Case study
Dear Professor Giovannoni
I don’t live in the UK but would appreciate your advice. I was diagnosed with MS in late 2018 and was started on ocrelizumab soon after diagnosis. I am now 53 years of age, and I am quite concerned about staying on ocrelizumab. My immunoglobulin levels are now low, and my neurologist wants me to switch therapies. I have done well on ocrelizumab. I have had no relapses since starting treatment and no new lesions on MRI. I want to stay on Ocrelizumab. What would you recommend?
Prof G’s opinion
I am leaving patients like you on ocrelizumab until we have more data to support evidence-based decision-making. I would only derisk you if you had a serious infection and/or if you requested to be derisked yourself. On the NHS, we don’t treat anti-CD20-induced hypogammaglobulinaemia. The reason is immunoglobulin replacement therapy is expensive and rationed. However, in some countries, immunologists proactively manage hypogammaglobulinaemia with immunoglobulin replacement therapy.
If we had to derisk you and you wanted to stay on a high-efficacy therapy, we tend to use oral cladribine. Another option is to stop ocrelizumab and see what happens. Or you can de-escalate to a therapy not associated with chronic immunosuppression, i.e. teriflunomide, interferon-beta or glatiramer acetate. I prefer teriflunomide because it also has anti-EBV activity. I hypothesise that if you reconstitute your B-cells in the presence of an antiviral, you prevent reinfection of emerging memory B-cells with EBV, which will keep your MS in long-term remission.
Your case illustrates our dilemma with anti-CD20 therapies and what we do in the long term. The following are my musings on why we must move beyond the B-cell to manage MS more effectively.
Beyond the B-cell
Having returned from the AAN 2023, it is clear that anti-CD20 B cell therapies have become the gold standard treatment option for MS. Most people with MS (pwMS) who start anti-CD20 therapy are rendered NEIDA (no evident inflammatory disease activity) on treatment when they are rebaselined at 6 months. With their relative safety, more pwMS are going onto anti-CD20 therapies as first-line therapy. And many pwMS are being switched to an anti-CD20 when they have breakthrough activity on another DMT. As a result, the proportion of pwMS on anti-CD20 therapies is increasing with time. Hence, most HCPs are satisfied that with an anti-CD20 therapy, they have achieved their treatment goal, NEIDA, and their job is done. A slam-dunk for anti-CD20 therapies, so let’s move on.
Not so fast. I have had a few questions from readers who question this emerging practice.
What about long-term safety? Can pwMS stay on anti-CD20 therapy lifelong?
Anti-CD20 therapies are immunosuppressive therapies, and with time, the risk of infections, particularly severe infections requiring hospital admission, and hypogammaglobulinaemia, increases. This is particularly relevant to older patients with immunosenescence and comorbidities, where the risk is much higher. Another aspect is the blunted antibody responses to vaccines, highlighted by the COVID-19 vaccines. Is it acceptable not to have an adequate vaccine response indefinitely? What will happen if the next pandemic involves a more virulent pathogen? In addition, I suspect we will also see a secondary malignancy signal emerge with time as B-cells play an important role in presenting tumour antigens to T-cells and are hence part of the tumour immune surveillance network.
So yes, I am concerned about the longer safety of anti-CD20 therapies, and no, I don’t think pwMS can stay on anti-CD20 therapies life-long. This is why we are considering testing strategies to derisk anti-CD20 therapies. I am particularly interested in testing an induction-maintenance strategy to test an anti-CD20 therapy given for two years, followed by a safer immunomodulatory therapy such as teriflunomide (iTeri study) (for more details, see “EBV immunotherapy for MS: glofitamab induction”, 11-Jan-2023)
Until we have data to support the induction-maintenance strategy, I prefer an immune reconstitution therapy (IRT) approach. IRTs don’t leave pwMS chronically immunosuppressed. With an IRT, the immunosuppression is front-loaded for a relatively short period.
What about CNS resident B-cells and plasma cells? Don’t we need to target them?
CNS resident B-cells and plasma cells are important drivers of smoldering MS and SAW (smoldering-MS-associated worsening). These cells are responsible for the production of intrathecal oligoclonal IgG bands. We need to target them to tackle smoldering MS. This is one of the reasons why we are testing higher-dose ocrelizumab, cladribine (Chariot-MS) and ixazomib (Sizomus) in MS to try and go beyond focal inflammation to target end-organ damage and worsening independent of focal inflammation (SAW).
