Tag Archives: maintenance therapies

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.
Treatment strategy

Do I understand the concepts of treat-2-target and NEDA?

Has anyone discussed a treatment target with you, including the need to rebaseline your disease activity? Have the concepts of preventing end-organ damage to the central nervous system (the ‘end-organ’ in MS) and brain volume loss or atrophy been broached?

Key points

  • Achieving long-term remission is a well-established treatment target in MS and several other autoimmune diseases.
  • Key measures of MS disease activity are used to define composite treatment targets; they provide objective means for monitoring and decision-making.
  • To demonstrate a target of no evident disease activity (NEDA) requires a minimum of three criteria to be met: no relapses, no MRI activity and no disability progression.
  • More stringent definitions of NEDA targets have evolved and will continue to do so as new predictors of treatment response are developed.

If you are on a disease-modifying therapy (DMT), what is the objective or treatment target for your MS? This is another question to be answered before committing yourself to a specific treatment strategy.

Treat-2-target

Relapses and ongoing focal inflammatory activity on MRI (new or enlarging T2 lesions and T1 gadolinium-enhancing lesions [Gd-enhancing]) are associated with poor outcomes. This has led to the adoption of ‘no evident disease activity’ (NEDA) as a treatment target in MS. NEDA, or NEDA-3, is a composite of three related measures of MS disease activity: (i) no relapses, (ii) no MRI activity (new or enlarging T2 lesions or Gd-enhancing lesions) and (iii) no disability progression. NEDA is an important goal for treating individuals with MS.

When to rebaseline

To use NEDA as a treatment target in day-to-day clinical practice, it is advisable to be ‘rebaselined’ after the onset of action of the DMT you have been started on. The timing of the MRI to provide a new baseline depends on the DMT concerned. The recommendations for immune reconstitution therapies (IRTs) are very different from those for maintenance therapies. In the case of an IRT (for example alemtuzumab or cladribine, which are given as short courses), breakthrough disease activity can be used as an indicator to retreat rather than necessarily to switch therapy. Therefore, a rebaselining MRI should be delayed until after the final course of therapy, e.g. 2 years, or close enough to the time when a third, or subsequent course, can be administered.

Determining treatment failure: IRTs

Questions remain of how many treatment cycles need to be given before considering that a specific IRT has not been effective.

  • For alemtuzumab, the threshold is three cycles under NHS England’s treatment algorithm (based on their cost-effectiveness analysis). Alemtuzumab is a biological or protein-based treatment, so the risk of developing neutralising anti-drug antibodies increases with each infusion.
  • Cladribine on the other hand is a small molecule, so neutralising antibodies are not a problem and there is no real limit on the number of courses that can be given.
  • Although HSCT tends to be a one-off treatment, there are rare reports of people with MS receiving more than one cycle.

Please note there are potentially cumulative risks associated with multiple cycles of an IRT: secondary malignancies in the case of HSCT and persistent lymphopaenia with cladribine. 

Determining treatment failure: maintenance therapies

In comparison to IRTs, if you have disease activity on a particular maintenance DMT, and provided you have been adherent to your treatment, this is usually interpreted as a suboptimal response or non-response and it should trigger a switch to another class of DMT. 

A criticism of NEDA is the omission of so-called ‘non-relapse-associated disease worsening’ as a component of the treatment target (in addition to evidence of incomplete recovery from relapses). I refer to this disease worsening as smouldering MS. Worsening disability in the absence of relapses may have little to do with ongoing focal inflammatory activity. It may simply represent a delayed dying-off of axons and nerve fibres following earlier focal inflammatory lesions. As a result, many neurologists feel uncomfortable switching, or stopping a DMT, based simply on non-relapse-associated worsening disability. For more information, please see Getting worse – smouldering MS.

