Multiple sclerosis (MS) is the most common neurological disease in young adults, affecting about 100 000 people in the UK (MS Trust, 2018). MS is an autoimmune disease of the central nervous system (CNS), which causes demylenation. Its symptoms result from inflammatory injury and neurodegeneration. In MS, autoreactive lymphocytes cross the blood brain barrier (BBB) and enter the CNS, causing inflammation, neuronal demyelination, axonal damage, and neurological degeneration and dysfunction (Bradstander and Katz Sand, 2017).
MS is classified into three main types: relapsing remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS) and primary progressive multiple sclerosis (PPMS). RRMS affects 85% of the MS population (MS Trust, 2018). It is categorised by episodes of new or worsening symptoms that last for more than 48 hours (relapse) followed by periods of recovery and remission (remission). This type of MS is more prevalent in 20–30-year-old women. There are a number of disease modifying therapies (DMTs) that aim to reduce the impact of relapses and the accumulation of disability. Each of these treatments has different mode of action, efficacy, route of administration and licencing criteria. The medication chosen for someone with MS will be a decision for the patient and their neurologist to make together by looking at the patient's disease activity, lifestyle and life choices (ie starting a family) (NHS England, 2018).
Many people with RRMS go on to have SPMS. They have a build-up of disability, and it can be accompanied by relapses or independent of relapses. There is currently no licenced medication specifically for this form of MS the UK; however, it is hoped that medications such as siponimod will be available in the next couple of years (MS Society, 2019a).
PPMS affects about 10% of MS population – it affects an older age group (50+) and usually men and is characterised by a gradual accumulation of symptoms, reduction in function and accumulation of disability. There is one medication in England licenced for this disease process – ocrevus (ocrelizumab) (MS Society, 2019b).
Natalizumab
Natalizumab is a DMT that is used in highly active RRMS, which has a high efficacy of 70% for reducing relapses and sustaining disease progression. It is given by intravenous infusion every 4 weeks, it has a long half-life and stays in the body for up to 12 weeks (Kappos et al, 2011).
In England, natalizumab is licensed for individuals with RRMS who are over 18 years old with highly active MS despite having been treated with a full course of one or more DMTs, or in individuals with rapidly evolving RRMS defined by two or more disabling relapses in 1 year and MRI scan that show at least 1 or more Gadolinium enhancing lesion or a significant increase in T2 lesions from the previous MRI scan. This differs in North Ireland, Scotland and Wales where it is licensed for individuals with RRMS who have had one relapse in the past year despite taking another DMT and MRI evidence of disease activity or two relapses with or without another DMT and evidence of MRI disease activity. (NHS England, 2018).
How does natalizumab work in MS?
The monoclonal antibody, natalizumab is a selective adhesion molecule inhibitor, which binds to the a4-integrin expressed on leucocytes. By binding to the leucocytes, natalizumab prevents their migration through the BBB stopping inflammation and MS activity. It is thought that the drug also suppresses the inflammatory activity in leucocytes at the disease site by inhibiting the recruitment of further immune cells to inflamed tissue (Kappos et al, 2011).
Timeline of natalizumab
Natalizumab was first licensed in the US in 2004 for the treatment of MS following a number of trials that found it to be highly efficacious and tolerated (Figure 1). The AFFIRMS study found 68% reduction in annualised relapse rate (ARR) and a 42% reduction in the level of sustained progression. The number of new T2 enhancing lesions was reduced by 57%, and a 76% reduction was seen in new T1 hypo-intense lesions (Polman et al, 2006). The SENTINEL trial showed a 54% ARR reduction and an 89% reduction in gadolinium-enhanced lesions (Richard et al, 2006). No evidence of disease activity was seen in 27% of patients on natalizumab compared to 2% on placebo (Havrdova et al, 2009). In placebo-controlled trials in 1617 MS patients treated with natalizumab for up to 2 years, adverse events leading to discontinuation of therapy occurred in 5.8% of patients on natalizumab compared to 4.8% on placebo (electronic Medicines Compendium (eMC), 2017).
In 2005, the first cases of progressive multifocal leukoencephalopathy (PML) were seen in a patient on natalizumab and natalizumab was voluntary withdrawn from US market. It was reintroduced in 2006 and was given European marketing authorisation. Since its reintroduction, there has been enhanced emphasis on making this product safe and reducing the PML risk.
