. GCN is characterised by lytic infection of the cerebellar granule cell layer and presents with a cerebellar ataxia and cerebellar atrophy and white matter changes in the cerebellum and brainstem on magnetic resonance imaging (MRI). Many cases of GCN also have white matter changes elsewhere, suggesting an overlap between GCN and PML. There is evidence that increasing the time interval between natalizumab doses – extended interval dosing  – may dramatically reduce the risk of PML.

Abnormal liver function

Autoimmune hepatitis, increased liver enzymes and hyperbilirubinaemia rarely occur with natalizumab.

Anaemia

Rare cases of anaemia and haemolytic anaemia have been reported in natalizumab-treated people with MS.

Malignancies

Several cases of CNS lymphoma have been reported in natalizumab-treated people with MS. The risk of CNS lymphoma is likely to be increased based on the mode of action of natalizumab, i.e. it blocks immune surveillance of the CNS and hence there will be an increased risk of CNS tumours.

Neutralising antibodies (NAbs)

Yes, in approximately 5% of natalizumab-treated patients.

Pharmacovigilance monitoring requirements

Baseline

Full blood count, urea and electrolytes, liver function tests, JC virus-serology and pregnancy test.

Follow-up

LFTs 3-monthly for one year, NAbs at 12 months and JCV–serology every 6 months. In people with MS at high risk of PML, 3 ̶ 4-monthly MRI; otherwise, annual MRI for disease activity monitoring.

Self-monitoring

All people with MS should be warned about opportunistic infections and informed to look out for symptoms suggestive of infections. Women should be reminded to self-examine their breasts monthly and should have cervical smears and/or human papillomavirus testing every 3 years.

Rebaselining

I recommend a rebaseline MRI 3 ̶ 6 months after starting treatment with natalizumab and including gadolinium enhancement as part of this.

Pregnancy

Animal studies have shown no toxicity from natalizumab, and data from clinical trials and post-marketing studies in humans suggest natalizumab exposure has no adverse effect on pregnancy outcomes. Babies born to people with MS on natalizumab have a transient mild-to-moderate low platelet count and anaemia, which typically disappear within weeks. Most neurologists now allow their female patients to fall pregnant whilst on natalizumab and then offer to stop it after they have become pregnant. Some neurologists are letting patients continue natalizumab throughout pregnancy. The decision to do this is based on the emerging safety profile of natalizumab in pregnancy and the risk of rebound MS activity when natalizumab washes out.

Breastfeeding

The amount of natalizumab that crosses over into the breast milk is very small and is likely to be digested by the baby’s digestive enzymes; therefore, it is safe to breastfeed on natalizumab.

Male fertility

Safe.

Vaccination

Safe for component or inactivated vaccines. Live vaccines are contraindicated. Live viruses, particularly ones that can infect the CNS, are potentially dangerous.

Summary of Product Characteristics (SmPC)

Tysabri, Tyruko.

Extended interval dosing

Reducing the risk of PML

At present, several factors can help us assess the risk of PML:  JC virus testing (negative and positive), level of JCV antibodies (antibody index), previous exposure to immunosuppression, and treatment duration. We also have frequent MRI monitoring (3 ̶ 4-monthly) to detect PML early and plasma exchange to remove natalizumab as a backup option if a patient develops PML. Another option to reduce the risk of PML may be extended interval dosing (EID).

I have several patients who, despite being JCV-seropositive, insist on staying on natalizumab rather than trying an alternative treatment. A few patients, even after switching to another DMT to prevent getting PML, have opted to go back onto natalizumab. The reason typically relates to the return of MS fatigue, or brain fog, after stopping natalizumab. After restarting natalizumab, patients come back and say, ‘I feel well, my fatigue has gone, and my thinking is clear’. This is why anything that decreases the risk of PML for patients on natalizumab is good.

Rationale for extended interval dosing

The theory behind EID is that some cells are less sensitive than others to the effects of natalizumab; if you delay the next natalizumab infusion by 1 or 2 weeks, the saturation of the surface receptors drops below a threshold and allows those cells to traffic into the CNS. If these cells with lower sensitivity to natalizumab are the antiviral T cells and/or the natural killer cells that fight viruses, this could allow immune surveillance of the CNS to occur and prevent PML from developing. By achieving the correct EID, the saturation of the immune cells that cause MS (possibly the memory B cells) is sufficient not to allow MS to reactivate. Clearly, not all cells are equal when it comes to the effect of natalizumab. Importantly, several other adhesion molecules impact the adhesion (stickiness) of immune cells to the blood vessels in the CNS. A delicate balance between the availability of different accessory adhesion molecules could also make the difference.

