Prof G will ocrelizumab and rituximab prevent SPMS?
Just back from the COMBAT-MS stakeholders meeting in Pasadena with the Kaiser (Kaiser Foundation Research Institute) and Swedish (Karolinska Institute) trial teams, PCORI (Patient-Centered Outcomes Research Institute) and many brave an wonderful people with MS and their families.
The COMBAT-MS study (NCT03193866) is recruiting well and is on schedule to deliver very important comparative data on the effectiveness of rituximab in real-life. The full title of the study is ‘COMparison Between All immunoTherapies for Multiple Sclerosis. An Observational Long-term Prospective Cohort Study of Safety, Efficacy and Patient’s Satisfaction of MS Disease Modulatory Treatments in Relapsing-remitting Multiple Sclerosis’. In short, COMBAT-MS will be comparing Rituximab with Natalizumab, Fingolimod, Alemtuzumab, Interferon-beta, Glatiramer acetate and Dimethyl Fumarate. Because the use of alemtuzumab seems to be quite limited in Sweden, with the majority of patients going onto rituximab, the study will not have enough power to compare rituximab with alemtuzumab. This a great pity because the real question I have is how does anti-CD20 therapy compare to our top-guns, i.e. alemtuzumab and HSCT. This question is becoming a priority for me.
We had a comprehensive safety update from the COMBAT-MS trial team, which will be presented later this year. However, the safety profile of rituximab is broadly in keeping with what is seen in rheumatology, with a few interesting exceptions. However, the overall safety profile will help with the adoption of rituximab as a treatment of MS in resource-poor environments.
I included in my presentation on why I think anti-CD20 is not good enough to treat MS in the long term and why we need to think beyond NEDA. I presented data, mainly from ocrelizumab, that shows MS continues to smoulder away on ocrelizumab despite patients being NEDA. The response to the data was what we are seeing was simply secondary progressive MS. Yes and no. It may be a secondary progressive disease, but the pathology driving smouldering MS (microglial activation, slowly expanding lesions, subpial cortical lesions, intrathecal immunoglobulin production, demyelination, mitochondrial toxicity and energy failure, oxidative damage, delayed axonal loss, synaptic pruning, premature ageing, etc.) are all present at the very earliest stages of the disease, even the asymptomatic stage of the disease, i.e. radiologically isolated syndromes. This is why I don’t think SPMS really exists and why MS is one and not two or three diseases.
The construct that MS has distinct phases, an early inflammatory and a delayed degenerative phase, is artificial and comes from the Pharma industry’s need to get interferon-beta licensed under the orphan drug act, i.e. MS had to have a prevalence of fewer than 200,000 affected people for the orphan drug act to apply. The only way to get the numbers down to less than 200,000 was to salami-slice up MS into three diseases, i.e. RRMS, SPMS and PPMS. Later on, a fourth category, CIS (clinically isolated syndrome) was added. However, CIS has largely disappeared as a category because of diagnostic creep and the earlier diagnosis of MS with the evolving definition of MS based on the newer versions of the McDonald criteria. Having looked hard I can find no scientific justification for making SPMS a different disease.
In my opinion, smouldering MS and the pathologies driving it do not seem to be anti-CD20 responsive. If they were then we would see a much better impact of anti-CD20 on brain volume loss, disease improvement and the slowly expanding lesion. What does this mean for people with MS? It means that anti-CD20 therapies may be a good platform to start on but you will require additional add-on therapies to stop smouldering MS. Can I please urge you to re-read Stephen Hauser’s case report below. You may argue that one swallow doesn’t make a summer, but Stephen Hauser implied two year’s ago in a response to a question at ECTRIMS that anti-CD20 was not the panacea everyone wants it to be and that a lot of his long-term rituximab-treated patients were now secondary progressive, i.e. they had smouldering MS.
