Do you understand the concept of treat-2-target?

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 disability progression and (iii) no MRI activity (new or enlarging T2 lesions or Gd-enhancing lesions).

NEDA is an important goal for treating individual MSers. 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) is 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 final initial course of therapy, e.g. 2 years, or close enough to the time when a third, or subsequent course, can be administered.

The question remains of how many cycles need to be given before considering that a person has failed a specific IRT. For alemtuzumab it is likely to be three cycles under the NHS. 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 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 MSers having more than one cycle.

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 to that of incomplete recovery from relapses, as a component of the treatment target. 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.

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 MSer 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.

End-organ damage

A meta-analysis of all large clinical studies that included:

• brain volume measurements;
• the development of new MRI lesions;
• and whole brain volume loss over 2 years,

looked at the data and predicted who would become more disabled. The conclusions were that from a treatment perspective it is important to stop relapses, new MRI lesion and brain volume loss to prevent, or slow down, worsening disability.

Interestingly, many neurologists are critical of using NEDA as a treatment target in clinical practice. They are concerned that the majority of MSers 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 MSers end up on the so-called ‘high-efficacy’ therapies because of breakthrough disease activity, then this is what they probably need, to have their MS treated adequately.

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. MSers treated to target of NEDA do better than those with breakthrough disease. I would therefore strongly encourage you to discuss this treatment target with your own MSologist.

The slideshow below includes a flowchart to illustrate 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 a 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).