Benefits of natalizumab
The AFFIRMS and SENTINEL trials reported the efficacy of natalizumab. In 2018, the Tysabri Observational Programme (TOPS) showed 10-year data, which highlighted the long-term efficacy of natalizumab in terms of stability in relapse rate and EDSS. The data showed a significant reduction in relapses (89.3%) compared to the year before starting treatment. Cumulative improvement in disability was found to be 30%. There were no new safety concerns reported and a PML rate of 0.002–0.003 per patient year was observed (Kappos et al, 2018).
Table 1 shows a quick guide to the risks and benefits of natalizumab, which can be used to aid patient choice and decision making.
Table 1. Benefits/risk profile
| Benefits | Risks |
|---|---|
| Good tolerability 0.5% higher incidence in adverse reactions on natalizumab than on placebo | Side effects dizziness, nausea and vomiting, joint pain increased fatigue, headaches |
| Good efficacy reduction in lesion load, annual relapse rate reduction 81% disability progression reduction 64% no evidence of disease activity 27% | PML risk 4.15 in 1000 |
| Regular consultations, MRI scans, blood tests | PML risk opportunistic infections |
| Meeting other patients in same situation | Monthly infusions |
| Pregnancy no specific pattern of birth defects detected with pregnancy register | Not indicated for use in pregnancy unknown risk of fetal abnormalities birth defects |
| Mode of action: reduces white blood cells crossing blood–brain barrier reducing inflammatory cascade and MS attacks | Mode of action: increase risk of activating opportunistic infections such as JCV causing PML and/or IRIS |
Opportunistic infections
It is thought that natalizumab also reduces immunosurveillance, whereby the body's immune system recognises and eliminates foreign pathogens such as viruses and bacteria, which subsequently increases the risk of opportunistic infections (Brandstadter and Katz Sand, 2017).
Opportunistic infections with the John Cunningham virus (JCV), encephalitis and meningitis (caused by the herpes simplex virus or varicella zoster viruses) have been seen in patients receiving natalizumab (eMC, 2018). If a patient develops encephalitis or meningitis, natalizumab should be discontinued and treatment for the herpes virus should be administered (eMC, 2018).
John Cunningham virus and PML
Globally, about 60% of population have been infected by JCV (Knowles, 2006). This virus usually remains dormant, but is often reactivated in immunocompromised patients. PML is a rare demyelinating disease of the CNS that occurs in people that are immunocompromised. It is caused by an opportunistic infection by JCV. The JCV uses a lytic cycle to cause PML by infecting and destroying white and gray matter in the CNS. It is potentially disabling and life threatening and therefore rapid diagnosis is crucial to improve prognosis and out comes (Figure 2). The symptoms of PML can mimic an MS relapse (Table 2), so it is vital that clinicians are aware of the symptoms of PML and can act quickly on their suspicion (eMC, 2017).
Table 2. Differences between MS and PML
| Features of MS | Features of PML | |
|---|---|---|
| Onset | Changes become apparent over days or weeks and gradually improve without medication | Changes become apparent over Many weeks and gradually progress |
| Clinical presentation | Increased fatigue | Cognition changes |
| Double vision (Diplopia) And/or optic neuritis | Visual field deficits due to disturbances of to the Retrochiasmal pathway | |
| Transient Weakness | Hemiparesis | |
| Sensory impairment | Seizures | |
| MRI presentation | Focal lesions periventricular localisation | Cortical grey matter and white matter involvement poorly defined presentation of lesion |
From: Wijburg et al (2016)
As of November 2018, the estimated incidence of PML was 4.15 per 1000 patients. Since December 2018, 804 cases of PML have been confirmed, of these 76% of patients are alive and there is a varying range of physical disability (Ryerson et al, 2018).
JCV is thought to be the cause of PML in patients who had received natalizumab. To confirm this, a biomarker can be used to detect JCV from blood samples of those people who have PML caused by natalizumab. A biomarker is a way of objectively measuring and evaluating a characteristic of a biological process, physiological process or pharmacological reaction. In the future, it is hoped that biomarkers will have the potential to further our understanding of MS and individual's risk factors in the aim of personalising treatment to suit the individual's disease severity (Grossman et al, 2017).
The JEMS trial found that the risk of becoming JCV-positive is increased with age (over 40 years), male gender and country of residence (Barry et al, 2000).
