Tag Archives: immunosuppression

Detail, DMTsDetail, Treatment strategy

What are the attributes of the specific DMTs?

Multiple sclerosis (MS) treatment has evolved rapidly, with 11 classes of disease-modifying therapy (DMT) now available in the UK. I will summarise them briefly and explain how they fit within a treatment paradigm for effective and safe use.

Maintenance therapies versus immune reconstitution: what’s the difference?

There is a divide between the two main treatment philosophies: maintenance ̶ escalation versus immune reconstitution therapies (IRTs).

An IRT is given as a short course – a one-off treatment in the case of autologous haematopoietic stem cell transplantation (AHSCT) or intermittently for alemtuzumab, cladribine or mitoxantrone. IRTs are not given continuously, and additional courses are given only if inflammatory activity recurs. IRTs can induce long-term remission and, in some cases, potentially a cure.

Maintenance therapies, by comparison, are given continuously without an interruption in dosing (‘continuous’ administration may be daily, one or more times weekly, monthly or even once every few months). Although maintenance therapies can induce long-term remission, they cannot, by definition, result in a cure. The recurrence or continuation of inflammatory activity indicates a suboptimal response to treatment and typically requires a treatment switch. Ideally, this switch should be an escalation to a more effective class of DMT.

An article in our list of key questions, entitled How do I want my MS to be treated?, provides a more detailed comparison of maintenance and IRT therapies, including frequency of administration, efficacy, risks, use in pregnancy, vaccine response and potential for a cure.

The DMTs currently licensed in the UK (in August 2024) are listed in the table under the relevant category.

table format updated 180625 SS

Disease-modifying therapies for MS licensed in the UK. *Please note, Bonspri is available in other markets but not the UK.

How effective are the different DMTs?

The measures used to assess the effectiveness of a DMT include its ability to reduce or prevent relapses, focal inflammatory activity (that is, new or enlarging lesions) on magnetic resonance imaging (MRI), and disability progression. Additional factors that can help to assess the relative efficacy of DMTs include the proportion of clinical trial subjects who experience improvement in disability and the impact of the treatment on brain volume loss.

The MS-Selfie InfoCards are an easy-to-use resource to help people with MS compare the key features of each DMT. They contain bite-sized information designed to aid treatment choices and an overview of the key aspects of each DMT.

Efficacy of the licensed DMTs for MS can be visualised as pyramid, with the moderately effective treatments at the bottom and the more effective approaches at the top. What determines the most appropriate DMT efficacy level for an individual depends on several factors, such as baseline prognostic profile, family planning requirements, local or national treatment guidelines, socioeconomic factors, consideration of any co-existing illnesses, cognitive impairment, risk aversion and lifestyle issues.

Pyramid format updated 180625 SS

UK licensed DMTs for MS, in ascending order of efficacy.
HSCT/AHSCT, haematopoietic stem cell transplantation/autologous haematopoietic stem cell transplantation.

What is the goal of treatment? Introducing NEIDA as a target

In the past, we used no evident disease activity (NEDA) as a treatment target. ‘Disease activity’ included progression or disease worsening independent of relapse activity (termed smouldering MS). Although some of the more effective DMTs may modify this stage of the disease, many neurologists feel uncomfortable switching or stopping a DMT based simply on smouldering MS disease activity. 

Relapses and ongoing focal MRI activity are associated with a worse short-term to intermediate-term prognosis. These observations have led to the increasing adoption of ‘no evident inflammatory disease activity’ (NEIDA) as a new treatment target. For more information about treatment targets, please see the article in our key questions, Do I understand the concepts of treat-2-target and NEDA?

Many healthcare professionals (HCPs) remain sceptical of using NEIDA as a treatment target, fearing that this could lead to more people with MS being on ‘riskier’ high-efficacy therapies. However, achieving long-term remission, or NEIDA, is a well-established treatment target in other autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease. People with MS treated-to-target of NEIDA from the outset do better than those whose treatment is escalated following breakthrough disease (at a clinical or subclinical/MRI level)1. I would, therefore, strongly encourage people with MS and their HCPs to adopt NEIDA as an initial treatment target.