The concept of smouldering MS is a difficult one for people in the field to grasp. Why? It is because NEDA-3 has become de-facto what defines MS. We need to move beyond what we can see and measure and focus on end-organ markers of disease activity, i.e. whole brain and regional or grey matter volumes, the expanding MS lesions, neurofilament levels and more sensitive clinical outcomes. An EDSS view of the world is simply too narrow. We need to look at cognition, visual function and more sensitive functional tests of different neuronal systems. One of the attendees was horrified when I said that the best thing that could happen to the field is if we could automate the neurological examination using a validated technology platform. The idea of using a neurologist to assess eye movements and balance, when it can be done so much better with eye tracking systems and balance sensors, shocked this individual. Bring on the robots and maybe our worldview of MS, in particular, smouldering MS, would change.
I was also able to deliver good news about our WHO Essential Medicine List (EML) application that includes ocrelizumab as one of the three drugs and rituximab as a suitable replacement for ocrelizumab if access to ocrelizumab is a problem. If our EML application is successful this will allow us to pressurise governments to prioritise the treatment of MS in low prevalence countries. I explained to the group that what had started out for me as an ‘Essential Off-label DMT list’ in 2014, may become an official WHO-backed Essential DMT list in 2019. I am holding thumbs we get MS onto the EML, it needs to be there for many reasons.
I also covered in my talk alternative hypotheses, i.e. that MS may be due to a virus and that our current world-view of MS being an autoimmune disease driven by T and B-cells may be wrong. I briefly presented the B-cell-EBV hypothesis and our proposed EBV vaccination trial. I stressed that we need to use anti-CD20 as a tool to explore the EBV hypothesis and the good news is that Fredrik Piehl is going to explore EBV biomarkers as part of the COMBAT-MS study.
I used my lecture to represent my ‘marginal gains’ philosophy as it applies to treating MS and how we need to manage MS holistically and focus on the small things that may make a big difference to MS outcomes in the future. This is only the second time that I have presented this concept to my peer group, but it is something that still needs work to make it sticky.
The following are my slides from the meeting, which you can download from my slide sharing site.
I would like to thank PCORI and the Kaiser team for including me in this study and for your wonderful hospitality. I have little doubt that the COMBAT-MS study is going to help change the way the MS community treats MS globally. I would also like to thank the MSers who attended and spoke at the meeting; you are are the reason why we are doing what we do.
von Büdingen et al. Onset of secondary progressive MS after long-term rituximab therapy – a case report. Ann Clin Transl Neurol. 2016 Dec 20;4(1):46-52.
A patient with relapsing multiple sclerosis (RMS) was treated with a standard immunomodulatory therapy, but due to ongoing disease activity was switched to rituximab. Relapses ceased, but secondary progressive MS (SPMS) eventually appeared, associated with new focal spinal cord white matter lesions. Cerebrospinal fluid (CSF) showed persistent oligoclonal bands (OCB) and clonally related B cells in CSF and peripheral blood. The treatment escalation approach failed to prevent evolution to SPMS, raising the question of whether initiation of B-cell depleting therapy at the time of RMS diagnosis should be tested to more effectively address the immune pathology leading to SPMS.
45 thoughts on “Why is everyone drinking anti-CD20 kool-aid?”
Has anyone ever studied the epidemiology of people with MS that have never had DMTs compared with different treatments? The medical records and the MS Register are there and only need consent, or is it not financially lucrative?
Yes, there are several real-life data sets out there; e.g. Italian, Danish, Swedish, Welsh, Australia, Canadian, MSBase, etc. It is clear that DMTs are making a huge difference to outcomes. The real inflection point occurred after 2005 when natalizumab came along. There is no doubt high-efficacy DMTs are what is making the difference.
Thank you, but 2005 is only recent. Excuse me for being confused. Difference between?
Thank you so much prof G for this post! Very interesting. I would bring the robots too!
Thanks for this.
