Tag Archives: biological

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

19/12/2022 Gavin Giovannoni

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.

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.

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

Harding K et al. Clinical outcomes of escalation vs early intensive disease-modifying therapy in patients with multiple sclerosis. JAMA Neurol 2019;76:536-41.
Merkel B et al. Timing of high-efficacy therapy in relapsing-remitting multiple sclerosis: A systematic review. Autoimmun Rev 2017;16:658-65.
Simpson A et al. Early aggressive treatment approaches for multiple sclerosis. Curr Treat Options Neurol 2021;23:19.
Giovannoni G. Disease-modifying treatments for early and advanced multiple sclerosis: a new treatment paradigm. Curr Opin Neurol 2018;31:233 ̶ 43.

Stages of MS

What type of MS do I have?

26/04/2022 Gavin Giovannoni

MS has historically been classified into different subtypes, and this subdivision dictates what treatments you are eligible for. These MS disease subtypes are not supported biologically, however, and many MS neurologists are of the opinion that MS is one disease.¹

Key points

The difference between relapsing MS and non-relapsing progressive MS is explained.
The stages of MS have different labels, for historical development and reimbursement reasons, but biologically MS is one disease.
From a treatment perspective, the key thing is to know if your MS is active or inactive.
Active MS can be differentiated from inactive MS by relapses, MRI evidence of disease activity and raised neurofilament levels in the cerebrospinal fluid.

Type of MS

You should be able to classify yourself as having either relapsing MS or non-relapsing progressive MS. Knowing what type of MS has been diagnosed and whether your MS is active or inactive will allow you to ask your MS neurologist questions about the MS treatments available to you.

Around 85–90% of people with MS start with so-called relapse-onset MS, i.e. they have a definite attack of symptoms that is usually followed by a period of complete or incomplete recovery. A single attack may be labelled as a clinically isolated syndrome (CIS): it does not fulfil the current diagnostic criteria for full-blown MS, but it means someone is at risk of further attacks and hence of developing MS in the future.

EDSS, Expanded Disability Status Scale score

Once you have more attacks, either clinically in the form of relapse or subclinically with new lesions on magnetic resonance imaging (MRI), then you are usually diagnosed as having MS. The diagram below illustrates the typical course of repeated relapses and remissions, with worsening disability over time, that characterises so-called relapsing–remitting MS (RRMS).

After a variable period, people with relapse-onset MS may notice worsening neurological function without improvement. This is called secondary progressive MS (SPMS) and it can occur with superimposed relapses (so-called relapsing SPMS [RSPMS]) or without relapses.

A small number of people with MS (10–15%) will present with worsening neurological function without a prior history of relapses; this is called primary progressive MS (PPMS).

Interestingly, some people with PPMS go on to have relapses, and this is referred to as progressive relapsing MS (PRMS).

Rarely, someone may present with worsening neurological function, similar to PPMS, but have a prior history of just one relapse. This is referred to as single-attack progressive MS (SAP), but most MS specialists classify these patients as having SPMS.

In summary …

Relapsing MS captures all people with MS who are still having relapses, i.e. within the last 2 years, and includes RRMS, RSPMS and PRMS.
Non-relapsing progressive MS refers to SPMS and PPMS: these latter two groups should have no history of recent relapses, i.e. in the last 2 years.

To further confuse things, non-relapsing progressive MS used to be referred to as chronic progressive MS (see below).

Why is this important?

Different DMTs are licensed for different types of MS, and many treatment guidelines specifically state the type of MS for which a particular drug can be used.

Is MS one or more diseases?

In the past, MS was regarded as one disease: either you had MS, or you did not. The stages were referred to as early relapsing MS or chronic progressive MS, but MS was still one disease.

When disease-modifying therapies (DMTs) were developed, MS was split into multiple sub-types. This categorisation was driven by commercial considerations, and it allowed interferon-beta to be licensed in the US under the Orphan Drug Act. The classification of orphan disease in the US requires there to be fewer than 200,000 people with that diagnosis. Dividing MS into RRMS, SPMS, PPMS and later CIS ensured that each category met this criterion.

Since then, PRMS and radiologically isolated syndrome (RIS) have been added as potential subtypes. These classifications tend to be arbitrary and overlap, but there is no biological basis to support MS being more than one disease.

Is your MS active or inactive?

From a treatment perspective, it is important to know if your disease is active or inactive. In active MS, there is evidence of ongoing inflammation in the brain and spinal cord. If you are having relapses, are developing new lesions on MRI or have raised neurofilament (NFL) levels in your cerebrospinal fluid (CSF) or blood, your MS is active.

Active MS responds to anti-inflammatory treatments; inactive MS is less responsive to currently licensed DMTs.

Criteria for ‘active’ MS accepted by many MS health professionals. CSF, cerebrospinal fluid; NFL, neurofilament light.
*Some neurologists accept 24 months, 36 months or even longer when assessing MRI activity. There is no international consensus on the gap between the baseline and new MRI scan to define active disease.

The term progressive MS refers to the stage of MS when your disability gets worse – independent of relapses, and possibly of focal inflammatory lesions. I say ‘possibly’, because our current MRI scans don’t show new or enlarging microscopic lesions but only those that are larger than ~3–4 mm. NFL measurements in either the CSF or blood have the advantage of being additive and integrating inflammatory activity. In my experience, about one in ten patients classified as ‘inactive’ based on clinical and MRI activity is found to have active MS when CSF NFL levels are analysed. Unfortunately, however, many MS neurologists, regulators and payers do not accept this latest definition of MS disease activity because tests for NFL levels are currently not widely available.

In conclusion, knowing the type of MS you have and whether your disease is active or inactive will allow you to discuss with your MS specialist the kinds of treatment available to you.

References

Giovannoni G, et al. Smouldering multiple sclerosis: the ‘real MS’. Ther Adv Neurol Disord 2022;15:17562864211066751.