When these principles were adopted by several neurologists in the USA, the data emerging from their centres suggested they were correct in hypothesising that the risk of developing PML was reduced when JCV-seropositive people with MS received EID natalizumab.

Comparison of extended and standard interval dosing

Biogen, the manufacturer of Tysabri, sponsored some large studies to explore this theory.1,2 Using the so-called TOUCH program (Tysabri Outreach: Unified Commitment to Health), which is a mandatory database of all people with MS receiving Tysabri in the USA, statisticians identified more than 35,000 anti-JC virus antibody-positive patients on Tysabri; they compared those on EID with those on standard interval dosing (SID) for PML risk.1 The TOUCH programme is real-life data, not a clinical trial database, so the periods of EID are variable. To deal with this, the statisticians defined three types of EID with increasing stringency. The remarkable finding was that EID was seen to reduce the risk of PML significantly compared with SID in two of the analyses; in the most stringently defined cohort of EID there were rare cases of PML.

Clinical implications

I have acted on this finding and have offered EID to my patients taking natalizumab who are at risk of PML. It is advisable to transition to 6-weekly EID over several months so as not to precipitate pre-infusion worsening of symptoms. I am now recommending three infusions at 5-weekly intervals before moving to 6-weekly infusions.

The question to consider is whether EID will be associated with some loss of natalizumab effectiveness. A recent study showed no loss of efficacy with EID.2 In addition, the study was not clear on finding a personalised dose. Therefore, all patients on EID received it every 6 weeks.

I personally am thrilled by these results. Why? Because anything that derisks PML for people with MS on natalizumab is good, particularly for people with more advanced MS. This is important because natalizumab is effective in more advanced MS, particularly in slowing down or preventing worsening of hand and arm function.

Switching-2-natalizumab  

Natalizumab

Recent data have shown that increasing the dosing interval between natalizumab infusions (EID) will lower the risk of developing PML.

Restarting natalizumab

Before restarting natalizumab it is important to do routine blood tests, a baseline MRI and check for anti-natalizumab antibodies. The presence of anti-natalizumab antibodies increases the risk of developing infusion reactions and is a contraindication to restarting natalizumab. It is not uncommon for someone with MS to want to switch back to natalizumab after trying another DMT. Natalizumab is known to reduce MS-related fatigue and brain fog, and this often returns when it washes out. The ability to reduce PML risk with EID will increase the number of patients requesting to go back onto natalizumab to help manage such cognitive symptoms.

Other DMTs

In general, natalizumab can be used after any of the DMTs provided the baseline screening bloods are satisfactory and there are no contraindications to the specific DMT. Some important caveats are highlighted below.

Interferon-beta and glatiramer acetate

I have no concerns and would not recommend any specific washout period after stopping either IFN-beta or glatiramer acetate.

Alemtuzumab and HSCT (non-selective cell depleting DMTs)

If you wish to start natalizumab after alemtuzumab or HSCT because of recurrent disease activity, I suggest doing so as soon as possible. Alemtuzumab and HSCT are immunosuppressive therapies, however, so if you are JCV-seropositive they will greatly increase your risk of developing PML and will render the so-called anti-JCV index unreliable. If your MS is not active post-alemtuzumab or HSCT, I would question the need for natalizumab because both these DMTs can induce long-term remission.

Cladribine and anti-CD20 therapies (selective cell depleting DMTs)

If you wish to start natalizumab after cladribine or an anti-CD20 therapy because of recurrent disease activity, then I would suggest doing so as soon as possible. Cladribine and anti-CD20s are immunosuppressive therapies, however, so if you are JCV-seropositive they will increase your risk of developing PML and will render the so-called anti-JCV index unreliable. If your MS is not active post-cladribine or an anti-CD20, I would question the need for natalizumab because these DMTs can induce long-term remission.

S1P modulators (fingolimod, siponimod, ozanimod and ponesimod)

No washout period is required when switching from an S1P modulator to natalizumab. However, if you have an infectious complication, particularly a CNS infection, then you would be ill-advised to start natalizumab until the CNS infection has been cleared. Natalizumab will prevent lymphocyte trafficking into the CNS and hence will blunt the immune response to the infectious agent. 