You say that:
“What does this mean for people with MS? It means that anti-CD20 therapies may be a good platform to start on but you will require additional add-on therapies to stop smouldering MS.”
This idea of add-on therapies is used a lot on this blog. But what are they? And when will they be precribable? I don’t believe there are any such add-on therapies at present. Am l right?
As a neurologist, don’t you feel uncomfortable knowing that prescribing an anti CD20 will not prevent the patient getting SPMS? (Advanced MS)?
I sill like the term SPMS. I agree that MS is likely to be one disease. However. Having sub-categories is helpful – a bit like knowing the stage of cancer you have. I was diagnosed with RRMS and grabbed the most potent therapy (together with exercise and diet) to reduce the risk of being categorised with SPMS. SPMS is the stage where disability just keeps accruing and treatments are next to useless at the moment. My inactive RRMS (neuroscience description) suits me fine.
Don’t get me wrong anti-CD20s will become the new platform therapies but don’t think that they are the ultimate solution to treating MS. We need to develop drugs to add-on to ocrelizumab, rituximab and ofatumumab to tackle smouldering MS. These include neuroprotective, remyelination and neurorestorative therapies. In addition, we may need antivirals and drugs to target comorbidities and ageing mechanisms. Yes, there are several trials that are being done to address add-on therapies.
I’ve had a few neurological examinations by doctors, neurologists in my time, and they were all fairly laughable. I always wondered what they expected to detect using such incredibly crude methods.
Great and essential talk!
There is no better way to prove that MS is one disease than HSCT and Alem.
However aren’t those treatments contradict with the theory of MS=EBV=memory B cells=> RTX as best treatment? The scene seems more complex (in my opinion because retroviruses are implicated too -hope this will emerge during this research).
I was really hoping that the Swedes could be interested in the trial of Alem+RTX because noone else is, but they don’t seem to be in it either
Thanks for the talk!
Who said rituximab is the best treatment? Not me. It is okay, but rituximab is behind alemtuzumab and HSCT in terms of end-organ damage markers. I also wouldn’t be surprised if ocrelizumab is superior to rituximab as well. Contrary to some peoples position I do think dosing may play a role in the efficacy of anti-CD20s. We need to scrub the brain clean of B-cell follicles and plasma cells and I suspect ocrelizumab may be more potent at doing this in the long-term than rituximab. However, cladribine with its ability to penetrate into the brain may be the best of them all.
Regarding the Swedes. The COMBAT-MS was set-up to compare rituximab with all of the other DMTs using real-life registry data. But you have to have a certain number of patients treated with alemtuzumab to make the comparisons viable. As most MSers become NEDA on rituximab there is little reason to switch them to another agent. The number of patients who fail anti-CD20 using NEDA-3 as the treatment target is very low. If we used NEDA-4 (BVL ) and NEDA-5 and beyond many more would be considered treatment failures.
Because BVL measurements on the individual patient level are not reliable (too many covariates like hydration, change of MRI machine, etc.), I can only hope that we do get plasma NfLs correlated with CSF NfLs and that we could use that as a guideline for retreatment. Frequent lumbar punctures are not feasible or practical enough.
More than enough reasons to speed up NeuroDocGnanapavan’s trial with biomarkers she was mentioning a while back! We NEED hard evidence to start pushing hard our Neuros from the stone age diagnostics (e.g. they were telling me that they asses BVL by looking at the MRIs. When your BVL is visible with naked eye, it’s already WAY TOO LATE)
Way too late. This is why MS needs to be treated early.
So why doesn’t cladribine slow down BVL to the same extent as Oc, Al, Nat, or Hsct? Or does it just take longer to see better results? Better BVL is the only reason I’m sitting in the clinic right now reluctantly getting my first Ocrelizumab infusion. I’m viewing this more as a stepping stone than a long term therapy while I await better information from Cladribine or new DMT’s.
