Is rituximab really superior to cladribine as a treatment for MS?
It is important to debunk this analysis of rituximab vs. cladribine because both agents are on the WHO’s essential medicine list (EML) as treatments for MS.
Rebaseling
When starting a disease-modifying therapy DMT, you shouldn’t expect it to work immediately. In short, the disease activity that is meant to happen will happen regardless of which DMT you start. The timing of the rebaseline MRI is crucial when evaluating the effectiveness of a treatment. For most continuous immunosuppressive therapies, a rebaseline MRI is typically performed between 3 and 6 months after initiation. I favour the 6-month time point as this is what is used in clinical trials. For pulsed immune reconstitution therapies (IRTs), such as alemtuzumab and cladribine, it is pointless to perform a rebaseline MRI until both treatment courses have been completed. This is an important point, as about 10-15% of pwMS treated with either alemtuzumab or cladribine will have a relapse or new MRI activity in year one after completing their first course of treatment. These pwMS have been shown to do as well as those without disease activity in year one when given the second course. This is why I recommend performing the rebaseline MRI only at 18 to 24 months.
It is only worth doing an MRI scan if the result is going to change your clinical practice. Showing new MRI lesions at 12 months that could have formed in the first few months of treatment, before the IRT has had a chance to work, is not going to change your practice. The problem with fee-for-service healthcare systems is that activity, i.e., follow-up appointments, MRI scans, and other investigations, generates income, so there is pressure to perform MRIs. Only have MRIs that will inform clinical decision-making.
Then there is the question about giving gadolinium (Gd). As you are aware, most MS Centres, including my own, have discontinued using Gd-enhanced scans for monitoring. This was primarily in response to the potential for Gd to accumulate in the body and cause potential health issues. However, there is an argument for the rebaseline scan to include Gd. If there is a Gd-enhancing lesion on the rebaseline MRI for both maintenance therapies and IRTs, it would imply the treatment has failed the patient, and a decision can be made to switch therapies at that point. If you don’t administer Gd, then that lesion may be dismissed as an old T2 lesion that likely emerged in the period before the DMT was effective. Does this make sense?
The importance of this has been highlighted by a recent paper from Norway, which claims that rituximab is superior to cladribine. What they did was include MRI and relapse data in the period before cladribine and rituximab had a chance to work. Based on the mode of action of these two DMTs, they should have rebaselined cladribine-treated patients at 18 or, preferably, at 24 months, and rituximab-treated patients at month 6. If you do this, the delta between cladribine and rituximab is much smaller, particularly with relapse. I suspect the number of pwMS discontinuing DMTs is driven by this incorrect use of rebaselining and interpreting new lesions after the baseline MRI study as a suboptimal treatment effect.
The other mistake they make is treating new MS disease activity on cladribine as a lack of efficacy. Breakthrough activity on an IRT is typically interpreted as an indication to retreat, rather than as a treatment failure and reason to switch therapies. The whole point of an IRT is to try to induce a long-term remission without chronic immunosuppression. IRTs are always going to be inferior to high-efficacy DMTs in terms of focal inflammatory activity when studied in this manner. Another issue is that we need to move beyond focal inflammatory activity when comparing DMTs and focus on end-organ damage (progression independent of relapse activity or PIRA and brain volume loss). We know that anti-CD20 therapies (ofatumumab and ublituximab) were superior to teriflunomide in terms of relapses and focal MRI activity, but not necessarily in terms of end-organ damage (as measured by PIRA and BVL). As we shift our focus towards smouldering MS, we are going to have to get the wider MS community to realise that our treatment targets are not necessarily relapses and focal MRI activity, but instead protecting the end-organ. The anti-CD20 therapies are not necessarily the most effective agents for tackling smouldering MS, which is why the Pharma companies that have anti-CD20 therapies are working on BTKIs and other CNS-penetrant DMTs.
We must debunk this analysis of rituximab versus cladribine, as both agents are on the WHO’s Essential Medicines List (EML) as treatments for MS. To claim that rituximab is superior to cladribine will impact cladribine's uptake in low- and middle-income countries. This is problematic because cladribine, as a generic, is likely to be significantly cheaper than biosimilar rituximab, and also easier to use. Cladribine is also expected to be the safer long-term option in these therapeutic environments. Therefore, it should be the go-to DMT in these settings. I sincerely hope we can get this data reanalysed in a non-biased way using end-organ damage markers instead of focal inflammatory markers of treatment efficacy. Do you agree? If not, we need to do a head-to-head trial with appropriate rebaselining protocols.
Spinal cord monitoring
Another question is whether spinal cord imaging should be included as part of the monitoring process. In general, we have not done so because our clinical practice is based on observations from clinical trials, which have shown that most new spinal cord lesions cause symptoms or relapses. This latter observation, however, was based on older technology using relatively poor resolution MRI scans. This is also important because a recent study from MSBase suggests that spinal cord activity may not be equivalent to brain activity (paper 2 below or Kreiter et al., 2024).
