Case studies
I have been asked by two patients, independently of each other, who had delayed access to treatment with a disease-modifying therapy if this could explain why they now have secondary progressive MS.
Prof G’s opinion
A good colleague of mine who was the primary driver behind collecting and analysing the 21-year interferon-beta-1b survival study (see below), said to me that to him this data was the most convincing data available to support the early treatment paradigm in MS. Do you agree?
In summary, trial subjects in the pivotal original interferon-beta-1b study (Betaseron / Betaferon) who had delayed access to interferon-beta-1b because they were randomised to receive placebo were 50% more likely to have died of MS-related complications (EDSS 10.0) 21 years after starting the study compared to study subjects with early access to treatment in the active-treatment arms of the study. Was this due to the impact of interferon-beta-1b on MS or some other confounding factor?
In the 69 pwMS for whom information on the relationship of death to MS was available 78% were judged to have died from MS-related complications. This tells us that IFN-beta increases your life expectancy by reducing MS-related complications that can cause death in the future. The latter include swallowing problems that are associated with aspiration pneumonia, urinary dysfunction that lead to urinary tract infections and septicaemia, immobility and pressure sores, falls and fractures, to name a few of the most common causes of premature death in people with MS (pwMS).
You need to remember that this was a placebo-controlled study and the subjects on placebo were switched to active treatment after approximately 3 years, with some subjects having to wait up to 5 years (trial recruitment was from June 1988 to May 1990; with placebo-treated subjects given free commercial supply as of October 1993). What this study clearly shows is that delaying access to treatment by just 3-5 years has a major impact on long-term disease outcomes.
Please note that apart from suicide most pwMS get to EDSS 10 or death as a result of having MS, by passing through EDSS stages 2, 4, 6 (stick), 8 (wheelchair/bed) and the stages in between. So my answer to these two patients above is yes your delayed access to DMTs in the early 2000s is almost certainly one of the reasons why you now have secondary progressive MS and are disabled. Another reason is smouldering MS for which we don’t have a treatment yet.
Please note this there is now overwhelming evidence from other controlled trials and real-life data to support the interferon-beta 21-year mortality data. In fact, the debate about early treatment and MS outcomes is so widely accepted that it has now has shifted from early access to DMTs to early access to highly effective DMTs, i.e. flipping the pyramid. It is clear that pwMS who are treated with more effective DMTs first-line do so much better than those who are asked to wait (watchful waiting) or are escalated gradually up the DMT ladder (slow escalation). This is why, despite us designing the early treat-2-target NEDA trial, our centre couldn’t participate in the trial comparing maintenance-escalation vs. flipping the pyramid. We simply don’t have equipoise; in other words, we don’t think it is ethical to randomise patients to a treatment arm that is less effective and hence will result in poorer long-term outcomes and probably poorer long-term survival. This is why it is our current clinical practice to offer pwMS who have active disease and are eligible under the NHSE algorithm for treatment access to highly effective treatment first-line.
We are so convinced about the early treatment that we are doing the #AttackMS trial, which will explore if access to the highly effective treatment natalizumab, 2 months earlier than what happens in routine practice, improves outcomes. Yes, we will be randomising patients before they have finished the MS diagnostic pathway to treatment vs. delayed access, i.e. only 2 months later when they have a definitive diagnosis of MS. We anticipate that the #AttackMS study will nudge the MS community to treat the MS brain as we treat the brain in stroke. Forget about years, every day, every week or every month for the untreated MS brain is like every second, minute or hour in the non-perfused brain of a person having a stroke. #TimeMatters and #TimeIsBrain in MS.
Yes, in MS time really is brain and delaying access to DMTs and potentially highly effective DMTs is unacceptable in the modern era of treating MS. The data below not only supports the maxim “Time is Brain” but “Time is Life“, so why would anyone wait to treat someone with active MS knowing this?
If you are interested you can watch my presentation from the 2020 ACTRIMS-ECTRIMS meeting during which I make the case for flipping the pyramid. Please note the #AttackMS study paradigm takes this concept of ‘time is brain’ even further. Do you agree with this approach?
Some of you will be aware that at present if you just have active MS and not highly-active (HAD) nor rapidly-evolving severe (RES) MS the only highly effective MS DMTs available to you under the NHS are the two licensed anti-CD20 therapies, ocrelizumab and ofatumumab.
I don’t agree with limiting the highly effective treatment options to one class of treatment, which is why we are pushing for cladribine to get the first-line label it deserves and for the MHRA and the MS community to reconsider the alemtuzumab and natalizumab labels. Why shouldn’t a well-informed pwMS be able to make a call on the benefits and risks of the treatment of their MS?