So even if the ocrevus trial data looks better on all accounts you think cladribine could have better longterm outcome? If so could you elaborate more on this
“We need to scrub the brain clean of B-cell follicles and plasma cells ”
If your hypothesis is correct how them you explain the 8 years brain atrophy results of alemtuzumab
Alemtuzumab does not penetrate cns
Those cells are not touch by alemtuzumab still people are “cure” (for 8 years)
“The only way to get the numbers down to less than 200,000 was to salami-slice up MS into three diseases”
Has the slicing up not been a fair bit about p-hacking… A mechanism to disregard patients who don’t respond the same / at all. To make results look better. Inconvenient “progressive” patients can be sidelined. Which is little sense, since everyone’s MS is meant to be progressive. It just takes a bit of damage accumulation before the progression surfaces.
The root cause of MS has not yet been explained.
At least it resulted in a treatment for MS and the subsequent investment to change the face of MS.
Great Article Prof G. Could Aubagio be used as add on therapy? Given its good safety profile and it doesn’t deplete the immune system but modifies it. Especially after drugs like Alemtuzumab it can also reduce the chances of 2nd autoimmunity!
Teriflunomide may be ideal as maintenance therapy after using an anti-CD20 as induction therapy. It is anti-proliferative so it may keep those pathogenic memory B cells in check. However, based on the biology of B-cells I would prefer a BTKi rather than teriflunomide in this situation.
The other thing about teriflunomide is that it is an anti-viral and may have interesting off-target effects that we have yet to study.
This is important discussion and I’m glad you are pushing your colleagues to do better. That said I’m afraid you’ve also told just terrified every pwMS on ocrelizumab. What do you advise should those of us on Ocrevus who are “doing well” (aka still <5 years diagnosed, stable mri and stable functioning) do – other than panic we are doomed?
MSINTHEUS this blog has always been about telling it the way it is. All of a sudden a lot of senior MSologists think we have MS licked with the anti-CD20s; high efficacy in term of NEDA, low treatment and monitoring burden and relatively safe. I agree with all this, but it is only the base of the treatment pyramid. There is way more we need to do on top of an anti-CD20. Don’t get me wrong as a class of DMT the anti-CD20s are going to revolutionise the treatment of MS, but we need the community to look at the data and ask the relevant questions so we can get the next stage.
Prof G thank you for the reply. You are right of course to challenge things. That said what practically can someone actually on Ocrelizumab do with this info now? Are you advocating that we travel abroad for hsct? Do we switch to alemtuzab? Do we continue with current therapy but press our neurologists to add something on off-label? Do we do nothing but continue to push this discourse with the knowledge that our impending brain loss is a ticking time bomb unless better treatments are approved soon?
Keep asking questions, volunteer for trials, lobby the MS Societies and progressive MS alliance to start add-on trials, focus on a brain-healthy lifestyle, get into self-monitoring using tools that are more sensitive than the neurological examination (e.g. floodlight app), engage with your neurologist’s monitoring (ask about new T2 and enlarging T1 lesions) and if you are an ocrelizumab non-responder ask the question what next?
Thank you again prof g for being brave enough to ask difficult questions and honorable enough to give direct answers. I’ve noticed (and other patients complain) about old symptoms coming back about 5 months after an infusion. Is this related to your concerns? What is the medical reason for this symptom return, does it support your theory on smouldering ms, and what can we learn from it?
What do you mean about marginal gains? Surely we want major gains? Nobody wants a marginal treatment response if they have MS.
On another point you haven’t really answered the question on whether or not anti-CD20 therapies are working as anti-EBV drugs.
“adoption of rituximab as a treatment of MS in resource-poor environments. ”
Sweden is not a resource-poor environment
Which is why Sweden is having a hard time with their national insurance scheme who is not prepared to cover rituximab-treated patients for severe adverse events. There is a lot of pressure on the Sweded to stop prescribing rituximab and switch to ocrelizumab. The pressure will surely mount with time.