They demonstrated that the spontaneous appearance of new T2 spinal cord lesions in individuals on DMT was largely asymptomatic, i.e., relapse-free (paper 2 below or Kreiter et al., 2024). This implies that these lesions are emerging from the spinal cord and are independent of relapse or focal inflammatory disease activity, possibly representing smouldering MS. What is remarkable is that there was no difference between intermediate- and high-efficacy DMTs in suppressing spinal cord lesions. This data suggests that what is happening in the spinal cord in terms of MS pathology is different to what is happening in the brain. If this is the case, we will have to rethink spinal cord pathology in MS.
Including spinal cord imaging in monitoring protocols would add extra time and cost, and is simply not feasible in our centre at present. The spinal cord is divided into three regions, hence adding this to the protocol quadruples the scanning time. This is why we need to wait and see if this study’s findings can be reproduced, because of the potential implications for MS monitoring.
Another possibility is that DMTs are ineffective in suppressing all focal inflammatory lesions, particularly those that are microscopic below the scanning resolution of current MRI scanners. It is worth noting that using high-efficacy DMT in patients with PIRA reduces the likelihood of long-term persistence and further PIRA events compared to lower-efficacy DMTs (see Paper 3 or Zhu et al., 2024, below). Just because you are not detecting focal inflammatory lesions clinically as relapses and/or on MRI does not mean that focal inflammation is not occurring. Sorting this out is critical for the future treatment of MS, as some people with apparent SAW may need to switch DMTs to suppress microscopic focal inflammation, and others may need a combination approach to add-on treatments to address SAW (smouldering-associated worsening).
So if you are getting worse from SAW, we can’t exclude spinal cord activity as a cause for your worsening. Contrary to the dogma, it appears you can acquire new spinal cord lesions without having a relapse. Whether the current high-efficacy DMTs can suppress these new lesions is a moot point.
This newsletter will likely spark significant debates in the field. They are debates worth having. Do you agree?
Paper 1 - Norway
Background: Head-to-head comparisons of high-efficacy therapies for relapsing-remitting multiple sclerosis (RRMS) are lacking. We conducted a target trial emulation to compare the long-term effectiveness of rituximab and cladribine.
Methods: We estimated the effect of initiating treatment with rituximab versus cladribine using observational data from the Norwegian MS Registry and Biobank at two university hospitals with different treatment strategies. Cumulative incidence and risk differences (RDs) were estimated using weighted Kaplan-Meier estimators, adjusting for baseline covariates. The primary outcome was magnetic resonance imaging (MRI) disease activity, with secondary outcomes including relapses and safety.
Results: The study included 285 patients, 159 receiving rituximab and 126 cladribine, with a median follow-up of 4.5 years (interquartile range (IQR): 4.2-4.7). The 4-year risk of new MRI disease activity was 17% (95% confidence interval (CI): 11-23) for rituximab-treated patients and 57% (95% CI: 44-66) for cladribine-treated patients, yielding an RD of 40 percentage-points (95% CI: 28-50). The 4-year RD for relapse was 12 percentage-points (95% CI: 4-19). The incidence of hospitalizations related to potential adverse events was 6.0 per 100 person-years for rituximab and 4 per 100 person-years for cladribine.
Conclusion: These findings suggest that rituximab has superior effectiveness compared to cladribine during a median follow-up of 4.5 years.
Paper 2 - MSBase-1
Background: Spinal cord lesions in multiple sclerosis (MS) have considerable impact on disability. High-efficacy disease-modifying treatments (hDMTs) are associated with greater reduction of relapses and new brain lesions compared to low-efficacy treatments (lDMTs). Knowledge on the impact of DMTs on cord lesion formation is limited as these outcome measures were not included in MS treatment trials. This study aims to investigate whether hDMTs reduce the formation of cord lesions more effectively than lDMTs.
Methods: Patients with relapse-onset MS, a cord magnetic resonance imaging (MRI) within 6 months before/after initiation of their first DMT and ≥1 cord MRI at follow-up (interval > 6 months) were extracted from the MSBase registry (ACTRN12605000455662). Patients treated with hDMTs ≥90% or lDMTs ≥90% of follow-up duration were considered the hDMT and lDMT groups, respectively. Matching was performed using propensity scores. Cox proportional hazards models were used to estimate the hazards of new cord lesions, brain lesions and relapses.
Results: Ninety-four and 783 satisfied hDMT and lDMT group criteria, respectively. Seventy-seven hDMT patients were matched to 184 lDMT patients. In the hDMT group there was no evidence of reduction of new cord lesions (hazard ratio [HR] 0.99 [95% CI 0.51, 1.92], p = 0.97), while there were fewer new brain lesions (HR 0.22 [95% CI 0.10, 0.49], p < 0.001) and fewer relapses (HR 0.45 [95% CI 0.28, 0.72], p = 0.004).
Conclusion: A potential discrepancy exists in the effect of hDMTs over lDMTs in preventing spinal cord lesions versus brain lesions and relapses. While hDMTs provided a significant reduction for the latter when compared to lDMTs, there was no significant reduction in new spinal cord lesions.
