I continue to be amazed when I hear senior MS neurologists make the claim they have never prescribed alemtuzumab or referred any of their patients for HSCT and don’t intend to do so either. These same neurologists seem to be happy with natalizumab and ocrelizumab as their #1 high-efficacy go to DMTs. When I challenge them with the exceptional longterm outcomes for pwMS treated early with alemtuzumab or HSCT I get a glazed look, which I now learnt is cognitive dissonance.
“Cognitive dissonance refers to a situation involving conflicting attitudes, beliefs or behaviours. This produces a feeling of mental discomfort leading to an alteration in one of the attitudes, beliefs or behaviours to reduce the discomfort and restore balance. For example, when people smoke (behaviour) and they know that smoking causes cancer (cognition), they are in a state of cognitive dissonance.” Source: Simply Psychology
It is quite clear that both ocrelizumab and natalizumab are very effective DMTs at switching-off focal inflammatory disease activity in MS; a large number of pwMS on these therapies are NEDA-2 (relapse-free and no new T2 lesions on MRI). This is interpreted by these neurologists and the wider MS community that MS is all sorted. Go away, get on with your life and be happy.
What these neurologists don’t tell their patients on ocrelizumab and natalizumab that despite no relapses or new MRI lesions the accelerated brain volume loss due to MS is continuing unabated. These neurologists and their patients are being lulled into a sense of false security because they believe MS is focal inflammatory disease, when in fact the real MS is the smouldering disease, which drives end-organ damage.
I have addressed these topics many times on this blog. If you are interested in reading some of my back catalogue of posts on this particular topic you can start with the posts below or you could watch a recent lecture I have given on the topic.
- EXPLAINING WHY YOU GET WORSE DESPITE BEING NEDA
- WHAT THE EYE DOESN’T SEE?
- BEYOND NEDA
- NEDADI OR ‘NEE DADDY’ ANOTHER TREATMENT TARGET BEYOND NEDA
- SMOULDERING MS: DOES IT EXIST?
It is clear that not all DMTs are made equal when it comes to preventing end-organ damage. At the top of the league table are alemtuzumab and HSCT (~0.2-0.25% loss per annum). Both these treatments are NIRTs (non-selective immune reconstitution therapies).
Natalizumab is probably next with an annual brain volume loss in the region of 0.25-0.30% per annum. Ocrelizumab (anti-CD20) comes next with a rate of brain volume loss of ~0.374% per annum (see latest data below).
Why do natalizumab and ocrelizumab, despite being very effective anti-inflammatory DMTs have only a moderate impact on end-organ damage? This and other observations have convinced me that MS is not focal inflammation, which represents the immune system’s response to what is causing MS. I suspect there is something going in the CNS of pwMS that is the real MS; I refer to this hypothesis as the ‘Field Hypothesis’.
What these observations are telling us that peripheral B-cells are an important part of the immune response to the cause of MS, but B-cells are not necessarily involved in driving the true MS pathology, which is causing the progressive brain volume loss.
What does this mean for the well-informed person with MS? Firstly, you and your neurologist may not want to dismiss alemtuzumab and HSCT as a first-line, or at least early, treatment option. These non-selective highly effective IRTs differ from anti-CD20 therapies in that they target both B and T cells. I suspect we need to target both these cells types early in the course of the disease to really get on top of the real MS.
I am aware of the appeal of anti-CD20 therapies and natalizumab in that they are safer and easier to use because of less monitoring, however, this may come at a cost in the long-term. Please remember that once you have lost brain you can’t get it back. With alemtuzumab and HSCT, the risk is frontloaded, and balanced against the potential long-term gains in efficacy, which are unprecedented. Choosing a DMT on a rung or two lower down on the therapeutic ladder gives you better short-term safety and makes the life of your MS neurologist less stressful, because of less monitoring and fewer risks, but at a potential long-term cost to your brain and spinal cord.
This is why making an informed decision about which DMT you choose is a very complicated process and subject to subtle and often hidden effects of cognitive biases; cognitive dissonance is just one of these biases. The one bias I am very aware of is the ‘Gambler’s Dilemma’, be careful not to be lulled into a false sense of security by your beliefs; most gamblers eventually end-up losing.