Pressure from whom? I would think Rituximab would be much cheaper than Ocrelizumab and likely have less adverse events based on dosing protocol and lesser drug strength.
Many of us are ‘doing very well’ on rituximab, after years of treatment. But it is clear that something is happening behind the scenes.
Is there anything that could be added on RIGHT NOW? Before too much damage accumulates from smouldering MS
What would you say to the idea of exploring HSCT? Since that is currently the most effective at controlling brain volume loss
May not be allowed by NHS guidelines, but many of your readers are not in the UK
What is the Swedish data on conversion to SPMS with Rituximab?
Why go by one case report?
Too few patients have progressed in their current cohort, it will take 10-15 years to answer this question.
Spelman et al. Comparative effectiveness of rituximab relative to IFN-β or glatiramer acetate in relapsing-remitting MS from the Swedish MS registry. Mult Scler. 2018 Jul;24(8):1087-1095.
OBJECTIVE: To compare treatment effectiveness and persistence in relapsing-remitting multiple sclerosis patients who initiated rituximab versus glatiramer acetate (GA) or interferon-beta (IFN-β).
METHODS: A total of 461 patients from the Swedish MS registry in the rituximab arm were propensity score matched on a 1:2 basis with 922 patients from the IFN-β/GA comparator, between April 2005 and November 2015. Annualised relapse rate (ARR) was compared using the Poisson method. A marginal Cox model was used to analyse time to first relapse, 3-month confirmed disability progression and treatment discontinuation in the matched sample. A signed-rank test was used to compare Expanded Disability Status Scale (EDSS) change from baseline.
RESULTS: Rituximab was associated with a reduction in ARR (0.003; 95% confidence interval (CI) = 0.001, 0.009) relative to IFN-β/GA (0.026; 95% CI = 0.020, 0.033) ( p < 0.001). Rituximab was associated with an 87% reduction in the relapse rate (hazard ratio (HR) = 0.13; 95% CI = 0.04, 0.41) and an 85% reduction in the discontinuation rate (HR = 0.15; 95% CI = 0.11, 0.20) relative to IFN-β/GA. EDSS regression from baseline was greater in the rituximab group at 12 and 24 months.
CONCLUSION: Rituximab appears to be superior to first-generation disease-modifying treatments (DMTs) with respect to relapse control and tolerability, whereas superiority on disability outcomes is less clear.
Proff. G thank you ever so much for honest answers to ultimate questions. Would you care to be as honest as possible about question of getting pregnant while having RRMS. It is known that MS most strikes women in their 20-40years, as reproductive age and can be transferred to children genetically , (although chances are very slim). I have recently diagnised with RRMS and am on rituximab and plan a baby. My question is related how safely rituximab protects patients from flare ups while in their pregnancies? Is there any add-on treatments that should be considered to avoid flare-ups during pregnancies? How safe is the baby?!
Overall I would also rise the question about ticking time and how long time will it yet take to find the cure for MS given that scientific world is actively seeking the solution and already knows so much more about MS than it did 5-10 years ago? Will 5-10 years be about, if possible to answer?
The UCSF team describe smouldering MS:
Cree et al. Silent Progression in Disease Activity-Free Relapsing Multiple Sclerosis. Ann Neurol. 2019 Mar 9. doi: 10.1002/ana.25463.
OBJECTIVE: Rates of worsening and evolution to secondary progressive multiple sclerosis (MS) may be substantially lower in actively treated patients compared to natural history studies from the pre-treatment era. Nonetheless, in our recently reported prospective cohort more than half of patients with relapsing MS accumulated significant new disability by the 10th year of follow-up. Notably, “no evidence of disease activity” at 2-years did not predict long-term stability. Here, we determined to what extent clinical relapses and radiographic evidence of disease activity contribute to long-term disability accumulation.
