Will I improve?

Prof G offers hope in that we can now go beyond simply no evident inflammatory disease activity as a treatment target and expect some disability improvement. Should this be the new aim of MS treatment

Is it realistic to expect your disability to improve?

Disability worsening

Many people with MS who have been on disease-modifying therapies for many years and have what the MS community calls inactive MS (no relapses or new MRI lesions), but notice that they are getting worse.  

‘How can I get worse when my MS is inactive?’; is among the commonest questions I get asked in the clinic.

I have written about why this happens in an earlier Newsletter, called ‘Getting Worse’. I refer to this as smouldering MS. In our centre we don’t accept this as a fait accompli, we now offer patients a lumbar puncture to see if they have raised neurofilament levels in their spinal fluid, which is a biochemical marker of ongoing inflammatory disease activity. Damaged axons and nerve cells release their contents into the fluid around them. Some of the structural proteins that are released into the spinal fluid are neurofilaments and the levels of neurofilaments are proportional to the amount of ongoing damage the inflammation is causing. If these levels are raised we use this information to justify a change in treatment, usually an escalation in treatment to a more effective DMT.

Please note that at the moment very few MS centres are monitoring neurofilament levels in routine practice and many neurologists don’t act on this marker in clinical practice. However, things will change when the assay to measure neurofilament in peripheral blood becomes available for general use. 

Disability improvement

We always focus on the getting worse side of things. Does the opposite ever happen, i.e. do people with MS ever experience improvement in disability? 

Quite recently a patient of mine with smouldering MS  asked me ‘why a friend’s daughter with very ‘bad MS’, who had been treated with alemtuzumab, had made such a remarkable recovery?’ Apparently, this young woman had been rendered partially paraplegic from a spinal cord relapse and after alemtuzumab had recovered function and was now walking almost ‘normally’ again. My patient wanted to know why there was such a difference between herself, someone with primary progressive MS, and her friend’s daughter, a young woman with highly active relapsing-remitting MS.

If you go to the top of the treatment ladder and look at AHSCT (autologous haemopoietic stem cell transplantation) in early MS, the vast majority of treated patients notice an improvement in disability. Not only are these patients have no evident inflammatory disease activity (NEIDA), but they have disability improvement (DI). I have started calling this NEDADI. 

NEDADI = no evident disease activity and disability improvement

In the much spoken about HSCT-MIST trial during the first year post-HSCT, the average EDSS scores improved from 3.4 to 2.4 vs. a worsening from 3.3 to 4.0 in the patients on licensed DMTs. In another HSCT trial in which patients on DMTs had a rescue option of being treated with HSCT in the first 12 months, 12/55 (22%) of patients on DMTs compared to 38/55 (69%) who were treated with HSCT had an improvement in their EDSS (Burt et al. JAMA. 2019 Jan 15;321(2):165-174).

These results are very impressive but are not unique to HSCT. 

The first DMT to show a convincing impact on disability improvement in phase 3 controlled trial was with natalizumab in the AFFIRM study; at 2 years the probability of a sustained improvement in disability was 30% for natalizumab-treated patients and 19% for patients who received placebo (Phillips et al., Mult Scler. 2011 Aug;17(8):970-9). The next convincing phase 3 results was with alemtuzumab-treated patients in the CARE-MS2 trial; alemtuzumab-treated patients were more than twice as likely as IFN-β-1a-treated patients to experience 3-month confirmed disability improvement (35% vs 19%) (Giovannoni et al. Neurology. 2016 Nov 8;87(19):1985-1992).

What about ocrelizumab and cladribine? Unfortunately, we don’t have published data on cladribine, however, in the phase 3 pooled OPERA data of ocrelizumab only 21% of ocrelizumab-treated patients had disability improvement confirmed after at least 12 weeks compared to only 16% of  IFN-β-1a-treated patients (Hauser et al., N Engl J Med. 2017 Jan 19;376(3):221-234). With ofatumumab, another anti-CD20 therapy, only 11.0% of trial patients had confirmed disability improvement, which was no different to the rate of 8.1% in the patients treated with teriflunomide, the comparator drug (Hauser et al. N Engl J Med 2020; 383:546-557).

So there is a league table in terms of disability improvement with HSCT and alemtuzumab at the top, next is natalizumab, followed by ocrelizumab and the also-rans. Interestingly, this league table, not surprisingly, mirrors the effect of these DMTs on brain volume loss, i.e. their ability to protect the end-organ your brain and spinal cord. Are you surprised? I am not. 

A large driver of disability improvement is reserve capacity, i.e. brain reserve or simply the size of your brain, which predicts and provides the substrate for recovery of function. This is another reason why you would want your MS treated early and just maybe you would want to flip the pyramid and go for the DMTs that offer you the best chance of disability improvement.

Hidden in this data may be a clue about the pathogenesis of MS. What differentiates HSCT and alemtuzumab from natalizumab and then from ocrelizumab and ofatumumab? Could it be the transient depletion and reconstitution of the T-cell compartment?

Research has shown that disability improvement after alemtuzumab is not necessarily attributable to its anti-inflammatory effects and suggested that T lymphocytes, reconstituting after alemtuzumab, permit or promote brain repair via the production of several growth factors in particular brain-derived neurotrophic factor (BDNF),  platelet-derived growth factor (PDGF) and ciliary neurotrophic factor (CNTF) (Jones et al., Brain. 2010 Aug;133(Pt 8):2232-47). This is yet another reason why IRTs (immune reconstitution therapies) are the treatment of choice if you want to go beyond NEIDA as a treatment target and actually give yourself a chance of significant disability improvement (NEDADI). 

It is worth noticing the positive effect alemtuzumab has on the MRI metric called magnetization transfer ratio or MTR, which is a measure of brain tissue integrity. The tissue integrity in the normal-appearing grey and white matter gets worse over time in pwMS who are not on a DMT. In comparison, MTR tends to stabilise in pwMS treated with alemtuzumab, which suggests alemtuzumab protects against further ongoing tissue damage. This MRI MTR data mirrors our clinical observations and is congruent with some of the other research findings (Button et al., Mult Scler. 2013 Feb;19(2):241-4). 

So yeas we are now entering an era where disability improvement (NEDADI) is not an unreasonable expectation for pwMS, provided they are treated early and with high-efficacy DMTs particularly IRTs. 

I would be interested to know how many of you were told about this disability improvement data when you were offered a DMT? 

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I am raising funds from subscriptions to administer the MS-Selfie Newsletter and microsite. The subscriptions, for case studies only, will be used to hire an administrator to proofread, curate and transfer the contents of the Newsletter onto the companion MS-Selfie microsite. If you find these Newsletters helpful and can afford to subscribe I would urge you to do so; it will help me and the MS community. Yesterday’s case study for subscribers was about a patient with active relapsing-remitting MS who had been offered ocrelizumab or ofatumumab and was asking for help in making a decision between these two treatments. Thank you.

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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.