Fumarates (dimethyl fumarate and diroximel fumarate)

No washout period is required when switching from a fumarate to natalizumab. The same warning about CNS infections applies to fumarates as to S1P modulators mentioned above.

Teriflunomide

No teriflunomide washout period is required when switching to natalizumab. However, if your reason for switching to natalizumab is to control MS disease or fall pregnant, then you will need to undergo rapid teriflunomide elimination because of its long half-life and potential for teratogenicity.

Mitoxantrone

Mitoxantrone is an immunosuppressive therapy. Therefore, if you are JCV-seropositive it will increase your risk of developing PML and will render the so-called anti-JCV index unreliable.

Special circumstances

The presence of specific comorbidities and adverse events may make it difficult to start natalizumab after certain DMTs. These are, however, uncommon in routine clinical practice.

What about switching from natalizumab to another DMT?

A switch is relatively straightforward if you are JC virus-seronegative and are switching because of lack of efficacy or for a lifestyle choice, for example:

  • you are tired of monthly infusions (please note, however, there is now a subcutaneous formulation that is given as two injections)
  • you want an immune reconstitution therapy (IRT) that offers the freedom to fall pregnant without worrying about rebound activity
  • you simply prefer the long-term potential of an IRT.

In this situation, switching from natalizumab without a washout period, to prevent rebound disease activity after natalizumab, makes sense and should be a relatively safe option.

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 an S1P modulator, we simply exclude asymptomatic PML by doing an MRI and, if you want to be extra vigilant, a lumbar puncture to look for JCV DNA in the spinal fluid. If these tests are clear, we start the S1P modulator as soon as possible after the last natalizumab infusion, knowing that if PML should develop we can stop the S1P modulator and it will be cleared from the body within 4 ̶ 6 weeks or less (depending which S1P modulator you are taking). This early switching strategy also prevents rebound activity when natalizumab wears off after approximately 3 ̶ 4 months.

With an IRT, such as alemtuzumab, things are more complicated because we can’t reverse its action. Hence, we must 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, you are likely to succumb to PML – which is potentially fatal. We rely on a functioning immune system, in particular a population of cells called CD8+ cytotoxic T lymphocytes, 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.

You might 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, opportunistic infections – can be treated. For more information, please read the sections on each DMT.

We now know that people with MS who are JCV-seropositive either need to come off natalizumab or switch to EID, because of the risk of PML. For high-risk subjects who decide to stay on natalizumab we offer 3-monthly MRI studies to detect asymptomatic PML, which has a better prognosis than symptomatic PML.

References

  1. Ryerson LZ, et al. Risk of natalizumab-associated PML in patients with MS is reduced with extended interval dosing. Neurology 2019;93:e1452 ̶ 62.
  2. Foley JF, et al. NOVA study investigators. Comparison of switching to 6-week dosing of natalizumab versus continuing with 4-week dosing in patients with relapsing-remitting multiple sclerosis (NOVA): a randomised, controlled, open-label, phase 3b trial. Lancet Neurol 2022;21:608 ̶ 19.
DMTsSafety

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 to the brain’s white matter, typically in multiple different areas – hence the descriptor ‘multifocal’. It is triggered 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 patient in whom PML was first described; the tradition of naming viruses after patients has now stopped.) The JC virus is harmless and only causes problems in people who are immunocompromised or have a weakened immune system.

You can get infected with the JC virus at any time. Infections start in childhood and increase gradually; by adulthood, about 50 ̶ 60% of the general population are infected with the virus. JCV causes an asymptomatic primary, or initial, infection; in other words, you have no known ill effects. The virus then resides in the kidney and possibly the bone marrow and lymphoid tissue. Infected people intermittently shed the virus in their urine and saliva, spreading the infection to others; we estimate that about 0.5% of the population gets infected every year.

Your immune system responds to the virus by making antibodies, i.e. you become JCV– seropositive. We detect these antibodies with a simple blood test. We assume that all JCV-seropositive people are still infected with the virus.

How does the JC virus cause PML?

If you are immunocompetent, your immune system keeps the virus in check. If your immune system is compromised, however, JCV replicates and mutates. Some of the mutants acquire the ability to infect glial cells in the brain. Once the mutant JCV infects the glial cells, it hijacks the cells’ machinery and reproduces itself, causing the cells to burst and release thousands of new viruses to infect adjacent cells. When a critical number of glial cells are infected and destroyed, focal neurological symptoms develop. The type of symptoms associated with PML depends on the areas of the brain infected with the virus. PML symptoms are non-specific and can mimic an MS relapse, leading to misdiagnosis initially. Some common PML presenting symptoms include a change in cognition, personality and performance of complex motor tasks (apraxia), accompanied by seizures.