METHODS: Disability progression was defined as an increase in Expanded Disability Status Scale (EDSS) of 1.5, 1.0 or 0.5 (or greater) from baseline EDSS = 0; 1.0-5.0; and 5.5 or higher, respectively, assessed from baseline to year 5 (± 1 year) and sustained to year 10 (± 1 year). Longitudinal analysis of relative brain volume loss used a linear mixed model with sex, age, disease duration, and HLA-DRB1*15:01 as covariates.
RESULTS: Relapses were associated with a transient increase in disability over one-year intervals (p = 0.012) but not with confirmed disability progression (p = 0.551). Relative brain volume declined at a greater rate among individuals with disability progression compared to those who remained stable (p < 0.05).
INTERPRETATION: Long term worsening is common in relapsing MS patients, is independent of relapse activity, and is associated with accelerated brain atrophy. We propose the term silent progression to describe the insidious disability that accrues in many patients who satisfy traditional criteria for relapsing remitting MS. This article is protected by copyright. All rights reserved.
How many are on rituximab?
Awesome info here! And thanks for adding the restorative and neuroprotective category! Just wanted to add if you see stress to be factored in as therapy since it causes a waterfall effect of increased risk of infection, MS attack, etc. And when it comes to exercise that it also be used as an add on therapy. Specifically, weight training. Bottai et al recently showed that there is a link between NSCs and exercise. Exercise has also been shown to induce neurogenesis via BDNF in the hippocampus, Lui PZ and Nusslock, 2017. Also, since estrogen has been proven to be anti inflammatory in the brain why is it not used as an added therapy? The Swedish MS Registry has data on women that are menopausal and on Estrogen therapy.
In July 2011, the blog had a post on early relapses, in which Prog G said “Contrary to recent previous comments relapses do matter; particularly within the first 2 years.”
Here’s part of the comments and discussion that followed:
ANONYMOUS (comment was from me)
This study was for untreated patients. What is the graph or treated patients?
A worrying thought: perhaps a DMT just suppresses relapses or reduces their severity without changing time to disability.
ANONYMOUS (a different Anonymous)
Re; “A worrying thought: perhaps a DMT just suppresses relapses or reduces their severity without changing time to disability.”
I agree. There is no serious proof that relapses and progression are the same pathological disease. That is why some people get progression from the outset and for others there is as period of relapses followed by full blown progression. By that stage the DMTs don’t work anymore, and who knows, maybe they never really did other than dampening the relapse. If relapses lead to progression then why do some people not have any relapses and just become progressive? Likewise, why do DMTs stop working when a RRMS patient become SPMS?
I’m not convinced by your argument Prof G.
Re “I’m not convinced by your argument.”
I can’t win this argument either way, so I will sit this one out. The good news is that the experiment is running already. We need to sit back and wait 10 to 15 years to see what happens to MS’ers treated with with Alemtuzumab and other aggressive therapies. If it stops them becoming progressive, or delays the onset of SPMS, I win.
The question is are you prepared to wait that long?
The same questions arose in rheumatoid arthritis (RA) when the very active new biological therapies emerged about 15 years ago. These therapies are very effective at suppressing inflammation in the joints and preventing flare-ups of disease, but would they prevent long-term damage to joints; the RA equivalent of SPMS? What happened? Well orthopaedic surgeons rarely have to do joint replacements in RA’ers these days. These therapies prevent progressive RA.
We have to take the same approach with MS; we can’t replace the brain and spinal cord in the same way that we replace damaged joints. The brain and spinal cord are too precious! We need to work on the premise that by treating early and aggressively we will change the natural history of MS.
If this blog is still running in 15 years time I suggest we revisit this debate.
It isn’t yet 15 years, but how certain are we of the answer now?
Will you say that Alemtuzumab and HSCT do halt progression if used early? And anti-cd20 does not halt or even delay progression?
What about natalizumab and other treatments?