In reality, we need to move treatment target in MS way beyond NEDA-2 to target end-organ damage, i.e. brain volume loss, T1 black holes, the slowly expanding lesions (SELs), neurofilament levels, cognition, sickness behaviour, OCBs, etc. Our treatment aim should be to ‘Maximise Brain Health’ across your life and not just the next few years.
As yet we don’t know what the impact of alemtuzumab and HSCT are on the pathology of smouldering MS, but these agents must be doing something to these pathologies based on clinical and MRI outcomes (see below). Despite this data gap, I think we have enough empirical evidence that alemtuzumab and HSCT are doing some fundamental to the pathology of MS.
Coming back to cognitive dissonance. It could be argued that if an MS neurologist or MS centre does not offer alemtuzumab or HSCT to at least some of their patients then they are not providing their patients with sufficient choice. In addition, they will almost certainly not accept the concept of smouldering MS being the real MS.
OCRELIZUMAB BRAIN VOLUME DATA
Hauser et al. Five-years of ocrelizumab in relapsing multiple sclerosis: OPERA studies open-label extension. Neurology 2020; First published July 20, 2020, DOI: https://doi.org/10.1212/WNL.0000000000010376
Objective: To assess over 3 years of follow-up, the effects of maintaining or switching to ocrelizumab (OCR) therapy on clinical and MRI outcomes and safety measures in the open-label extension (OLE) phase of the pooled OPERA studies in relapsing multiple sclerosis.
Methods: After 2 years of double-blind, controlled treatment, patients continued OCR (600 mg infusions every 24 weeks) or switched from interferon (IFN) β-1a (44 μg 3 times weekly) to OCR when entering the OLE phase (3 years). Adjusted annualized relapse rate, time to onset of 24-week confirmed disability progression/improvement (CDP/CDI), brain MRI activity (gadolinium-enhanced and new/enlarging T2 lesions), and percentage brain volume change were analyzed.
Results: Of patients entering the OLE phase, 88.6% completed Year 5. The cumulative proportion with 24-week CDP was lower in patients who initiated OCR earlier, vs patients initially receiving IFN β-1a (16.1% vs 21.3% at Year 5; p=0.014). Patients continuing OCR maintained, and those switching from IFN β-1a to OCR attained near complete and sustained suppression of new brain MRI lesion activity from Year 3 to 5. Over the OLE phase, patients continuing OCR exhibited less whole brain volume loss from double-blind study baseline vs those switching from IFN β-1a (–1.87% vs –2.15% at Year 5; p<0.01). Adverse events were consistent with past reports and no new safety signals emerged with prolonged treatment.
Conclusion: Compared with patients switching from IFN β-1a, earlier and continuous OCR treatment up to 5 years provided sustained benefit on clinical and MRI measures of disease progression.
Classification of evidence: This study provides Class III evidence that earlier and continuous treatment with ocrelizumab provided sustained benefit on clinical and MRI outcomes of disease activity and progression compared with patients switching from IFN β-1a. The study is rated Class III because of the initial treatment randomization disclosure that occurred after inclusion in OLE.
HSCT BRAIN VOLUME DATA
Lee et al. Brain atrophy after bone marrow transplantation for treatment of multiple sclerosis. Mult Scler. 2017 Mar;23(3):420-431.
BACKGROUND: A cohort of patients with poor-prognosis multiple sclerosis (MS) underwent chemotherapy-based immune ablation followed by immune reconstitution with an autologous hematopoietic stem cell transplant (IA/aHSCT). This eliminated new focal inflammatory activity, but resulted in early acceleration of brain atrophy.
OBJECTIVE: We modeled the time course of whole-brain volume in 19 patients to identify the baseline predictors of atrophy and to estimate the average rate of atrophy after IA/aHSCT.
METHODS: Percentage whole-brain volume changes were calculated between the baseline and follow-up magnetic resonance imaging (MRI; mean duration: 5 years). A mixed-effects model was applied using two predictors: total busulfan dose and baseline volume of T1-weighted white-matter lesions.
RESULTS: Treatment was followed by accelerated whole-brain volume loss averaging 3.3%. Both the busulfan dose and the baseline lesion volume were significant predictors. The atrophy slowed progressively over approximately 2.5 years. There was no evidence that resolution of edema contributed to volume loss. The mean rate of long-term atrophy was -0.23% per year, consistent with the rate expected from normal aging.