How do you diagnose PML?

PML is diagnosed clinically with the aid of a magnetic resonance imaging (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 rare nowadays.

How common is PML in people with MS?

PML is quite rare in people with MS and was not reported until the era of immunosuppressive DMTs. (This lack of earlier reporting may be because of misdiagnosis.)

PML is particularly a problem with natalizumab. Natalizumab blocks the 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, unrelated to previous natalizumab treatment, including fingolimod and dimethyl fumarate.

Carry-over PML

Some people with MS have developed PML while on alemtuzumab, teriflunomide, fingolimod, rituximab or ocrelizumab as a carry-over effect from previous natalizumab therapy. We assume here that the PML was asymptomatic when they stopped natalizumab and only presented after they had switched to another DMT. PML is classified as ‘carry-over’ if it occurs within 12 months of stopping natalizumab. However, I don’t believe the risk from natalizumab ever goes away because PML is a complex disease and takes time to develop. The mutant strain that evolves to potentially cause PML may persist in the body long term and hence increase your risk, or at least lower your threshold, for developing PML in the future if you remain on immunosuppression.

How do I know if I’m at risk of PML?

JCV-seropositive test result

Everyone with MS on natalizumab is at risk of PML. If you are JCV-seronegative your risk of PML is very low, unless you become infected with the virus; each year, about 0.5 ̶ 2% of people with MS who are JCV-seronegative become seropositive. If you are JCV-seropositive your risk increases with duration of natalizumab treatment; it is particularly low if you have been on natalizumab less than 12 ̶ 24 months.

Raised JCV antibodies

The level of antibody against JCV also predicts risk. In people with a raised JCV antibody index, the high or rising level of antibodies indicates ongoing active infection, which boosts the antibody response. This means the virus is active, possibly mutating, so there is a higher risk of developing PML. People with MS who were previously on an immunosuppressive therapy such as mitoxantrone or azathioprine are also at high risk of developing PML. Immunosuppressive therapies presumably allow the virus to escape immune surveillance, to acquire the necessary PML-associated mutations and thus to put you at higher risk.

Not everyone with MS who is JCV-seropositive sheds virus; a subset of individuals 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, i.e. it suggests past infection and no active infection at present.

Immunosuppressive therapy

Immunosuppressive therapies also blunt the immune response to the virus and affect the JCV antibody index. People with MS previously exposed to immunosuppression are still at high risk of developing PML even if they have a low JCV antibody index. This makes the index unreliable in people with MS previously exposed to an immunosuppressive therapy. The following table and graph summarise these risk factors.

Barts-MS PML Risk Guide table simplified_27 06 23

Key risk factors for developing PML; risk increases with increasing time on Tysabri. Based on manufacturer’s February 2023 data and modified from Barts-MS PML Risk Guide. Extrapolated extended interval dosing values show ~94% risk reduction compared with standard dosing.
IS, immunosuppressive therapy; JCV, JC virus; PML, progressive multifocal leukoencephalopathy.

Extended interval dosing

Reducing the risk of PML

At present, several factors can help us assess the risk of PML:  JC virus testing (negative and positive), level of JCV antibodies (antibody index), previous exposure to immunosuppression, and treatment duration. We also have frequent MRI monitoring (3 ̶ 4-monthly) to detect PML early and plasma exchange to remove natalizumab as a backup option if a patient develops PML. Another option to reduce the risk of PML may be extended interval dosing (EID).

I have several patients who, despite being JCV-seropositive, insist on staying on natalizumab rather than trying an alternative treatment. A few patients, even after switching to another DMT to prevent getting PML, have opted to go back onto natalizumab. The reason typically relates to the return of MS fatigue, or brain fog, after stopping natalizumab. After restarting natalizumab, patients come back and say, ‘I feel well, my fatigue has gone, and my thinking is clear’. This is why anything that decreases the risk of PML for patients on natalizumab is good.