Brown et al. Association of Initial Disease-Modifying Therapy With Later Conversion to Secondary Progressive Multiple Sclerosis. JAMA. 2019 Jan 15;321(2):175-187. doi: 10.1001/jama.2018.20588.
IMPORTANCE: Within 2 decades of onset, 80% of untreated patients with relapsing-remitting multiple sclerosis (MS) convert to a phase of irreversible disability accrual termed secondary progressive MS. The association between disease-modifying treatments (DMTs), and this conversion has rarely been studied and never using a validated definition.
OBJECTIVE: To determine the association between the use, the type of, and the timing of DMTs with the risk of conversion to secondary progressive MS diagnosed with a validated definition.
DESIGN, SETTING, AND PARTICIPANTS: Cohort study with prospective data from 68 neurology centers in 21 countries examining patients with relapsing-remitting MS commencing DMTs (or clinical monitoring) between 1988-2012 with minimum 4 years’ follow-up.
EXPOSURES: The use, type, and timing of the following DMTs: interferon beta, glatiramer acetate, fingolimod, natalizumab, or alemtuzumab. After propensity-score matching, 1555 patients were included (last follow-up, February 14, 2017).
MAIN OUTCOME AND MEASURE: Conversion to objectively defined secondary progressive MS.
RESULTS: Of the 1555 patients, 1123 were female (mean baseline age, 35 years [SD, 10]). Patients initially treated with glatiramer acetate or interferon beta had a lower hazard of conversion to secondary progressive MS than matched untreated patients (HR, 0.71; 95% CI, 0.61-0.81; P < .001; 5-year absolute risk, 12% [49 of 407] vs 27% [58 of 213]; median follow-up, 7.6 years [IQR, 5.8-9.6]), as did fingolimod (HR, 0.37; 95% CI, 0.22-0.62; P < .001; 5-year absolute risk, 7% [6 of 85] vs 32% [56 of 174]; median follow-up, 4.5 years [IQR, 4.3-5.1]); natalizumab (HR, 0.61; 95% CI, 0.43-0.86; P = .005; 5-year absolute risk, 19% [16 of 82] vs 38% [62 of 164]; median follow-up, 4.9 years [IQR, 4.4-5.8]); and alemtuzumab (HR, 0.52; 95% CI, 0.32-0.85; P = .009; 5-year absolute risk, 10% [4 of 44] vs 25% [23 of 92]; median follow-up, 7.4 years [IQR, 6.0-8.6]). Initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion than initial treatment with glatiramer acetate or interferon beta (HR, 0.66; 95% CI, 0.44-0.99; P = .046); 5-year absolute risk, 7% [16 of 235] vs 12% [46 of 380]; median follow-up, 5.8 years [IQR, 4.7-8.0]). The probability of conversion was lower when glatiramer acetate or interferon beta was started within 5 years of disease onset vs later (HR, 0.77; 95% CI, 0.61-0.98; P = .03; 5-year absolute risk, 3% [4 of 120] vs 6% [2 of 38]; median follow-up, 13.4 years [IQR, 11-18.1]). When glatiramer acetate or interferon beta were escalated to fingolimod, alemtuzumab, or natalizumab within 5 years vs later, the HR was 0.76 (95% CI, 0.66-0.88; P < .001; 5-year absolute risk, 8% [25 of 307] vs 14% [46 of 331], median follow-up, 5.3 years [IQR], 4.6-6.1).
CONCLUSIONS AND RELEVANCE: Among patients with relapsing-remitting MS, initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion to secondary progressive MS vs initial treatment with glatiramer acetate or interferon beta. These findings, considered along with these therapies' risks, may help inform decisions about DMT selection.
Harding et al. Clinical Outcomes of Escalation vs Early Intensive Disease-Modifying Therapy in Patients With Multiple Sclerosis. JAMA Neurol. 2019 Feb 18. doi: 10.1001/jamaneurol.2018.4905.
