Barts-MS rose-tinted-odometer: ★★ (Purple Haze Friday #7D7098; looking forward to the weekend)
It is quite amazing how large and extensive the focal inflammatory lesion blindspot or scotoma is in the field of MS. I was on a call with a few American neurologists last week and they were saying how anti-CD20 therapy has transformed their MS practice. One neurologist claimed that 4 out of 5 of their patients were now going onto ocrelizumab or ofatumumab. He even said that ofatumumab will become the new Copaxone; i.e. no blood monitoring and very safe. Do you agree? When I reminded this neurologist of the end-organ damage data, i.e. brain volume loss, and the progression independent of relapse data in relation to anti-CD20 therapies he dismissed me saying that these patients were free of relapses and their MRI’s were quiet so he had done his job.
And herein lies the problem, the wider MS community including MS experts are not prepared to look beyond relapses and MRI activity; for them this is MS. In other words, if you render people relapse and MRI activity free then you have treated their MS. However, if you scratch the surface this is clearly not the case. If relapses were MS then they would predict long term outcome, but they don’t except when you are on therapy. According to the Prentice criteria that define a surrogate endpoint for relapses to be MS they need to predict outcome regardless of treatment. This is why relapses cannot be MS; relapses and their MRI equivalent (focal lesions) simply represent the immune system’s response to what is causing the disease or the real MS.
The data set below from the MS-Base register supports this proposition; i.e. off-therapy relapses do not predict long-term outcome, unlike on-therapy relapses. This point is so fundamental to understanding the real MS that most people can’t get their heads around it.
So what does this mean to you if you have MS? It means that if you have no evident inflammatory disease activity (NEIDA), and are relapse-free and MRI-activity free, it doesn’t mean your MS is necessarily under control. In other words, you could still be losing brain volume at double the rate of what is expected for your age and you could still be worsening. This is why we mustn’t be lulled into a sense of false security that we have cracked MS with our current therapies, in particular with the anti-CD20 therapies. We really need to go beyond NEIDA and target smouldering MS with new add-on strategies.
I hope all this makes sense? I have asked you before, would you rather be NEIDA or NEIDA and NEO-EOD (no evident ongoing end-organ damage)? The challenge for the MS community is to shift our focus to the latter target.
Jokubaitis et al. Predictors of long-term disability accrual in relapse-onset multiple sclerosis. Ann Neurol. 2016 Jul;80(1):89-100.
Objective: To identify predictors of 10-year Expanded Disability Status Scale (EDSS) change after treatment initiation in patients with relapse-onset multiple sclerosis.
Methods: Using data obtained from MSBase, we defined baseline as the date of first injectable therapy initiation. Patients need only have remained on injectable therapy for 1 day and were monitored on any approved disease-modifying therapy, or no therapy thereafter. Median EDSS score changes over a 10-year period were determined. Predictors of EDSS change were then assessed using median quantile regression analysis. Sensitivity analyses were further performed.
Results: We identified 2,466 patients followed up for at least 10 years reporting post-baseline disability scores. Patients were treated an average 83% of their follow-up time. EDSS scores increased by a median 1 point (interquartile range = 0-2) at 10 years post-baseline. Annualized relapse rate was highly predictive of increases in median EDSS over 10 years (coeff = 1.14, p = 1.9 × 10(-22) ). On-therapy relapses carried greater burden than off-therapy relapses. Cumulative treatment exposure was independently associated with lower EDSS at 10 years (coeff = -0.86, p = 1.3 × 10(-9) ). Furthermore, pregnancies were also independently associated with lower EDSS scores over the 10-year observation period (coeff = -0.36, p = 0.009).
Interpretation: We provide evidence of long-term treatment benefit in a large registry cohort, and provide evidence of long-term protective effects of pregnancy against disability accrual. We demonstrate that high annualized relapse rate, particularly on-treatment relapse, is an indicator of poor prognosis. Ann Neurol 2016;80:89-100.
General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.