NORTHERN enLIGHTened? Combating MS from Rituxiland;

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Sweden is not only famous for its love of Eurovision Song Contest and Iron Maiden (a strange mix), they are perhaps the Neurological Mavericks. In the dictionary this gives a meaning to be “independent-minded” and so I am being very complementary. Sweden is also home of the Nobel Prize and therefore I am sure they say let the data speak.

Rituximab is not a licenced treatment for MS. However, particulalrly in Sweden, rituximab is used extensively as it seems treatment choices and budgets have been put in the hands of the neuros. Rituximab is a CD20 depleting drug like a number of others and there are even generic versions of this, that could drop the cost more. In the UK, rituximab is used very little, as I believe it is not re-embursed and there are licenced alternatives that can be used. If I was on a cost-cutter crusade this could be important, but that type of crusade generally goes nowhere when there are licenced alternatives. However, the most important thing here is the use of rituximab in Sweden massively informs on how other anti-CD20 depleting antibodies or other B cell depleting drugs could be used. Therefore, it has relevance to ocrelizumab, ofatumumab etc, etc etc.

Now in the new era….I am not a neurologist and am not making any recommendations. Apparently a trial is ongoing to test the hypothesis of first line escalation verses initial high efficacy treatment. This may give non-Swedish neuros the evidence they need to change practice or not. I simply prefer to read.

I have selected these papers, others could be selected to make a different view, e.g. data from rituxiland shows that rituximab was associated with more infections than other DMT (Luna et al). However, I use these to show the power of B cell depletion (Remember all MS DMT are B cell depleters some do it better/more consitently than others).

0198. Comparative effectiveness of different DMT strategies in new onset RRMS; first results of the combatms trial
S. Virtanen, F. Piehl, T. Frisell. Virtual MS MSVirtual 2020.

Background: Increasing evidence suggest that early initiation of highly effective disease modulatory therapies (DMTs) reduce disability progression in relapsing-remitting MS (RRMS), but few studies strive to identify the most successful DMT strategy for new onset RRMS by also including drug survival. The CombatMS study is a Swedish nationwide observational drug trial involving all Sweden’s University Clinics (NCT03193866).
Objectives: To compare effectiveness of different DMT strategies for early RRMS, defined as treatment start latest two years after symptom onset.
Methods: The CombatMS population comprises 3500 RRMS patients starting a first DMT or doing a first DMT switch between Jan 1st 2011 to Oct 31st 2018, who from study start (June 2017) undergo an annual structured follow up with EDSS, patient reported outcomes and imaging. For this study we selected patients aged 18 to 50 years starting a first DMT within two years from symptom onset with a previously registered EDSS score ⩽12 months before or ⩽ 2 months after treatment start. We restricted the analysis to the four most frequent DMT choices in this category: interferons (INF), natalizumab (NTZ), dimethyl fumarate(DMF) and rituximab (RTX), resulting in total study population of 954 patients. We used an ever-treated approach, disregarding if the patient later switched or stopped therapy. Two-year disability progression was determined by comparing the baseline EDSS score to the EDSS score closest to two years, while relapse rate and drug survival were measured for a two-year follow-up period
from treatment start.
Results: The proportion of patients experiencing disability progression was 7.3 % (NTZ), 7.6 % (RTX), 12.4 % (DMF) and 19.2 % (INF). After adjusting for baseline differences in age, sex, region of residence, baseline EDSS, relapse rate before DMT start, and follow-up time, only the difference between RTX and INF remained significant. Two-year drug survival ranged from 38.3 % (INF) to 92.4 % (RTX), with these two extremes being significantly different from all other DMTs. Annualized relapse rates varied from 0.04 (RTX) to 0.27 (INF), with significant difference between all other
DMTs and INF and between RTX and DMF.
Conclusions: We observe relatively large differences in two-year outcomes across the studied DMTs, where the most striking findings are that patients initiating INF perform worse and those starting RTX better in most comparisons. Longer observation times will be needed to inform on risk-benefit with different DMT choices beyond two years.