Flipping the pyramid

The effectiveness, or relative effectiveness, of individual DMTs becomes less critical in the context of a treatment target of NEIDA. Choosing a DMT with a lower efficacy rate simply means that a greater proportion of treated people with MS will need to be switched to higher efficacy therapies over time to achieve NEIDA. We refer to the latter of these three approaches – starting with high-efficacy treatment – as flipping the pyramid. In recent trials of alemtuzumab, ocrelizumab, ofatumumab and ublituximab, people with MS randomised to 2 years of lower efficacy DMTs (interferon-beta-1a or teriflunomide) had poorer outcomes than those receiving highly active therapy from the outset. Real-world data from registries also support this; groups of people with MS with delayed access to high-efficacy DMTs did worse than those who received high-efficacy treatments early.1,2

Horizontal versus vertical switching

If we consider the conventional step care paradigm, people with MS who switch horizontally from interferon-beta to glatiramer acetate, or vice-versa (i.e. from one moderate efficacy DMT to another moderate efficacy DMT) do less well than those who switch vertically to fingolimod, a highly effective DMT. Similarly, people with MS escalating to natalizumab, a very high-efficacy DMT, do better than those being escalated to the less effective, but still high-efficacy, DMT fingolimod. 

Continuous and intermittent immunosuppression

Another useful way of classifying DMTs is whether they are immunosuppressive, that is, they reduce the activation, or effectiveness, of the immune system. Drug regulators stipulate that a drug may be classified as immunosuppressive if it (1) causes significant lymphopaenia (low lymphocyte count) or leukopenia (low white blood cell count), (2) is associated with opportunistic infections, (3) reduces the antibody and immune response to vaccines and (4) increases the risk of secondary malignancies.

The duration and intensity of immunosuppression further determine the risks. For example, short-term or intermittent immunosuppression associated with IRTs front-loads the risks, which are substantially lower once the immune system has reconstituted itself. In comparison, long-term continuous or persistent immunosuppression, which occurs with some of the maintenance DMTs, accumulates problems over time, particularly opportunistic infections and secondary malignancies. You can read more detail on this topic in the key question How immunosuppressed am I? The following table summarises the main attributes of intermittent and persistent immunosuppression.

How immunosuppressed are you table updated format 180625 SS

The main characteristics of continuous (persistent) and short-term (intermittent) immunosuppression. Modified from Giovannoni, Curr Opin Neurol.2
AHSCT, autologous haematopoietic stem cell transplantation; PML, progressive multifocal leukoencephalopathy.

Adverse effects, monitoring and risk reduction

The complications associated with immunosuppression vary from DMT to DMT. Each individual drug summary in the DMTs section of MS-Selfie contains detailed information about the main adverse events, key monitoring requirements, use (or contraindication) during pregnancy and breastfeeding, and response to vaccines. The MS-Selfie InfoCards provide bite-sized summaries of several practical aspects, including side effects, to enable easy comparison of any treatments you are considering; some of this information is collated below for easy reference.

Short-term versus long-term adverse effects

Each drug has been given scores from 1 to 10 based on published analyses of its short-term and long-term side effects. Short-term refers to side effects that emerge when a treatment is started and decrease in severity or disappear within days or weeks. A well-known example of short-term side effects on starting interferon-beta is flu-like symptoms that typically abate within 4 ̶ 8 weeks.

A long-term side effect persists for months or doesn’t disappear on continuing the DMT. Examples include intermittent but persistent flushing after taking dimethyl fumarate, or low B lymphocyte counts with anti-CD20 therapies that may lead to low antibody or immunoglobulin levels (hypogammaglobulinaemia).

A low score denotes few or rare side effects; a high score denotes many or frequent side effects. The score does not correlate to a percentage. More information can be found in each drug summary and the manufacturer’s Summary of Product Characteristics.