An anti-JCV antibody index value has been introduced to allow patients to be stratified into groups associated with risk factors. Before the anti-JCV antibody index value, patients were considered to be either JCV-negative or JCV-positive (Bozic et al, 2014). This anti-JCV antibody index value allows patients to be monitored accordingly to their risk factors; however, the assay has a false negative rate of about 2% (McGuigan et al, 2016). This proves the need for clinical vigilance and regular testing to ensure patients' safety. Due to the number of PML cases that had anti-JCV positive status, the European Medicines Agency (2014) recommended that stratification testing for JCV is carried out 6-monthly to improve the safety profile of natalizumab and to reduce risk of PML.
Three main risk factors for PML have been identified:
- Prior immunosuppressant use
- Length of time on natalizumab >2 years
- Presence of anti-JCV antibodies.
The risk of PML with all three risk factors is 1 in 90 (Bloomgreh et al, 2012).
These risk factors should be considered by clinicians and the patients should be re-educated about their PML risk 2 years after starting natalizumab or if their JCV status changes to positive (eMC, 2018).
PML has been detected in patients 6 months post-natalizumab; therefore, it is vital that the patient is monitored after treatment discontinuation. Family members or carers should also be mindful of the signs of PML and given education at discontinuation (eMC, 2018).
Treatment of PML
A patient with suspected symptomatic PML should be seen immediately for a consultation. They should be given an MRI scan and a lumber puncture for cerebrospinal fluid analysis of JCV DNA to determine a diagnosis. With late diagnosis of PML, there is a significant risk of disability and a 1 in 3 chance of death (eMC, 2017).
The patient may not show any symptoms of PML, but a routine MRI scan could show evidence of the condition. Early detection of PML lowers the risk of physical disability and reduces risk of death to 1 in 30. It is recommended that for early detection to be consistent, patients on natalizumab should have an MRI scan every 3–4 months (Wattjes et al, 2015).
There is no approved treatment for PML because placebo-controlled clinical trials would be difficult to carry out due to the urgency of treatment, the impossibility of predicting who will get PML and the ethics surrounding using a placebo. Therapeutic plasma exchange is performed to remove natalizumab from the circulation, allowing immune reconstitution of the central nervous system (Khatri et al, 2009; Tyler and Vollmer, 2017).
Immune reconstruction inflammatory syndrome
When clinicians are treating PML, the possibility of immune reconstruction inflammatory syndrome (IRIS) should be considered. When the immune system is functioning normally, improvement in neurological symptoms following treatment for PML would be expected. However, with IRIS the clinical presentation worsens and increasing disability and neurodegeneration is seen. IRIS can occur several weeks after plasma exchange has been completed; therefore, it is important to monitor the patient for signs of the syndrome. In study on the first 35 cases of PML, 32 patients developed IRIS (Tan et al, 2011). There are no evidence-based guidelines for suggested treatment, but corticosteroid steroids are often used to reduce the inflammation (eMC, 2017).
Other risk factors on natalizumab
Calabresi et al (2007) found that of the patients who had a hypersensitive reaction to natalizumab, 6% had neutralising antibodies. Natalizumab is a protein; therefore, if a patient's immune system rejects this protein it will make antibodies against it to defend the body if ‘reinfection’ occurs. This can lead to the medication being ineffective and to hypersensitive reactions.
A hypersensitive reaction occurs when the immune system has already been exposed to an antigen and has produced antibodies called immunoglobulin E (IgE), which binds to basophils and mass cells causing sensitivity, but generally does not cause any symptoms to the individual. On further exposure, the basophils and mast cells that have IgE on their surface release prostaglandins, leukotrienes and histamine causing an inflammatory cascade, which can lead to a severe systematic allergic reaction. Symptoms include, but are not limited to, shortness of breath, bradycardia or tachycardia hypotension, urticaria. With natalizumab hypersensitive reactions usually occur early on in the treatment regimen usually on 2nd dose (but can occur at any time). There is an increased risk in patients who had interruption in natalizumab. Infusion reactions can occur up to a 2 hours post-infusion so it is advised the patient is monitored accordingly.
Fertility, pregnancy and breastfeeding
Preclinical studies on animals did find a reduction in fertility, but these studies have not been replicated in humans. It is thought, however, that natalizumab does not have an effect on fertility in men or women (Dobson et al, 2019).
Studies in animals did show reproductive toxicity (Wehner et al, 2009); however, the Tysabri pregnancy register (Friend et al, 2016) did not suggest any detrimental effects on pregnancy and did not show any evidence of any specific birth defects associated with natalizumab.
