Bullseye: is your MS being treated-2-target?

Has a treatment target been discussed with you including the need to rebaseline your disease activity? Have the concepts of preventing end-organ damage and brain volume loss or atrophy been broached?

Are you on a DMT? What is the objective or treatment target for your MS? This is another question that needs to be answered before you commit yourself to a specific treatment strategy or DMT.

1. What is multiple sclerosis (MS)?

2. Am I sure that I have MS?

3. What type of MS do I have?

4. What prognostic group do I fall into? 

5. What is the risk of not being treated with a disease-modifying therapy (DMT)? 

6. Do I have active MS? 

7. Am I eligible for treatment with a DMT? 

8. What is the difference between a maintenance/escalation DMT and an IRT (immune reconstitution therapy)?

9. Do I understand the difference between short-term intermittent and long-term continuous immunosuppression?

10. Do I understand the concept of treat-2-target?

11. What are the attributes of the specific DMTs?

12. How can I derisk or reduce my chances of getting certain adverse events on specific DMTs?

13. ……….?

Photo by Afif Kusuma on Unsplash

Treat-2-Target

Relapses and ongoing focal inflammatory activity on MRI (new or enlarging T2-lesions and gadolinium (Gd)-enhancing lesions) are associated with a worse outcome. 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 individual pwMS. 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 rebaselining MRI depends on the DMT concerned. Please note that recommendations for immune reconstitution therapies (IRTs) are very different to 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 to necessarily 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.

Questions remain of how many cycles need to be given before considering that a person has failed a specific IRT. For alemtuzumab, it is three cycles under the NHS England’s treatment algorithm. This is based on a cost-effectiveness analysis by NHS England. But as alemtuzumab is a biological or protein-based treatment the risk of developing neutralizing anti-drug antibodies increases with each infusion. As cladribine is a small molecule neutralizing antibodies are not a problem so 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 reports of rare pwMS having more than one cycle of treatment. Please note there are potentially cumulative risks associated with multiple cycles of an IRT; in the case of HSCT, it is secondary malignancies and with cladribine potentially persistent lymphopaenia. 

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 sub-optimal or non-response and should trigger a switch to another class of DMT. 

A criticism of NEDA is the inclusion of so-called non-relapse associated disease worsening, separate from that of incomplete recovery from relapses, as a component of the treatment target. I refer to this as smouldering MS. Worsening disability in the absence of relapses may have little to do with ongoing focal inflammatory activity and may simply represent a delayed dying-off of axons and nerves fibres as a result of preceding focal inflammatory lesions. As a result of this many neurologists feel uncomfortable switching, or stopping a DMT, based simply on non-relapse associated worsening disability. For information on smouldering MS please read my MS-Selfie Newsletter ‘Getting Worse’ from the 2nd-Luly-2021.

Beyond NEDA-3

The definition of NEDA is evolving with clinical practice. Some centres are now incorporating brain volume loss or brain atrophy and/or cerebrospinal fluid neurofilament light chain (NFL)  into the treatment target. NEDA-4 refers to normalising brain atrophy rates to within the normal range. The problem we have found with brain atrophy is that the measure at the individual person with MS level is very unreliable. For example dehydration, excessive alcohol consumption and some symptomatic medications can cause the brain to shrink temporarily. We think that spinal fluid neurofilament light chain (NFL) levels are a better treatment target as this measure is not as noisy. 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 spinal fluid 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.  

End-organ damage

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 to prevent or slow down, worsening disability. This is why we have to go beyond NEIDA (no evident inflammatory activity), which refers to relapses and focal MRI activity, and normalise brain volume loss if we can. 

Please note many neurologists are critical of using NEDA as a treatment target in clinical practice. They are concerned that the majority of pwMS would end up being on the ‘more risky’ highly effective DMTs. Some are therefore promoting a less active approach and allow for some residual but a lower level of MS disease activity. 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 the focal inflammatory lesion being ‘bad’ and is associated with poor short, intermediate and long-term outcomes. If the majority of pwMS end up on the so-called high-efficacy therapies because of breakthrough disease activity, then this is what they probably need, i.e. to have their MS treated adequately. Compelling data has emerged from both trials and real-world data that in pwMS who are treated with highly effective DMTs early (flipping the pyramid) do better than those who have delayed access to more effective DMTs. 

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. PwMS 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 MSologist. 

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

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

I would be interested to know if you are on a DMT or are about to start a DMT if a treatment target has been discussed with you including the need to rebaseline your disease activity? Have the concepts of preventing end-organ damage and brain volume loss or atrophy been broached?

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. The advice is intended as general advice and should not be interpreted as being personal clinical advice. If you have problems please tell your own healthcare professional who will be able to help you.