IMPORTANCE: Uncertainty remains about how aggressively to treat early multiple sclerosis. High-efficacy disease-modifying therapies (DMTs) are often reserved for individuals expressing poor prognostic features at baseline.
OBJECTIVE: To analyze long-term outcomes in a population-based cohort according to initial treatment strategy.
DESIGN, SETTING AND PARTICIPANTS: In this cohort study, data were derived from January 1998 to December 2016, and analysis was performed in January 2017. From a total of 720 patients prescribed a DMT, 592 (82%) were included in analysis. Reasons for exclusion were first treated elsewhere or privately (n = 39), clinical trial participant (n = 25), and insufficient clinical data (n = 45).
EXPOSURES: Patients were classified according to first-line treatment strategy: high-efficacy (early intensive treatment [EIT]) or moderate-efficacy DMT (escalation [ESC]).
MAIN OUTCOMES AND MEASURES: Primary outcome was 5-year change in Expanded Disability Status Scale score. Secondary outcome was time to sustained accumulation of disability (SAD). Models were adjusted for sex, age at treatment, year of starting DMT, and escalation to high-efficacy treatment in the ESC group.
RESULTS: Mean (SD) age of 592 patients at symptom onset was 27.0 (9.4) years. Mean (SD) 5-year change in Expanded Disability Status Scale score was lower in the EIT group than the ESC group (0.3 [1.5] vs 1.2 [1.5]); this remained significant after adjustment for relevant covariates (β = -0.85; 95% CI, -1.38 to -0.32; P = .002). Median (95% CI) time to SAD was 6.0 (3.17-9.16) years for EIT and 3.14 (2.77-4.00) years for ESC (P = .05). For those within the ESC group who escalated to high-efficacy DMT as second-line treatment, median (95% CI) time to SAD was 3.3 years (1.8-5.6; compared with EIT group log-rank test P = .08). After adjustment for relevant covariates, there was no difference in hazard of SAD between the groups. However, 60% of those who escalated to high-efficacy DMTs were observed to develop SAD while still receiving initial moderate-efficacy treatment before escalation.
CONCLUSIONS AND RELEVANCE: In a real-life setting, long-term outcomes were more favorable following early intensive therapy vs first-line moderate-efficacy DMT. Contemporary surveillance strategies and escalation protocols may be insufficiently responsive. This finding is particularly relevant as patients in real-world practice are typically selected for an EIT approach to therapy on the basis of clinical and radiological features predictive of a poor outcome. These data support the need for a prospective randomized clinical trial.
Excuse me if I’m proving rather dense ProfG, and especially if you know you’ve clarified this before, but can you please spell it out for me:
Where does the efficacy of HSCT and Alemtuzumab sit in respect to smoldering MS and progression despite having NEDA? Is there the possibility some of those who receive one of these two treatments with not go on to have SPMS or further disabilities?
I remember thinking that your suggesting that, just as with cancer, the word ‘cure’ should be replaced with ‘remission’ makes a lot of sense. Is that now applicable?
” These therapies prevent progressive RA.”
One thing for sure is that ProfG was wrong correlating RA progression with MS progression (general lack of knowledge in MS neuroscience I guess). I believe now, 8 years later, he has changed his view about how more complex MS progression is and that it cannot be treated just with anti-inflammatory agents. However, you still see the axonopathy theory around and how preventing lesions will “save brain”. Only brain flies by while we talk about lesions. Still a long road…
What can be learned from this?
It is in line with the ORATORIO (ocrelizumab in PPMS) and PIRA (progression independent of relapse) data in PPMS and RMS, respectively. Why wouldn’t an effective anti-inflammatory slow down progression in relapsing or more advanced MS? The problem is that it doesn’t stop the worsening and for that we need additional add-on therapies.
The message of this post is that rituximab and for that matter, ocrelizumab are simply not enough!
Haha I bet most patients on alemz would end up SPMS too