Scores for short-term and long-term side effects assigned to the individual DMTs summarised in the MS-Selfie InfoCards, based on a published network meta-analysis.3
Alem, alemtuzumab; GA, glatiramer acetate; HSCT, haematopoietic stem cell transplantation; IFN-beta; interferon-beta; Nat, natalizumab.

Monitoring and risk reduction

Numerous tests are carried out at the start of treatment, and ongoing monitoring is required for many factors, to reduce the risk from adverse events. The key question, How can I reduce my chances of adverse events on specific DMTs?, explains what needs to be done at the start of DMT administration (baseline) and during subsequent monitoring. The specifics vary from DMT to DMT; please refer to the individual summaries for details such as baseline tests, follow-up, infection prevention, cancer risk, pregnancy, breastfeeding and vaccination. It is important to remember that all licensed MS DMTs have had a thorough risk ̶ benefit assessment, and their benefits are considered to outweigh the potential risks.

Administration and other practical considerations

Routes and frequency of administration

The MS-Selfie InfoCards contain a symbol for each DMT, showing how it is administered. Some DMTs are available in more than one formulation (e.g. tablets and injection). The frequency of administration varies greatly from DMT to DMT; please consult the relevant summary in the DMTs section and discuss your preferences and priorities with your MS HCP.

The route of administration for each drug in the MS-Selfie InfoCards is clearly identified by the relevant symbol. (If a DMT is available in more than one formulation, there is a separate card for each delivery route.)

Number of clinic visits

It may be important for you to consider the frequency of clinic visits. This will depend on factors such as the delivery route of your DMT, the monitoring requirements of the drug regulators and the risk of specific side effects. The table below summarises the assessments from the MS-Selfie InfoCards. This is another factor to consider in discussions with your MS HCPs about the most appropriate DMT for you.

Conclusions

People with MS must understand the objectives of MS treatments and the different treatment strategies currently available to achieve these objectives. Although the MS therapeutic landscape is complex and hence may seem overwhelming, framing the choices using a relatively simple construct should help each individual to make informed decisions about managing their MS. MS-Selfie aims to guide you in the process of deciding on the most appropriate therapeutic strategy and specific DMT for treating your disease.

References

  1. Rotstein D, et al. Association of No Evidence of Disease Activity with no long-term disability progression in multiple sclerosis: a systematic review and meta-analysis. Neurology 2022;99:e209̶ ̶ 20.
  2. Giovannoni G. Disease-modifying treatments for early and advanced multiple sclerosis: a new treatment paradigm. Curr Opin Neurol 2018;31:233 ̶ 43.
  3. Samjoo IA, et al. Efficacy classification of modern therapies in multiple sclerosis. J Comp Eff Res 2021;10:495–507.
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.

DMTs, Treatment strategy

How immunosuppressed am I?

Do you understand the difference between short-term intermittent and long-term continuous immunosuppression? Here we address another of the key questions to consider before deciding on a specific disease-modifying therapy (DMT).

Key points

  • Immunosuppressive disease-modifying therapies (DMTs) reduce the immune system’s effectiveness.
  • It is important to weigh up the benefits and risks of short-term versus continuous immunosuppression.
  • Non-selective DMTs suppress the adaptive and innate immune systems; selective DMTs do not affect the innate immune system and are thus associated with a low risk of bacterial infections.
  • The implications of immunosuppression need to be considered within the context of other health and lifestyle factors.

Which DMTs cause immunosuppression?

A useful way of thinking about DMTs is based on whether they are immunosuppressive. Broadly speaking, an immunosuppressive is any DMT that reduces the immune system’s activation or effectiveness. 

From a regulatory perspective, for a drug to be classified as immunosuppressive, it should: 

  • cause significant lymphopaenia or leukopenia (reduced white cell counts)
  • be associated with opportunistic infections (infections that don’t occur in people with a normal, healthy immune system)
  • reduce antibody and/or T-cell responses to vaccines 
  • increase the risk of secondary malignancies. 

