Have we optimised the dose of anti-CD20 therapies to target the real MS or smouldering MS, i.e. disease progression independent of relapse activity (PIRA)?
I did an iWiMS webinar on Wednesday covering anti-CD20 therapies and the risk of COVID-19 and severe COVID-19. I covered vaccine responses and how to be vaccine-ready or vaccine responsive to a future SARS-CoV-2 vaccine if you are on an anti-CD20 therapy.
I also discussed optimising the dose of anti-CD20 therapies making the point we may need much higher doses than what we currently use to treat MS. The latter is because we have been blinkered by the impact of anti-CD20 therapy on focal inflammatory events, i.e. relapses and MRI lesions, when the real MS (disability/smouldering MS) appears to more responsive to higher doses of anti-CD20 therapies.
I re-recorded my lecture to spend more time on why these issues are important for people with MS. I have also shared my slides below.
I am being asked why I have moved ocrelizumab and other anti-CD20 therapies into the low-risk categories of DMTs in my latest version of my DMT table.
The reasons I use to justify the change are several-fold.
Anti-CD20 therapies deplete B-cells and only have a small impact on T-cell counts and innate immune cell function. This is important because anti-viral responses don’t seem to be affected to a great extent on ocrelizumab and other anti-CD20 therapies. In the phase three ocrelizumab trial programme apart from seeing a small herpes zoster signal there was no clear viral infection signal. When viral infections occurred they tended to be mild or moderate. The severe infections were bacterial (pneumonia, UTIs and cellulitis).
We are seeing an increasing number of patients who have been treated with anti-CD20 therapies who have had COVID-19 doing well. We have just published a case report in MSARDs of a man with PPMS treated with ocrelizumab who did well (see below). This has to be good news for patients on anti-CD20 therapies.
Ocrelizumab also blunts antibody responses, which may be important in severe COVID-19. This may delay or prevent damage to the COVID-19 lung as some of the damage seems to be mediated by complement activation and microthrombi. The latter is indicative of damage consistent with IgG3 anti-viral responses and IgG antibody-dependent cellular cytotoxicity by macrophages and in some instance neutrophils. Antibody production against the SARS-CoV-2 spike protein may promote cytokine production that activates macrophage to become more destructive. Blunting these antibody responses with an anti-CD20 therapy may actually be beneficial, which is why we are predicting that anti-CD20 treated patients will have a lower risk of getting severe COVID-19.
What about hypogammaglobulinaemia then?
Yes, this does occur with anti-CD20 therapies but occurs at a relatively low level. As SARS-CoV-2 is a new human pathogen and hence we don’t have immunological memory against the virus this makes little difference to the risk of becoming infected with SARS-CoV-2. Hypogammaglobulinaemia may, however, put you at risk of getting secondary bacterial infections. Fortunately, these can be treated with antibiotics.
What about vaccine responses?
Yes, anti-CD20 and other immunosuppressive therapies can blunt antibody responses to some vaccines. And yes, contrary to the dogma patients on anti-CD20 therapies do make antibodies to viruses and vaccines. I assume this happens because we still have B-cells in secondary lymphoid organs and/or there may be CD20 negative B-cells that can takeover antibody production. Please note that the latter is a hypothesis.
Antibody responses to glycoproteins (sugar antigens) are particularly affected by anti-CD20 therapies and this may be important in the context of coronavirus immunity as the spike protein is heavily modified with sugar molecules. However, all these arguments are theoretical; until a vaccine emerges I would focus on getting MS treated. We can cross the vaccine bridge if and when it gets built. I am still of the opinion that the government’s strategy is herd immunity and hence the majority of us will at some point become infected with SARS-CoV-2. Waiting for a vaccine that never arises is going to be difficult for individuals; how long can you realistically self-isolate and/or shield?
We are very keen to do an anti-SARS-CoV-2 seroprevalence study in pwMS to see how many have been exposed to the virus and have not developed COVID-19 and to also look at antibody responses to SARS-CoV-2 in patients on different DMTs. We hypothesise that patients on anti-CD20 therapies will have as good an antibody response to SARS-CoV-2 as patients not on anti-CD20 therapies. This hypothesis refers to qualitative antibody responses, i.e. neutralising or protective antibody responses.
For the reasons above I have not stopped offering patients with active MS anti-CD20 therapies during the pandemic. This refers to both starting and retreatment. Some patients have chosen to delay their treatments until the pandemic is over and others have taken my advice and gone ahead with their treatments; this is their choice. But as I have said before the pandemic won’t be over anytime soon; the tail is likely to extend for 18-24 months and possibly longer. Therefore all the guidelines that have recommended delaying or postponing treatment with depletion therapies, i.e. the anti-CD20s, cladribine, alemtuzumab, mitoxantrone, cyclophosphamide and HSCT will have to be reviewed. We can’t stop treating MS or offering patients less effective options for the next 18-24 months. If we do what will be the consequences?
How many swallows does it take to make a summer? I am aware that one case report is not much, but there are an increasing number of patients being reported on social media who have been treated with an anti-CD20 and have had gotten through COVID-19 without a problem.