CONCLUSION: Following IA/aHSCT, MS patients showed accelerated whole-brain atrophy that was likely associated with treatment-related toxicity and degeneration of “committed” tissues. Atrophy eventually slowed to that expected from normal aging, suggesting that stopping inflammatory activity in MS can reduce secondary degeneration and atrophy.
ALEMTUZUMAB BRAIN VOLUME LOSS
Arnold et al. Superior MRI outcomes with alemtuzumab compared with subcutaneous interferon β-1a in MS. Neurology. 2016 Oct 4;87(14):1464-1472.Neurology. 2016 Oct 4;87(14):1464-1472.
OBJECTIVE: To describe detailed MRI results from 2 head-to-head phase III trials, Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis Study I (CARE-MS I; NCT00530348) and Study II (CARE-MS II; NCT00548405), of alemtuzumab vs subcutaneous interferon β-1a (SC IFN-β-1a) in patients with active relapsing-remitting multiple sclerosis (RRMS).
METHODS: The impact of alemtuzumab 12 mg vs SC IFN-β-1a 44 μg on MRI measures was evaluated in patients with RRMS who were treatment-naive (CARE-MS I) or who had an inadequate response, defined as at least one relapse, to prior therapy (CARE-MS II).
RESULTS: Both treatments prevented T2-hyperintense lesion volume increases from baseline. Alemtuzumab was more effective than SC IFN-β-1a on most lesion-based endpoints in both studies (p < 0.05), including decreased risk of new/enlarging T2 lesions over 2 years and gadolinium-enhancing lesions at year 2. Reduced risk of new T1 lesions (p < 0.0001) and gadolinium-enhancing lesion conversion to T1-hypointense black holes (p = 0.0078) were observed with alemtuzumab vs SC IFN-β-1a in CARE-MS II. Alemtuzumab slowed brain volume loss over 2 years in CARE-MS I (p < 0.0001) and II (p = 0.012) vs SC IFN-β-1a.
CONCLUSIONS: Alemtuzumab demonstrated greater efficacy than SC IFN-β-1a on MRI endpoints in active RRMS. The superiority of alemtuzumab was more prominent during the second year of both studies. These findings complement the superior clinical efficacy of alemtuzumab over SC IFN-β-1a in RRMS.
CLINICALTRIALSGOV IDENTIFIER: NCT00530348 and NCT00548405.
CLASSIFICATION OF EVIDENCE: The results reported here provide Class I evidence that, for patients with active RRMS, alemtuzumab is superior to SC IFN-β-1a on multiple MRI endpoints.
ALEMTUZUMAB MRI END-ORGAN DATA
Vavasour et al. A 24-month advanced magnetic resonance imaging study of multiple sclerosis patients treated with alemtuzumab. Mult Scler. 2018 Apr 1:1352458518770085. doi: 10.1177/1352458518770085.
BACKGROUND: Tissue damage in both multiple sclerosis (MS) lesions and normal-appearing white matter (NAWM) are important contributors to disability and progression. Specific aspects of MS pathology can be measured using advanced imaging. Alemtuzumab is a humanised monoclonal antibody targeting CD52 developed for MS treatment.
OBJECTIVE: To investigate changes over 2 years of advanced magnetic resonance (MR) metrics in lesions and NAWM of MS patients treated with alemtuzumab.
METHODS: A total of 42 relapsing-remitting alemtuzumab-treated MS subjects were scanned for 2 years at 3 T. T1 relaxation, T2relaxation, diffusion tensor, MR spectroscopy and volumetric sequences were performed. Mean T1 and myelin water fraction (MWF) were determined for stable lesions, new lesions and NAWM. Fractional anisotropy was calculated for the corpus callosum (CC) and N-acetylaspartate (NAA) concentration was determined from a large NAWM voxel. Brain parenchymal fraction (BPF), cortical thickness and CC area were also calculated.
RESULTS: No change in any MR measurement was found in lesions or NAWM over 24 months. BPF, cortical thickness and CC area all showed decreases in the first year followed by stability in the second year.
CONCLUSION: Advanced MR biomarkers of myelin (MWF) and neuron/axons (NAA) show no change in NAWM over 24 months in alemtuzumab-treated MS participants.