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).
Natalizumab is immunosuppressive, and it is associated with opportunistic infections 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.
Very high, particularly in people with rapidly evolving severe MS.
Yes, but limited to the CNS.
- Natalizumab 300 mg is administered by intravenous infusion or subcutaneous injection 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.
These tend to be mild and occur in about 20% of patients; they may be associated with headache, dizziness, nausea, urticaria and rigors.
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.
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 causes 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.
Rare cases of anaemia and haemolytic anaemia have been reported in natalizumab-treated people with MS.
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.
Yes, in approximately 5% of natalizumab-treated patients.
Full blood count, urea and electrolytes, liver function tests, JC virus-serology and pregnancy test.
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.
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.
I recommend a rebaseline MRI 3 ̶ 6 months after starting treatment with natalizumab and including gadolinium enhancement as part of this.
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.
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.
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 natalizumab, 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 natalizumab in the USA, statisticians identified more than 35,000 anti-JC virus antibody-positive patients on natalizumab; 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.
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.
Recent data have shown that increasing the dosing interval between natalizumab infusions (EID) will lower the risk of developing PML.
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.
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.
I have no concerns and would not recommend any specific washout period after stopping either IFN-beta or glatiramer acetate.
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.
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.
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.
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 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.
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.
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 to 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.
- Ryerson LZ, et al. Risk of natalizumab-associated PML in patients with MS is reduced with extended interval dosing. Neurology 2019;93:e1452 ̶ 62.
- 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.