I am also a strong proponent for AHSCT being offered first-line and I am not necessarily an outlier here. Many of my colleagues who treat MS, and have seen the potential consequences of MS, would want their own MS treated with either alemtuzumab or AHSCT. Why would a neurologist treat their patients with MS differently from how they would want their own MS managed?
ECTRIMS 2022
I have just been invited to give a ‘hot topic’ talk at ECTRIMS 2022 on ‘Flipping the pyramid and beyond’, which will almost certainly be about treating-2-target beyond NEIDA (no evident inflammatory activity), targeting smouldering MS and the holistic management of MS with the primary objective of protecting the end-organ, i.e. your brain and spinal cord, so you can age normally. So the issues raised in this MS-Selfie Newsletter are at the heart of the contemporary management of MS.
Paper 1
Goodin et al. Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFNβ-1b trial. Neurology. 2012 Apr 24;78(17):1315-22.
Objective: To examine the effects of interferon beta (IFNβ)-1b on all-cause mortality over 21 years in the cohort of 372 patients who participated in the pivotal randomized clinical trial (RCT), retaining (in the analysis) the original randomized treatment-assignments.
Methods: For this randomized long-term cohort study, the primary outcome, defined before data collection, was the comparison of all-cause mortality between the IFNβ-1b 250 μg and placebo groups from the time of randomization through the entire 21-year follow-up interval (intention-to-treat, log-rank test for Kaplan-Meier survival curves). All other survival outcomes were secondary.
Results: After a median of 21.1 years from RCT enrollment, 98.4%(366 of 372) of patients were identified, and, of these, 81 deaths were recorded (22.1% [81 of 366]). Patients originally randomly assigned to IFNβ-1b 250 μg showed a significant reduction in all-cause mortality over the 21-year period compared with placebo (p = 0.0173), with a hazard ratio of 0.532 (95% confidence interval 0.314-0.902). The hazard rate of death at long-term follow-up by Kaplan-Meier estimates was reduced by 46.8% among IFNβ-1b 250 μg-treated patients (46.0% among IFNβ-1b 50 μg-treated patients) compared with placebo. Baseline variables did not influence the observed treatment effect.
Conclusions: There was a significant survival advantage in this cohort of patients receiving early IFNβ-1b treatment at either dose compared with placebo. Near-complete ascertainment, together with confirmatory findings from both active treatment groups, strengthens the evidence for an IFNβ-1b benefit on all-cause mortality.
Classification of evidence: This study provides Class III evidence that early treatment with IFNβ-1b is associated with prolonged survival in initially treatment-naive patients with relapsing-remitting multiple sclerosis.
Paper 2
Goodin et al. Cause of death in MS: long-term follow-up of a randomised cohort, 21 years after the start of the pivotal IFNβ-1b study. BMJ Open. 2012 Nov 30;2(6).
Objectives: Compared with controls, multiple sclerosis (MS) patients die, on average, 7–14 years prematurely. Previously, we reported that, 21 years after their participation in the pivotal randomised, controlled trial (RCT) of interferon β-1b, mortality was reduced by 46–47% in the two groups who received active therapy during the RCT. To determine whether the excessive deaths observed in placebo-treated patients was due to MS-related causes, we analysed the causes-of-death (CODs) in these three, randomised, patient cohorts.
Design: Long-term follow-up (LTF) of the pivotal RCT of interferon β-1b.
Setting: Eleven North American MS-centres participated.
Participants: In the original RCT, 372 patients participated, of whom 366 (98.4%) were identified after a median of 21.1 years from RCT enrolment.
Interventions: Using multiple information sources, we attempted to establish COD and its relationship to MS in deceased patients.
Primary outcome: An independent adjudication committee, masked to treatment assignment and using prespecified criteria, determined the likely CODs and their MS relationships.
Results: Among the 366 MS patients included in this LTF study, 81 deaths were recorded. Mean age-at-death was 51.7 (±8.7) years. COD, MS relationship, or both were determined for 88% of deaths (71/81). Patients were assigned to one of nine COD categories: cardiovascular disease/stroke; cancer; pulmonary infections; sepsis; accidents; suicide; death due to MS; other known CODs; and unknown COD. Of the 69 patients for whom information on the relationship of death to MS was available, 78.3% (54/69) were adjudicated to be MS related. Patients randomised to receive placebo during the RCT (compared with patients receiving active treatment) experienced an excessive number of MS-related deaths.
Conclusions: In this long-term, randomised, cohort study, MS patients receiving placebo during the RCT experienced greater all-cause mortality compared to those on active treatment. The excessive mortality in the original placebo group was largely from MS-related causes, especially, MS-related pulmonary infections.
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Prof G’s MS Blog Archive (please note this Newsletter is based on a blog post from the 21-April-2021)
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.
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