Therefore early high efficacy treatment is beneficial. This is not surprisingly as more people will respond to treatment. From the prospect of ATTACKMS where ProfK intends to treat at first sign with natalizumab, it is just as good as rituximab. However, remember the label at the EMA says this is for “Patients with highly active disease despite a full and adequate course of treatment with at least one disease modifying therapy (DMT) or “Patients with rapidly evolving severe RRMS defined by 2 or more disabling relapses in one year, and with 1 or more Gadolinium enhancing lesions on brain Magnetic Resonance Imaging (MRI) or a significant increase in T2 lesion load as compared to a previous recent MRI”. This is why this is being investigated in a trial

COI: ProfG is on the scientific advisory board. This abstract does not address adverse effects and is not a peer-reviewed publication

Granqvist M, Boremalm M, Poorghobad A, Svenningsson A, Salzer J, Frisell T, Piehl F. Comparative Effectiveness of Rituximab and Other Initial Treatment Choices for Multiple Sclerosis. JAMA Neurol; 75:320-32

Importance: Comparative real-world effectiveness studies of initial disease-modifying treatment (DMT) choices for relapsing-remitting multiple sclerosis (RRMS) that include rituximab are lacking.

Objective: To assess the effectiveness and drug discontinuation rates of rituximab among patients with newly diagnosed RRMS compared with injectable DMTs, dimethyl fumarate, fingolimod, or natalizumab.

Design, setting, and patients: This retrospective cohort study used prospectively collected data to examine specialized care of 2 Swedish county-based community samples of patients with RRMS. Patients with RRMS who received diagnoses from January 1, 2012, to October 31, 2015, who resided in Stockholm (in the South) or Västerbotten (in the North) Counties were identified from a Swedish multiple sclerosis registry.

Main outcomes and measures: All reasons for drug discontinuation of initial treatment choice (main outcome) and specific reasons for switching (secondary outcomes) were analyzed

Results: Among 494 patients (median [interquartile range] age, 34.4 [27.4-43.4] years; 158 men [32.0%]), 215 received an injectable DMT (43.5%); 86 (17.4%), dimethyl fumarate; 17 (3.4%), fingolimod; 50 (10.1%), natalizumab; 120 (24.3%), rituximab; and 6 (1.2%), other DMT. Regional preferences were pronounced, with 42 of 52 (81%) and 78 of 442 (18%) receiving rituximab in Västerbotten and Stockholm, respectively . The annual discontinuation rate for rituximab, injectable DMTs, dimethyl fumarate, fingolimod, and natalizumab were 0.03 (few people stopped), 0.53 (About a half stopped with INF), 0.32, 0.38, and 0.29, respectively. Continued disease activity was the main reason for discontinuation of injectable DMTs, dimethyl fumarate, and fingolimod (Swopped for issues of efficacy); positive John Cunningham virus serology (Swopped to avoid PML risk) results were the main reason for discontinuation of natalizumab. Rate of clinical relapses and/or neuroradiologic disease activity were significantly lower for rituximab compared with injectable DMTs and dimethyl fumarate, with a tendency for lower relapse rates also compared with natalizumab and fingolimod. The annual discontinuation rate of initial treatment choice was significantly lower in Västerbotten compared with Stockholm (0.09 and 0.37, respectively). Conclusions and relevance: Rituximab was superior to all other DMT in terms of drug discontinuation and displayed better clinical efficacy compared with injectable DMTs and dimethyl fumarate with borderline significance compared with natalizumab and fingolimod. The county where rituximab constituted the main initial treatment choice displayed better outcomes in most measured variables. Collectively, our findings suggest that rituximab performs better than other commonly used DMTs in patients with newly diagnosed RRMS.

So you can see it is not only the UK that has a post-code lottery, in Sweden this is evident too. As you can see the vast majority of people in the North of Sweden are offered and accept Rituximab…Is this Northern Enlightenment, because it seems that people do not need to switch? It seems the Southern Neurologists use a wider spread of agents: allowing this study to be done. I know nothing about the individual circumstances, which is between the pwMS and their neuro.

Safety and efficacy of rituximab as first- and second line treatment in multiple sclerosis – A cohort study.Torgauten HM, Myhr KM, Wergeland S, Bø L, Aarseth JH, Torkildsen Ø.Mult Scler J Exp Transl Clin. 2021;7:2055217320973049.

Background: Rituximab is increasingly used as off-label therapy in multiple sclerosis (MS). More data are needed on safety and efficacy of rituximab, particularly in cohorts of de novo patients and patients in early therapy escalation.

Objective: To investigate the safety and efficacy of off-label treatment with rituximab in an MS-cohort of predominantly de novo patients or as therapy escalation.

Methods: We retrieved safety and efficacy data from the Norwegian MS-registry and biobank for all MS-patients treated with rituximab at Haukeland University Hospital, Bergen, Norway, during a four year period.