Paper 3 - MSBase-2
Introduction: Some patients with relapsing-remitting multiple sclerosis (RRMS) experience sustained disability progression independent of relapse activity (PIRA), which can be a sign of early secondary progressive MS (SPMS). However, PIRA events may regress over time. Persistent PIRA indicates ongoing sustained disability or progression of disability without improvement, so understanding the factors that would predict this is crucial.
Objectives/Aims: To examine risk factors for persistent PIRA (defined as persisting to the end of follow-up) and the risk differences in long-term disability worsening between patients with persistent and non-persistent PIRA.
Methods: This cohort study used data collected from patients enrolled in the MSBase registry between April 16, 1995 and Jan 10, 2024. The median follow-up was 6.8 years.
The baseline was set at the time of PIRA occurrence. The primary outcome was time to 6-month confirmed non-persistent PIRA. The secondary outcomes were time to 6-month confirmed EDSS 6 and time to SPMS (following Lorscheider criteria). A stratified Cox regression model was used to identify the risk factors associated with non-persistent PIRA. We matched persistent PIRA patients with non-persistent PIRA patients in a 1:1 ratio (1164 patients in each group) using their propensity scores, and then compared the risk of reaching EDSS 6 using the Cox regression model. We re-matched patients with complete Kurtzke Functional Systems Scores (733 patients in each group) to compare the risk of reaching SPMS.
Results: We included 3536 RRMS patients with PIRA (mean [SD] age, 42.41 [9.77]). Use of high-efficacy disease-modifying therapies (DMT) at baseline (hazard ratio [HR], 1.37; 95% CI, 1.20-1.56; p<.0001), baseline EDSS (HR, 0.74; 0.69-0.79; p<.0001), age (HR, 0.98; 0.97-0.99, p<.0001), and disease duration (HR, 0.99; 0.98-1.00; p=.04) were associated with non-persistent PIRA. Compared with non-persistent PIRA, the HR was 6.56 (95% CI, 4.71-9.13, p<.0001) for reaching EDSS 6 and 4.46 (3.00-6.65, p<.0001) for reaching SPMS in the patients with persistent PIRA.
Conclusion: Persistent PIRA risk was higher in older patients, with longer disease duration or worse disability at baseline. Use of high-efficacy DMT during PIRA events markedly reduced the likelihood of long-term persistence. Patients with persistent PIRA were at a substantially higher risk of reaching EDSS 6 and SPMS.
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Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Queen Mary University of London or 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.
The rituximab vs cladribine study is super disappointing to me, because I feel like clinicians significantly discount the general risks of maintenance/escalation therapy. Maybe that's because they are used to those risks, and because the risks used to apply to all the available therapies. But they're no longer part of the calculus for all DMTs, because IRT is available.
Those risks also differ wildly depending on personal circumstances. I'm in the US and finished my IRT last year. My employment situation, and therefore my healthcare situation, is not stable. If I were on a maintenance/escalation therapy, I'd be terrified at what is happening to the healthcare system. As it is, I have a _very_ good chance that I won't need anything for years. Maybe never. I might have trouble getting all the follow-up I should have, but that's very different from having to fight insurance for access to a DMT, go through step therapy, etc.
We're also having a resurgence of antivax sentiment. I am on Team Vaccine. Not needing to worry about long-term immune suppression, and being able to get vaccinated myself, is really important to me. That's on top of all the other infections so common in people with MS. And with maintenance/escalation therapy, you're likely going to be going to hospitals/pharmacies a lot more than someone who did IRT, which means more time spent around people with infections. I'm 99.9% sure my one Covid infection came from the hospital.
Nothing is certain. I could "fail" cladribine, have a major relapse that means I need more medical attention, for some reason be unable to try the other IRT (Lemtrada, right?). Maybe copaxone (the escalation/maintenance DMT I was initially offered and refused) would have been perfect for me and never had any side effects or need to switch. But I feel like I picked the tradeoffs I could live with, and I'm concerned that so many people just don't even seem to _see_ those tradeoffs. I am all for informed consent, just... the information seems pretty bad.
I find this article particularly interesting, Prof G. My own neurologist is keen for me to begin Rituximab within the coming weeks, yet I remain deeply hesitant. I live with several other autoimmune conditions, which he believes Rituximab may also help to manage. However, while I fully acknowledge the potential of high-efficacy therapies to reduce both focal inflammation and PIRA, I can't help but question the broader impact, namely, the cost to a patient’s overall health, particularly in terms of increased infection risk.
Are they truly worth it? Perhaps. Although it is exceptionally hard as a patient to accept such risk when you don’t feel your MS is “too bad,” but know you are vulnerable to something far more frightening, such as an adrenal crisis, should an infection get out of hand. I just wish there were more open discussion and deeper understanding of the impact these treatment decisions can have on patients and their families. Comparing relative efficacy is one thing, but it risks dehumanising what is, for many of us, a personal and often daunting process.