Beyond NEDA-3

The definition of NEDA is evolving with clinical practice. Some centres are now testing for brain volume loss (that is, brain atrophy) and/or increased neurofilament light chain (NFL) in cerebrospinal fluid (CSF) as part of the NEDA-3 treatment target. NEDA-4 builds on NEDA-3, by including the target of normalising brain atrophy rates to within the normal range. The problem we have found with this is that the measurement of brain atrophy in an individual with MS level is very unreliable. For example, dehydration, excessive alcohol consumption and some symptomatic medications can cause the brain to shrink temporarily. We, therefore, think that CSF NFL levels are a better treatment target, less prone to misinterpretation. Neurofilaments are proteins that are found in nerves and axons (nerve fibres) and are released in proportion to the amount of nerve fibre damage that occurs in MS. Normalising CSF NFL levels, which would indicate that nerve damage is stopped, is referred to as NEDA-5. From a scientific perspective, including a more objective end-organ biomarker makes sense and will almost certainly be incorporated into our treatment target in the future.  

Table format updated 180625 SS

The components of NEDA-recommended targets are expanding as our ability to measure predictors of treatment response grows.
CSF, cerebrospinal fluid; MRI, Magnetic resonance imaging; NEDA, no evident disease activity; NEIDA, no evident inflammatory disease activity; NFL, neurofilament light; PROMS, patient-related outcome measures.

End-organ damage

The combination of relapses, the development of new MRI lesions and brain volume loss over 2 years in clinical trials predicts quite accurately who will become disabled over the same time period. From a treatment perspective, it is important to stop relapses, new MRI lesions and brain volume loss if we are to prevent or slow down worsening disability. Therefore, we must go beyond NEIDA (no evident inflammatory activity), which refers to relapses and focal MRI activity, and normalise brain volume loss if we can. 

Alternatives to NEDA?

Many neurologists are critical of using NEDA as a treatment target in clinical practice, fearing that it encourages people with MS to take highly effective DMTs that they consider may be ‘more risky’ (see short summaries of the available DMTs for information about individual drugs). Such neurologists, therefore, promote a less proactive approach and allow for some residual MS disease activity, but at a lower level. This treatment target is referred to as minimal evidence of disease activity, or MEDA.

In my opinion, MEDA flies in the face of the science of focal inflammatory lesions being ‘bad’ and it is associated with poor short-term, intermediate and long-term outcomes. If most people with MS end up receiving so-called high-efficacy therapies because of breakthrough disease activity, then this is what they probably need, that is, to have their MS treated adequately. Compelling evidence has emerged from trials, large registries and real-world data that people with MS treated early with highly effective DMTs (flipping the pyramid) do better than those who have delayed access to more effective DMTs.1,2,3 You can find a short summary of some key findings on the MS Brain Health website.

Implementing NEDA in clinical practice

Please note that achieving long-term remission, or NEDA, is a well-established treatment target in other autoimmune diseases, such as rheumatoid arthritis, autoimmune kidney disease and inflammatory bowel disease. People with MS treated to a target of NEDA do better than those with breakthrough disease activity. I would therefore strongly encourage you to discuss this treatment target with your own MS neurologist. 

The flowchart below illustrates how we implement a treat-2-target of NEDA strategy. The important take-home message is that the treatment targets in MS have moved; goal-setting and the active monitoring of outcomes is now required to achieve these goals. 

Treat to target NEDA algorithm

Recommended approaches to implementing a treat-2-target of NEDA strategy, using maintenance ̶ escalation or immune reconstitution therapy (IRT). The dotted lines indicate that if treatment fails you can either switch within the class (maintenance or IRT) or reassess the strategy. From Giovannoni, Curr Opin Neurol.4
Alem, alemtuzumab; Clad, cladribine; DMF, dimethyl fumarate; Fingo, fingolimod; GA, glatiramer acetate; HSCT, haematopoietic stem cell transplantation; IFNβ, interferon-beta; Mitox, mitoxantrone; NEDA, no evident disease activity; Nz, natalizumab; Ocre, ocrelizumab; Ofat, ofatumumab; Teri, teriflunomide.

There is also a clear need to update the definition of NEDA regularly as new technologies become available and are validated as predictors of treatment response. I therefore envisage the definition of NEDA changing still further in future to include more objective measures, particularly ones measuring end-organ damage and the inclusion of patient-related outcome measures.

References