Results: In the 365 MS-patients (320 relapsing-remitting MS (RRMS), 23 secondary progressive MS (SPMS), and 22 primary progressive MS (PPMS)), the overall annualized relapse rate (ARR) was 0.03 and annualized drug discontinuation rate (ADDR) was 0.05. NEDA-3 was achived in 79% of patients with available data (n=351). Sixty-one patients experienced infusion-related adverse events of which two were serious (CTCAE grade 3-4). Eighteen patients experienced serious non-infusion related adverse events, of which 16 were infections. Infections (n = 34; 9.3%, CTCAE grade 2-5), hypogammaglobulinemia (low circulating antibody levels. n = 19, 5.2%) and neutropenia (loss of neutrophils which are a type of blood cells which are often part of your first line defence against infection. n = 16; 4.4%) were the most common non-infusion-related adverse events….. annualized relapse rate (ARR) for the subgroup receiving an initial dosage of 2000 mg (1000 mg + 1000 mg) was 0.05 (n = 44), and 0.02 for an initial dosage of 1000 mg (n = 321). ARR in the subgroup of newly diagnosed patients was 0.02 (n = 104), and 0.03 in other patients (n = 219) during study observation time.

Conclusion: Rituximab was a safe and highly efficient disease modifying therapy in this cohort of MS-patients; however, infections and neutropenia need to be monitored.

This study has different dosing but maybe it does not matter, so to give abit of the “Ole” and we can add information from Spain

PS01.05 Rituximab treatment for ms: an observational multicentric dose comparison Strategies for disease modification L. Midaglia et al. 

Background: Rituximab (RTX) is an anti-CD20 monoclonal antibody, widely used as an off-label treatment for multiple sclerosis (MS). Despite well-known efficacy and safety, RTX regimen has not yet been standardized

ObjectivesWe aimed to compare efficacy and safety data of two different rituximab doses at two large Catalan multiple sclerosis centres. 

Methods: A two-centre ambispective study considering all MS patients that have received at least one RTX cycle until February 2020 was conducted. In Barcelona centre (BC), RTX regimen used was 2g intravenously (IV), at least during 3 cycles, followed by 1g every 6 monthswhile in Girona centre (GC), was 2g IV, at least the first cycle, followed by 500mg every 6 months.

Results: A total of 303 patients (249 at BC and 54 at GC) were included.  No differences on age at RTX onset, gender and disease duration were found between both centres. At baseline, mean ARR was 0.37±0.6 (BC) vs. 0.33±0.5 (GC); median EDSS was 5.5 (1-9.0) (BC) vs. 6.0 (1-8.0) (GC) (so similar); and proportion of MRI with CELs was 32.4% (BC) vs. 42.6% (GC). ARR decrease to 0.05 (87.5%, p<0.001) for BC vs. 0.03 (90.3%, p=0.018) for GC at first year, and to 0.08 (88.3%, p=0.016) vs. 0 (100%, p=0.172) at third year (Pretty similar). Considering only progressive MS phenotypes, 79.4% vs. 71.4% of patients remained stable or improved the EDSS. Regarding MRI findings, percentages of patients with CELs and new T2 lesions (BC vs GC) were 2.7% vs. 8% and 19% vs. 16% at one year; and 0% vs. 0% and 12% vs. 0% at third year. AE incidence was higher at BC during the first year (14.8% vs 4.1%)No difference in the dynamics of CD19% lymphocytes was found, while IgG values decreased significantly in the BC cohort throughout the first 3 years.

Conclusions: In the treatment of multiple sclerosis, low doses of rituximab seem to offer similar effectiveness with better safety profile than high doses.

Although it may look like it, I am not really blowing the trumpet for rituximab, but it shows the power of B cell depletion when used early in MS. But hey we know this, if you can read and think:-). You may have noticed that it has been seen with alemtuzumab (MS-CARE I) and cladribine (ORACLE), which are likewise B cell depleting agents used first line and early. Therefore, I suspect that there is nothing in the above posts that could not be achieved with other agents and there are other B cell depleting agents besides rituximab.

Hopefully in these studies they have monitored Brain Atrophy. If this is inhibited then it addresses the issue about whether you need T and B cell depletion, because if you remember the trial atrophy data with CD20 depletion, starting 6 years after onset, was not as good as CD52 depletion starting about 2 years after onset.

Can we make this approach even safer? This is what taylored individualised treatment could have the potential to do, but we don’t have the evidence….but I bet the guys and gals from Rituxiland can give us great clues.

P.S. I heard the term rituxiland used by a Swedish neurologists for the first time, when I had the pleasure to visit Stockholm for a Scandinavian neurology meeting

CoI: Multiple

Disclaimer: Please note that the opinions expressed here are those of the author and do not reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust or Queen Mary Univeristy of London. The author is not a neurologist and is not making any treatment recomendations!

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