Based on the above criteria, the interferon-beta preparations and glatiramer acetate are immunomodulatory rather than immunosuppressive. Teriflunomide is also an immunomodulatory therapy with the potential, albeit small, to cause immunosuppression. In real life, however, very few people with MS treated with teriflunomide develop significant lymphopaenia or leukopenia; if they do, we tend to stop the drug. The other licensed DMTs are immunosuppressive to a greater or lesser degree. 

Short-term versus continuous immunosuppression

The duration and intensity of immunosuppression further determine the risks. Short-term or intermittent immunosuppression associated with an immune reconstitution therapy (IRT) front-loads the risks, which decrease substantially once the immune system has reconstituted itself. In comparison, long-term continuous or persistent immunosuppression, which occurs with most maintenance DMTs, accumulates problems over time, particularly opportunistic infections and secondary malignancies.

Live vaccines are, in general, contraindicated in patients on continuous immunosuppressive therapies. However, someone with MS on an IRT who has reconstituted their immune system can tolerate and respond to live vaccines. The benefits of administering live vaccines always need to be balanced against the risks of the vaccine.

How immunosuppressed are you table updated format 180625 SS

The main characteristics of continuous persistent and short-term (intermittent) immunosuppression. Modified from Giovannoni, Curr Opin Neurol.1
AHSCT, autologous haematopoietic stem cell transplantation; PML, progressive multifocal leukoencephalopathy.

Selective versus non-selective immunosuppression

Immunosuppression that accompanies DMTs may be selective or non-selective. Non-selective therapies deplete and/or suppress both the adaptive immune system (T cells and B cells) and the innate immune system (monocytes, neutrophils and natural killer [NK] cells). Alemtuzumab, AHSCT (autologous haematopoietic stem cell transplantation) and mitoxantrone are non-selective and are therefore associated with acute bacterial infections such as listeriosis, nocardiosis and cytomegalovirus reactivation. In comparison, anti-CD20 agents (ocrelizumab and ofatumumab) and cladribine are selective, do not affect the innate immune system and are therefore associated with a low risk of acute bacterial infections. 

How immunosuppressed are you_MET vs IRT_2 Dec 2024

Classification of disease-modifying therapies for relapsing forms of MS. Modified from Giovannoni, Curr Opin Neurol.1
AHSCT, autologous haematopoietic stem cell transplantation.

Other considerations

Please note that the implications of immunosuppression are not black and white but interact with other factors such as:

These factors have been highlighted during the COVID-19 pandemic, particularly in relation to the risk of severe COVID-19 and the variations in vaccine responses among people with MS (including waning of the immune response).

It is important to realise that we can derisk (reduce the risk of) some complications associated with long-term immunosuppression and the use of DMTs. Please see the post entitled How can I reduce my chances of adverse events on specific DMTs?

References

  1. Giovannoni G. Disease-modifying treatments for early and advanced multiple sclerosis: a new treatment paradigm. Curr Opin Neurol 2018;31:233 ̶ 43.
DMTs, Treatment strategy

How do I want my MS to be treated?

What is the difference between a maintenance ̶ escalation DMT and an immune reconstitution therapy (IRT)? Why is it important to understand the distinction?

Key points

  • Maintenance–escalation and immune reconstitution therapy (IRT) are two approaches to MS treatment currently favoured.
  • IRT is a one-off, short course which acts on immune system cells in three stages: reduction, repopulation and reconstitution.
  • Maintenance–escalation is given continuously without interruption. If it does not work well, the treatment is changed to a more effective DMT (known as ‘escalation’).
  • Additional future approaches are likely to include induction ̶ maintenance and/or combination therapy.

If I had MS, how would I want to be treated? This is a difficult question, and one that many of my patients ask me. The answer depends on your life stage, what risks you are prepared to take, personal factors such as family planning considerations and the extent of your understanding of MS and how we approach its treatment.