To minimise risk, it is recommended that natalizumab is not given after 34 weeks gestation because natalizumab crosses the placenta. Thrombocytopenia and anaemia were observed in babies whose mothers were given natalizumab in the third trimester (Haghikia et al, 2014; Friend et al, 2016).
If a patient becomes pregnant on natalizumab, the risks and benefits of continuing treatment should be discussed with the patient and should be based on the risk benefit factors of each individual case. The factors that should be considered are:
- The nature of the disease pathway of the women if treatment was to be stopped
- Will pregnancy hormones be adequate to control MS disease activity?
- If treatment is stopped, what is the risk of rebound?
- PML risk level
- Concurrent illnesses that might influence treatment decision during pregnancy.
The British National Formulary does not recommend breastfeeding while on natalizumab due to it being present in breast milk (Joint Formulary Committee, 2019). However the UK consensus of pregnancy in MS (Dobson et al, 2019) suggest that a discussion be had with the patient on the benefits of breastfeeding along with the risk factors. The consensus suggests that a minimal amount of natalizumab is secreted in breast milk and therefore it is unlikely that the baby will absorb this systematically and therefore breastfeeding should be an option (Dobson et al, 2019).
Interval dosing
The use of natalizumab in patients at high-risk of PML has to be a decision made by the patient and the clinician and the patient should be educated about the risk factors of continuing this treatment. The reluctance of some patients to change to a different DMT has led to some centres increasing the dose interval of natalizumab to 6 or 8 weeks (Dobson et al, 2019). It has not been licensed for use in this way, but studies have found that the reduction in dose interval in high risk PML patients to 5–6 weeks reduces the risk of by 88% (Ryerson et al, 2018). A further study is being carried out by Biogen to establish the clinical effectiveness of extended dose intervals in natalizumab. This study – NOVA – will conclude in 2021.
Rebound
When natalizumab is interrupted or stopped, immunological processes which are involved in the inflammatory cascade in MS resume and can cause new clinical and radiological findings of MS activity. (Gueguen et al, 2014). The RESTORE trial did not show any increase in activity above the level of pre-natalizumab treatment (Fox et al, 2014).
There are a number of DMTs available for MS and they all have different pharmacodynamics and pharmacokinetic properties. It is therefore important to take into account the elimination of the drug from the body (half-life) and the mode of action of the medication before considering swapping a patient to natalizumab. In some instances, a wash out period will be necessary before initiation of natalizumab and increased clinical vigilance may be required to ensure the patients safety (Brandstadter and Katz Sand, 2017).
Patients who have an increase in their MS activity or if they suffer from infusion reactions should be tested for antibodies against natalizumab. If antibodies are found and remain consistent, the patient may not be benefiting from the treatment and discussion around treatment options should be given. (Brandstadter and Katz Sand, 2017).
Improving practice minimising risk
There is minimal evidence to suggest that areas outside neurology are kept up-to-date with natalizumab use and its association with PML. Outside of core hours, patients may present at their GP or A&E with new neurological symptoms. It is therefore felt that more adequate training for professionals in these areas would be beneficial.
Hospital or GP treatment alert systems together with an algorithm of where to signpost a patient receiving natalizumab with increase in neurological symptoms would ensure that the patient receives the correct treatment. This is a consideration that requires further research.
Conclusion
Natalizumab has been marketed for the treatment of MS for 13 years in the UK. Since then, there have been a number of PML cases associated with natalizumab and it is important that clinicians and patients understand the risk factors and treatment methods for PML and IRIS and stay up-to-date on the research.
In the UK there is an estimated 80 natalizumab centres treating over 5000 MS patients. Although there is guidance on the use and monitoring of natalizumab, there is no standardised practice. However, it would be difficult to do this due to individual influencing factors (ie PML risk). The monitoring of natalizumab should be individualised to specific patient risk factors and clinical vigilance should be used alongside guidance provided to support clinical decisions. Natalizumab has shown high efficacy and good tolerability and continues to be used widely in MS. Continual safety measures and biomarkers should be studied to continue to provide updates and safety information to allow natalizumab continuation for the treatment of MS.
Key Points
- Natalizumab is a treatment used in highly active multiple sclerosis
- It has been shown to be effective at reducing the impact of multiple sclerosis
- The main safety issue is progressive multifocal leukoencephalopathy and patients should be monitored closely throughout treatment and 1 year post-treatment because of risk
CPD reflective questions
- What three risk factors have been identified that put patients at a higher risk of developing progressive multifocal leukoencephalopathy (PML)
- What are the symptoms associated with PML?
- What is the aim of stratifying patients?