Rationale for extended interval dosing

The theory behind EID is that some cells are less sensitive than others to the effects of natalizumab; if you delay the next natalizumab infusion by 1 or 2 weeks, the saturation of the surface receptors drops below a threshold and allows those cells to traffic into the CNS. If these cells with lower sensitivity to natalizumab are the antiviral T cells and/or the natural killer cells that fight viruses, this could allow immune surveillance of the CNS to occur and prevent PML from developing. By achieving the correct EID, the saturation of the immune cells that cause MS (possibly the memory B cells) is sufficient not to allow MS to reactivate. Clearly, not all cells are equal when it comes to the effect of natalizumab. Importantly, several other adhesion molecules impact the adhesion (stickiness) of immune cells to the blood vessels in the CNS. A delicate balance between the availability of different accessory adhesion molecules could also make the difference.

When these principles were adopted by several neurologists in the USA, the data emerging from their centres suggested they were correct in hypothesising that the risk of developing PML was reduced when JCV-seropositive people with MS received EID natalizumab.

Comparison of extended and standard interval dosing

Biogen, the manufacturer of Tysabri, sponsored some large studies to explore this theory.1,2 Using the so-called TOUCH program (Tysabri Outreach: Unified Commitment to Health), which is a mandatory database of all people with MS receiving Tysabri in the USA, statisticians identified more than 35,000 anti-JC virus antibody-positive patients on Tysabri; they compared those on EID with those on standard interval dosing (SID) for PML risk.1 The TOUCH programme is real-life data, not a clinical trial database, so the periods of EID are variable. To deal with this, the statisticians defined three types of EID with increasing stringency. The remarkable finding was that EID was seen to reduce the risk of PML significantly compared with SID in two of the analyses; in the most stringently defined cohort of EID there were rare cases of PML.

Clinical implications

I have acted on this finding and have offered EID to my patients taking natalizumab who are at risk of PML. It is advisable to transition to 6-weekly EID over several months so as not to precipitate pre-infusion worsening of symptoms. I am now recommending three infusions at 5-weekly intervals before moving to 6-weekly infusions.

The question to consider is whether EID will be associated with some loss of natalizumab effectiveness. A recent study showed no loss of efficacy with EID.2 In addition, the study was not clear on finding a personalised dose. Therefore, all patients on EID received it every 6 weeks.

I personally am thrilled by these results. Why? Because anything that derisks PML for people with MS on natalizumab is good, particularly for people with more advanced MS. This is important because natalizumab is effective in more advanced MS, particularly in slowing down or preventing worsening of hand and arm function.

Can you treat PML?

The short answer is no. Some potential treatments for PML have been proposed, but none has been shown to work. In the MS context, you need immune reconstitution to clear the virus from the brain, and herein lies the problem. When you remove natalizumab with either plasma exchange or by waiting for it to wash out spontaneously, your immune cells start re-trafficking into the brain and you develop encephalitis. This is called IRIS (immune reconstitution inflammatory syndrome) and it can be potentially very dangerous. Therefore, in patients with a large PML burden or PML in strategic brain areas such as the brainstem, we try to reduce the damage associated with IRIS by giving steroids. Anecdotal experience suggests steroids work.

Is there another strategy that we can try? The anti-HIV drug, maviroc, blocks a particular chemokine receptor (CCR5) on lymphocytes and 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 in two reported cases it appeared to prevent IRIS-related damage. Clearly, maviroc as a monotherapy is not enough to stop the immune system clearing the JC virus from the CNS. To determine whether maraviroc does this more effectively than steroids will require a clinical trial.

The mainstay of treating natalizumab-associated PML is reversal of the natalizumab effect. Plasma exchange can speed this up, i.e. removal of the plasma and hence the circulating natalizumab. When natalizumab levels in the peripheral blood fall sufficiently low, the receptors become active again and immune system re-trafficking occurs, allowing your own T cells to fight the infection. However, recent data suggest that benefits of plasma exchange are marginal and for this reason most centres don’t perform plasma exchange to treat PML.  A problem arises when we can’t reconstitute CNS immunosurveillance. This can happen after immune reconstitution therapy, particularly with alemtuzumab or possibly cladribine, or in people with persistent lymphopaenia. One strategy here is an immune transplant, i.e. giving donor anti-JCV lymphocytes to someone with PML, matched to their own HLA (human leukocyte antigens), to fight the JCV infection. This strategy has helped several people recover from PML who might otherwise have died.