I have discussed this issue many times in the past. I do not think that anti-CD20 therapies, at their current dose, achieve higher enough levels in the CNS to impact smoldering MS biology. For more information on anti-CD20 dosing, please see “Should I switch from ocrelizumab to ofatumumab?” (18-April-2023).
What about smoldering MS? I thought we needed to treat beyond NEIDA. Is NEIDA sufficient to control MS?
I have made the point over and over again that focal inflammatory events in the form of Gd-enhancing MS lesions and new T2 lesions and relapses, the radiological and clinical manifestations of focal inflammation, respectively, are not MS. These biomarkers of MS are poor predictors of outcome and don’t fulfil contemporary criteria for being a surrogate outcome for MS. It is also worth pointing out that several serial MRI studies using different methods have shown subtle changes in the brain regions months where Gd-enhancing lesion is destined to appear. This tells me the Gd-enhancement and the subsequent new T2 lesion is not the primary event but simply the immune response to what is causing the lesion. I explain this using leprosy as an analogy and refer to this as my leprosy hypothesis of MS (please see “Hot topic AAN 2023: smoldering MS”, 24-April-2023).
We note that many pwMS who are NEIDA on an anti-CD20 will continue to worsen or notice worsening sometime in the future. Some refer to this worsening as PIRA (progression independent of relapses). However, I prefer the term SAW (smoldering-MS-associated worsening), a much broader definition and rhymes with RAW (relapse-associated worsening). This tells us that it is not good enough to be just NEIDA; we need to go beyond that treatment target. This is why BTKi (Bruton Tyrosine Kinase Inhibitors) and other therapeutic strategies are being developed to target the mechanisms driving SAW.
So no, it is not good enough to be just NEIDA. Anti-CD20 therapies are not good enough as monotherapies because the annual percentage of brain volume loss on anti-CD20s is greater than what I consider compatible with normal ageing.
What about T-cells? I thought MS was a T-cell-mediated disease and that we needed to control T-cells to get on top of MS.
I have always argued that the real ladder for assessing treatment efficacy amongst DMTs is their impact on brain volume loss beyond 12-24 months and the proportion of patients who notice an improvement in disability (sustained improvement). Alemtuzumab and AHSCT (autologous haemopoietic stem cell therapy) are the clear winners when comparing them to other DMTs. What differentiates these two IRTS from other DMTs is their profound impact on B-cells and T-cells. Is the T-cell important in explaining the superior efficacy of alemtuzumab and AHSCT?
There are other arguments for the critical role that T-cells play in MS. Pathologically, T-cells are a large proportion of cells in the infiltrates seen around blood vessels and in the brain tissue of pwMS. The strong MHC association with MS suggests antigen presentation is an important component of MS, and antigen presentation requires T-cells.
The genomic studies into MS, using network analyses, clearly show T-cells play an important, if not pivotal, role in the pathogenesis of MS. A major pathway highlighted by our group and others involves CD40 and its binding partnering, CD40 ligand (CD40L) (see paper below). CD40 and CD40L provide necessary costimulatory signals critical in driving T-cell-driven autoimmunity.
Please note the MS community is not ignoring T-cells. There is an ongoing trial testing an anti-CD40L monoclonal antibody in MS. I would not be surprised if it is very effective in treating MS. By blocking costimulation between antigen-presenting cells of the innate immune system and the T-cell converts the signal from a proinflammatory activating signal to a tolerogenic signal. So if MS is an autoimmune disease blocking CD40-CD40L signalling may induce tolerance and long-term remission. I am very excited about the anti-CD40L trial; it is always nice to see basic science being translated into the clinic.
So yes, I am convinced we need to go back to the drawing board and work out how to combine B-cell depletion with anti-T-cell therapies to control focal inflammation and smoldering MS.
Can we cure MS with B-cell therapies?
No, I think not, at least based on the limited data we have at hand with the current anti-CD20 therapies. I say this because many pwMS treated with anti-CD20 therapies continue to get worse (SAW or smoldering-MS-associated worsening), and the impact of anti-CD20 therapies on end-organ damage and the CSF profile suggests smoldering MS continues.
However, suppose EBV latent-lytic cycling drives MS disease activity. In that case, it is feasible that anti-CD20 therapies will deplete the pool of latently infected B-cells and cure MS. For this to happen, we may need CNS penetrant therapies to target B-cells resident in the CNS. The current anti-CD20 therapies, at their licensed doses, don’t achieve sufficient levels in the CNS to purge the CNS B-cell compartment. This is why the results of the BTKi phase 3 trials are so eagerly anticipated. Some of the BTKi are CNS-penetrant and may inhibit and purge EBV-infected B-cells. I have made this point before that BTKIs are anti-EBV. An important EBV protein called LMP2 (latent membrane protein 2) uses BTK to provide a prosurvival signal to the EBV-infected memory B-cells. Overtime inhibition of BTKi may result in these latently infected B-cells dying and removing latent EBV from the body.