Currently, there are two main philosophies regarding the treatment of MS with DMTs: maintenance/escalation versus immune reconstitution therapies (IRTs). 

What is an immune reconstitution therapy?

By definition, an IRT is given as a short course, i.e. as a one-off treatment in the case of autologous haematopoietic stem cell transplantation (AHSCT) or intermittently in the case of alemtuzumab, cladribine or mitoxantrone. IRTs are not given continuously, and additional courses of the therapy are given only if there is a recurrence of MS inflammatory activity. IRTs can induce long-term remission and, arguably, in some cases a potential cure.

IRTs have three phases to their mode of action, which I refer to as the ‘three Rs’.

  1. Reduction, or depletion, when we try to kill the autoimmune cells that cause MS.
  2. Repopulation, when the immune system recovers from stem cell transplantation and, hopefully, the autoimmune cells don’t return.
  3. Reconstitution, when the immune system is recovered and fully competent. The recovered immune system following treatment with an IRT is different from what was there before. Some people like to think of an IRT as a reboot of the immune system, but without MS.
Slide1

The three Rs of immune reconstitution therapy: reduction, repopulation and reconstitution. From Giovannoni, Curr Opin Neurol.1 

What is an MS ’cure’?

One attempt at a definition describes an MS cure as no evidence of disease activity (NEDA) 15 years after the administration of an IRT. I justify using 15 years because it is the time-point most accepted for defining ‘benign MS‘ and is also beyond the average time to onset of secondary progressive MS in natural history studies.

What is a maintenance therapy?

A maintenance therapy is given continuously without an interruption in dosing. Although maintenance therapies can induce long-term remission (i.e. NEDA), they cannot result in a cure. The recurrence or continuation of inflammatory disease activity with maintenance therapies is an indication of a suboptimal response to treatment and typically results in a treatment switch. Ideally, this switch should be to a more effective class of DMTs – hence the term ‘escalation’. 

What would I recommend?

I can’t choose for you. The debate is complex and depends on many factors. One important consideration is vaccine readiness: will I be able to mount an adequate immune response to a vaccine? IRTs have the advantage that they allow reconstitution of the immune system; once it recovers, vaccine responses are restored, and even live vaccines can be given.

The table below highlights key differentiators. Further, detailed information about most of the products listed in the Table can be accessed through the DMT comparison tool available at ClinicSpeak or via the Multiple Sclerosis Trust MS Decisions aid.

Similarities and differences between maintenance treatments and immune reconstitution therapies. Registered trade names (UK market) of the generic drugs listed are shown in brackets. *How to define a ‘cure’ in MS is controversial. Modified from Giovannoni, Curr Opin Neurol.1
DMT, disease-modifying therapy; HSCT, haematopoietic stem cell transplant; IRT, immune reconstitution therapy.

The future

I envisage two more treatment strategies emerging.

  • One approach is induction ̶ maintenance therapy, using an IRT followed by an immunomodulatory therapy rather than an immunosuppressive DMT (which is a safer option) the aim is to keep MS in long-term remission. This approach is used in oncology, where the cancer is hit hard with induction chemotherapy and then kept at bay with a well-tolerated maintenance therapy (e.g. antihormonal therapies in breast cancer).
  • Another approach is combination maintenance therapy; the aim would be to combine an anti-inflammatory therapy with, say, neuroprotective therapies to target smouldering MS.

The diagram below illustrates the scheduling of the four approaches discussed in this section. You may like to try out the DMT comparison tool to find out how some of the drugs listed in the comparison Table above align with your personal life choices and priorities.

Slide5

Four approaches discussed in this section. The white panels illustrate the two approaches currently available; the shaded panels illustrate two strategies that may emerge in the future. Modified from Giovannoni, Curr Opin Neurol.1

References

  1. Giovannoni G. Disease-modifying treatments for early and advanced multiple sclerosis: a new treatment paradigm. Curr Opin Neurol 2018;31:233 ̶ 43.