I hope that cases of natalizumab-associated PML become increasingly rare. Now that we have derisking strategies and other safer, highly effective DMTs, should we continue to put people with MS at such a high risk of PML? However, until we get a drug that clears JCV from the body we will never remove the PML risk completely. It is a complication of immunosuppression and therefore it will remain a rare complication of our MS treatments. Further information about natalizumab can be found under DMT: Details

References

  1. Ryerson LZ, et al. Risk of natalizumab-associated PML in patients with MS is reduced with extended interval dosing. Neurology 2019;93:e1452 ̶ 62.
  2. Foley JF, et al. NOVA study investigators. Comparison of switching to 6-week dosing of natalizumab versus continuing with 4-week dosing in patients with relapsing-remitting multiple sclerosis (NOVA): a randomised, controlled, open-label, phase 3b trial. Lancet Neurol 2022;21:608 ̶ 19.
DMTsSafety, Monitoring MS

How can I reduce my chances of adverse events on specific DMTs?

The complications associated with immunosuppression vary from DMT to DMT. You will find it helpful to understand what investigations to expect before and during treatment and how these may vary depending on the DMT(s) you are considering.

Key points

  • Numerous tests are carried out at the start of your treatment (baseline); these include blood, urine and tests for a range of infections.
  • Some patients will need tests or procedures specific to their DMT that are inappropriate for everyone with MS – for example, vaccination against some infections; pregnancy and/or genetic counselling; prevention of cardiovascular complications; and management of infusion reactions.
  • Ongoing monitoring is required for many but not all of the above factors.
  • All licensed MS DMTs have had a thorough risk ̶ benefit assessment, and their benefits are considered to outweigh the potential risks.

Standard tests … and why we do them

If you have read the article on immunosuppression, you will know that immunosuppressive DMTs may reduce white blood cell counts and antibody responses to vaccines and increase the likelihood of some infections and cancers. However, we can reduce the risk of many complications associated with long-term immunosuppression (we use the shorthand ‘de-risk’). This article explains what needs to be done at the start of DMT administration (baseline) and during subsequent monitoring. The specifics, however, vary from DMT to DMT.

Baseline tests

Tests at baseline (before starting DMT administration) include full blood count, platelets, liver, kidney and thyroid function tests, and a urine screen. Recording baseline immunoglobulin levels is particularly important if you are about to start an anti-CD20 therapy (ocrelizumab, ofatumumab or rituximab) so that we have a reference level for future comparisons. 

Serum protein electrophoresis is done for patients considering starting interferon-beta; having a so-called monoclonal gammopathy (an abnormal immunoglobulin) is a contraindication to starting an interferon-beta formulation in people with MS. The drug has been associated with a form of capillary leak syndrome, leading in rare cases to death from an adult respiratory distress syndrome.

The table below summarises the routine investigations required at baseline; subsequent sections provide further detail.

Tests routinely carried out at the start of treatment (baseline).
AHSCT, autologous haematopoietic stem cell transplantation; CMV, cytomegalovirus; CSF, cerebrospinal fluid; DMT, disease-modifying therapy; EBV, Epstein ̶ Barr virus; ECG, electrocardiogram; FBC, full blood count; HIV, human immunodeficiency virus; HPV, human papillomavirus; JCV, JC virus; LFTs, liver function tests; MMR, measles/mumps/rubella; MRI, magnetic resonance imaging; PCP, pneumocystis pneumonia; PML, progressive multifocal leukoencephalopathy; TB ELISpot, tuberculosis enzyme-linked immune absorbent spot; TFTs, thyroid function tests; U&E, urea and electrolytes; VZV, varicella zoster virus.

Infection screening

At our centre, we screen for a relatively large number of infectious diseases so that we can treat any subclinical infection before starting a DMT. This is particularly relevant for HIV-1 and 2, hepatitis B and C, syphilis and tuberculosis (TB).  

Screening for the JC virus (JCV), which causes progressive multifocal leukoencephalopathy (PML), is only really needed for people with MS considering starting natalizumab. Even if you are JCV positive, you can be treated with natalizumab for 6 ̶ 12 months and sometimes longer if you are prepared to take on the risk of PML and the extra monitoring required to detect PML early. 

We only check measles/mumps/rubella (MMR) status in patients without documentation of full vaccination as children. We check varicella zoster virus (VZV) status before starting immunosuppression and vaccinate seronegative individuals. Currently, we are still using the live VZV vaccine. This will change, and we will likely be offering all people with MS in the UK the component inactive VZV vaccine (Shingrix, that has had its licence extended) to reduce the chances of zoster reactivation in all adults starting immunosuppression. This new Shingrix indication is similar to the pneumococcal vaccine (Pneumovax). Our centre is only recommending Pneumovax in patients about to start an anti-CD20. However, when Shingrix becomes available on the NHS, it will make sense to bundle this with the Pneumovax and make it routine for all people with MS before starting immunosuppressive therapy. Please check with your healthcare team which products are available locally.