This is why I am a BTKi optimist and predict that centrally acting BTKis will be another class of DMTs that dissociate relapse and MRI activity from their impact on disability progression and other end-organ damage biomarkers (brain volume loss, slowly expanding lesions and iron-rimmed lesions, …). In other words, BTKIs are going to have a greater impact in slowing disability worsening or SAW than they are going to have on relapse and focal MRI activity relative to teriflunomide. I am predicting relative to teriflunomide as a class, BTKIs will reduce disability progression by about 45% (range 40-60%). In comparison, ofatumumab only achieved a ~30% reduction. Please note not all BTKi’s in phase 3 are equal; the ones with better CNS penetration and inhibition of BTK will be the most effective. Based on pharmacokinetics and pharmacodynamics, the best in class seems to be Gossamer’s product (GB7208).
Do we need to go beyond the B-cell?
Yes, we need to go beyond the B-cell. We can’t accept the status quo and think we have sorted MS out because most pwMS treated early with MS are NEIDA. If we do, large numbers of these people will continue to come back with SAW (smouldering-associated worsening) or, using old terminology, progressive MS. Please don’t accept NEIDA as a treatment target. Yes, targeting NEIDA has changed the face of MS, but if we need to transform the prognosis of MS and get people with MS to old age with a healthy brain, we need to go beyond the B-cell.
My vision is for pwMS to be both NEIDA and NESAW (no evident smoldering-MS-associated worsening).
Maybe I am wrong. What are your thoughts on moving the goalposts beyond NEIDA? And what do you think of the term SAW?
Paper 1
Multiple sclerosis is a complex autoimmune disease caused by a combination of genetic and environmental factors. Translation of Genome-Wide Association Study findings into therapeutics and effective preventive strategies has been limited to date. We used summary-data-based Mendelian randomization to synthesize findings from public expression quantitative trait locus, methylation quantitative trait locus and Multiple Sclerosis Genome-Wide Association Study datasets. By correlating the effects of methylation on multiple sclerosis, methylation on expression and expression on multiple sclerosis susceptibility, we prioritize genetic loci with evidence of influencing multiple sclerosis susceptibility. We overlay these findings onto a list of 'druggable' genes, i.e. genes which are currently, or could theoretically, be targeted by therapeutic compounds. We use GeNets and search tool for the retrieval of interacting genes/proteins to identify protein-protein interactions and druggable pathways enriched in our results. We extend these findings to a model of Epstein-Barr virus-infected B cells, lymphoblastoid cell lines. We conducted a systematic review of prioritized genes using the Open Targets platform to identify completed and planned trials targeting prioritized genes in multiple sclerosis and related disease areas. Expression of 45 genes in peripheral blood was strongly associated with multiple sclerosis susceptibility (False discovery rate 0.05). Of these 45 genes, 20 encode a protein which is currently targeted by an existing therapeutic compound. These genes were enriched for Gene Ontology terms pertaining to immune system function and leucocyte signalling. We refined this prioritized gene list by restricting to loci where CpG site methylation was associated with multiple sclerosis susceptibility, with gene expression and where expression was associated with multiple sclerosis susceptibility. This approach yielded a list of 15 prioritized druggable target genes for which there was evidence of a pathway linking methylation, expression and multiple sclerosis. Five of these 15 genes are targeted by existing drugs and three were replicated in a smaller expression Quantitative Trait Loci dataset (CD40, MERTK and PARP1). In lymphoblastoid cell lines, this approach prioritized 7 druggable gene targets, of which only one was prioritized by the multi-omic approach in peripheral blood (FCRL3). Systematic review of Open Targets revealed multiple early-phase trials targeting 13/20 prioritized genes in disorders related to multiple sclerosis. We use public datasets and summary-data-based Mendelian randomization to identify a list of prioritized druggable genetic targets in multiple sclerosis. We hope our findings could be translated into a platform for developing targeted preventive therapies.
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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 and should not be interpreted as personal clinical advice. If you have problems, please tell your healthcare professional, who will be able to help you.
Beyond the B-cell - an alternative treatment paradigm for MS