Routine tests and monitoring for Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are only needed for subjects undergoing autologous haematopoietic stem cell transplantation (AHSCT), which causes profound short-term immunosuppression that can result in CMV and EBV reactivation. CMV reactivation also occurs with alemtuzumab, so this needs to be considered when investigating patients who develop complications after receiving alemtuzumab (please see Opportunistic infection in MS). 

For patients starting long-term immunosuppression, it is advisable to screen for active human papillomavirus (HPV) infection (by cervical smear or vaginal swab) and for warts or active infection with molluscum contagiosum. Warts are caused by HPV skin infection; molluscum contagiosum is due to a relatively benign pox virus that typically affects young children but occasionally affects adults. Warts and molluscum contagiosum can spread rapidly in patients receiving alemtuzumab, so I recommend treating these skin infections before starting immunosuppression for MS. 

Vaccinations

We encourage all patients to be vaccinated against COVID-19 and seasonal flu; outside the flu vaccine season, we remind people to get vaccinated during the next vaccine season. 

Hepatitis B, meningococcal and Haemophilus influenzae vaccines are considered only for people with MS who are at high risk of infection and have not had these vaccines as part of a national vaccine programme, i.e. healthcare and laboratory workers for hepatitis B, school and university students and military recruits for meningococcal vaccine and paediatric patients for Haemophilus influenzae. 

The issue around having the HPV vaccine as an adult is more complex. For example, in the UK, the NHS does not cover the cost of the vaccine for people over 25. In addition, most people have only had the quadrivalent vaccine (Gardasil-4), which covers about two-thirds of the strains that cause cancer. Some people with MS may want to upgrade their immunity with the polyvalent vaccine (Gardasil-9) that covers over 95% of the cancer-causing strains of HPV. For more information on HPV vaccination, please see Case study: cervical intraepithelial neoplasia (CIN) and ocrelizumab.

MMR is a live vaccine given in childhood (see MMR vaccine: to vaccinate or not? ). Owing to vaccine hesitancy, however, many people do not receive this vaccine as children. Therefore, if an adult with MS is about to start immunosuppressive therapy and has not been vaccinated against MMR, we advise them to do so. This is particularly important for people about to start natalizumab because these viruses are neurotropic and can infect the brain. Natalizumab blocks immune response within the brain; hence, exposure to a neurotropic virus could cause serious infection, similar to what we see with the JC virus – which causes PML.

Travel vaccines for people who travel as part of their work or plan to travel shortly need to be considered. In particular, the yellow fever vaccine is a live vaccine (made from a weakened yellow fever virus strain) and it should ideally be given before someone starts on immunosuppressive therapy. 

Cardiovascular screening

You may need an ECG (electrocardiogram), to rule out an abnormal heart rhythm or electrical conduction abnormality and to check your left ventricular function (ejection fraction). These abnormalities are a relative contraindication to using the S1P modulators (fingolimod, siponimod, ozanimod, ponesimod), which may affect the conduction of the heart. In patients treated with mitoxantrone, the left ventricular ejection fraction (LVEF) must be done at baseline and regularly monitored because mitoxantrone is toxic to the heart. If the LVEF drops significantly, further dosing of mitoxantrone is contraindicated. 

Pregnancy, family planning and genetic testing

Many chemotherapy agents used in AHSCT for ablating (extracting) the bone marrow are toxic to the ovaries and testes. Therefore, patients receive counselling before treatment and can have eggs (oocytes) or sperm banked for future use. Egg banking is also a consideration for women with MS being treated with mitoxantrone. Men receiving mitoxantrone do not need to bank sperm, however, because mitoxantrone does not cross the testes ̶ blood barrier. 

Genetic testing is only required at present if you wish to receive siponimod. Siponimod is metabolised by a specific liver enzyme (biological catalyst) with two functional variants – slow metabolising and fast metabolising. People who carry two slow-metabolising variants of the enzyme cannot receive siponimod. Intermediate metabolisers (those that carry one slow- and one fast-metabolising version of the enzyme) receive low-dose siponimod, while those with two fast-metabolising enzymes receive high-dose siponimod. 

Protecting against progressive multifocal leukoencephalopathy

I have included magnetic resonance imaging (MRI) and lumbar puncture with cerebrospinal fluid (CSF) testing for JCV among the baseline tests. This is specific to patients at high risk of developing PML who are switching from natalizumab to a depleting immune reconstitution therapy such as alemtuzumab or another therapy that depletes their immune system (e.g. cladribine or an anti-CD20 therapy). These tests are done to exclude asymptomatic PML, which will otherwise be carried over to the new treatment. The effects of these immunosuppressive therapies on your immune system cannot be rapidly reversed, which is a problem because immune reconstitution is needed to clear PML. Most MS centres do not mandate CSF testing in this situation because it does not always reveal the presence of PML. However, I still request this test on my patients to gain as much information as possible on which to base potentially life-changing decisions.

Prophylactic antivirals and antibiotics

Patients in our centre undergoing AHSCT or receiving alemtuzumab will be given antivirals and antibiotics to reduce the likelihood of certain infections. This is particularly relevant for listeriosis, which is a rare infection transmitted via food. We also encourage all our patients to start and maintain a specific diet to reduce the chances of listeriosis. The risk of listeriosis is only present for a short period when both the adaptive and innate immune systems are compromised, that is, for 4 weeks after receiving alemtuzumab, so we recommend antibiotic prophylaxis for 4 weeks. Our online resource provides more information about listeriosis. If you live in the UK, you can order our free listeriosis prevention kit, which contains a booklet (also downloadable) and various practical items to help keep you safe.

Strategies for limiting the risks from immune reconstitution therapies and infusion DMTs.

Infusion reactions

When you use agents that cause cell lysis (breakdown), such as alemtuzumab and intravenous anti-CD20 therapies, the contents of cells cause infusion reactions. To prevent such reactions or reduce their severity, we pretreat patients with corticosteroids, antihistamines and antipyretics. The exact protocols for each DMT differ; for example, ocrelizumab infusion reactions are generally only a problem with the first and second doses; therefore, many centres don’t give steroids with the third and subsequent infusions. The latter was particularly important during the COVID-19 pandemic when it was shown that the recent administration of high-dose steroids increased your chances of severe COVID-19. 

Ongoing monitoring

Once someone has been treated with a DMT, ongoing monitoring is required. What gets monitored and how frequently depends on the individual DMT. For a list of DMTs associated with important adverse events, please see our summary Table in ‘De-risking’ guide: monitoring requirements of individual DMTs.

The regulatory authorities usually put in place specific monitoring requirements, which can differ worldwide. It is important that you also enrol in your national cancer screening programmes. Being on chronic immunosuppression increases your chances of developing secondary malignancies, so please remain vigilant. 

Tests carried out regularly as part of ongoing monitoring.
FBC, full blood count; LFTs, liver function tests; MRI, magnetic resonance imaging; PML, progressive multifocal leukoencephalopathy; TFTs, thyroid function tests; U&E, urea and electrolytes.

I want to reassure you that all licensed MS DMTs have undergone a thorough risk ̶ benefit assessment by the drug regulators, and the benefits of these treatments are considered to outweigh the potential risks. On balance, the level of immunosuppression associated with MS DMTs is typically mild to moderate; hence, the complications are relatively uncommon. MS is a serious disease and, if left to run its natural course, would result in most patients becoming disabled. To learn more about the natural course of MS, please read the section entitled What are the consequences of not treating MS?

DMTsSafety, Monitoring MS

‘De-risking’ guide: monitoring requirements of individual DMTs

Before you start taking a disease-modifying therapy (DMT), your MS team will carry out routine tests and investigations, many of which are repeated during subsequent monitoring or before switching to another DMT. The regulatory authorities that license the drugs specify their monitoring requirements. What gets monitored and how frequently depends on the individual DMT.

All licensed MS DMTs have undergone a thorough risk ̶ benefit assessment by the drug regulators, and the benefits of these treatments are considered to outweigh the potential risks. The table below summarises the main monitoring requirements of individual DMTs or DMT classes. For more detailed information, see the post on reducing your chances of adverse events.

AHSCT, autologous haematopoietic stem cell transplantation; CMV, cytomegalovirus; CSF, cerebrospinal fluid; EBV, Epstein ̶ Barr virus; ECG, electrocardiogram; HPV, human papillomavirus; JCV, JC virus; LVEF, left ventricular ejection fraction; MRI, magnetic resonance imaging; PML, progressive multifocal leukoencephalopathy.