I would urge all the national register studies to be please report your data on COVID-19 outcomes in pwMS as soon as possible. We need the data to formalise our treatment guidelines and to help allay the fears of our patients. Please use one of the archive repositories to get your data out to the MS community as soon as possible. Thank you.
Background: Coronavirus disease 19 (COVID-19) is a novel disease entity that is spreading throughout the world. It has been speculated that patients with comorbidities and elderly patients could be at high risk for respiratory insufficiency and death. Immunosuppression could expose infected patients to even higher risks of disease complications due to dampened immune response. However, it has been speculated that overactive immune response could drive clinical deterioration and, based on this hypothesis, several immunosuppressants are currently being tested as potential treatment for COVID-19.
Methods: In this paper we report on a patient that has been treated with ocrelizumab (a B-cell depleting monoclonal antibody) for primary progressive multiple sclerosis who developed COVID-19.
Results: Despite complete B cell depletion, patient symptoms abated few days after hospitalization, and he was discharged to home-quarantine. Phone interview follow-up confirmed that, after 14 days, no new symptoms occurred.
Discussion: This report supports the putative role of immunosuppressive therapy in COVID-19 affected patients.
A dark age is when society regresses; it goes backwards in time. The shocking revelations in last week’s New England of Journal of Medicine on the dire situation of some type 1 diabetics upset me and indicates we may be entering a dark age. An age when we are forcing our patients to turn their backs on innovation because they, or society, can’t afford to purchase the necessary medications to allow them to treat their disease.
“The price of insulin has risen to a level where some patients have reported rationing their medication, which has resulted in worsening glycemic control and, in some cases, diabetic ketoacidosis and death. Approximately 90% of insulin sold in the U.S. is manufactured by one of three companies (Eli Lilly, Novo Nordisk, and Sanofi). The rising cost of insulin in the United States can be attributed primarily to two phenomena. First, U.S. law allows pharmaceutical manufacturers to price their products at whatever level they believe the market will bear and to raise prices over time without limit. Second, direct competition in the insulin market is lacking.”
I can only conclude that the politicians, with their neoliberal agenda, are failing these patients and society in general. The plight of type 1 diabetics is just the tip of the iceberg in a healthcare system that is being ripped apart by raw and unbridled capitalism. This is why the Labour party in Britain are warning us about the potential consequences for the NHS when we lose the protection of the EU post-Brexit.
Is the rationing of DMTs happening to people with MS? Several pwMS have commented on this blog how unaffordable DMTs are in the U.S. if you don’t have medical insurance and/or are covered by one of the socialist healthcare systems you are being forced to forego treatment. For me, as an academic working in MS, this is worrying because as we move into an era of combination therapies we are going to have to make combinations of treatments affordable. If one company controls all the components of the combination they can then price the therapy at an affordable price. However, if the components of the combination are controlled via different companies then the price of the individual components may make combination therapies too expensive.
We have been making the case of building a sandwich with a potent anti-inflammatory at the base and superimposing on top centrally acting anti-inflammatories, neuroprotective and remyelination therapies, neurorestorative treatments and anti-ageing agents. In addition to this, we may need a cocktail of drugs targeting comorbidities, either treating them or preventing them. As you can see the cost of treating MS will rapidly become prohibitively expensive.
In HIV Gilead tackled this problem by in-licensing different drugs from other companies to create their polypills. I envisage this happening in MS. If it doesn’t happen then the price of treating MS will beyond most people.
At the moment anti-CD20 therapies are rapidly becoming the base of the treatment pyramid, but the innovator anti-CD20 compounds are simply too expensive at present for competitors to use them as part of a combination therapy strategy. Even when ofatumumab and ublituximab get licensed for treating MS the cost of anti-CD20 therapies, in general, is unlikely to fall significantly. Maybe as part of our #AffordableDMT initiative, we can get wide adoption of rituximab biosimilars and use these more affordable anti-CD20 biosimilars at the base of the pyramid?
The problem we have is that rituximab is not licensed to treat MS. Outside of Sweden and the Kaiser Permanente in the U.S. systematic rituximab prescribing is patchy. Most HCPs are not confident enough to take on the risks of prescribing rituximab off-label. Even in Sweden the medical insurance company that covers Swedish neurologists in relation to their practice has said they won’t be able to cover their rituximab prescribing because of the extent of its use in Sweden. I am told that the Swedish government is having to create a bespoke medical insurance policy to cover system-wide off-label prescribing. Surely a better solution would be for the Swedish government to license rituximab as a treatment for relapsing MS and then this issue will go away?
If rituximab is licensed as a treatment for MS in Sweden then under reciprocal recognition rules in Europe we may be able to start using rituximab in the UK and other EU countries. This is assuming it happens before Brexit-related divorce laws disconnect us from Sweden and the EU. Another option would be for the NHS to license rituximab in the UK. I am not sure of the NHS has the will and/or the mechanisms for licensing a therapy for a specific disease, but it is something worth exploring. This would be a real game-changer both in the UK and internationally. This will allow us academics to at least build a combination therapy strategy with an affordable anti-CD20 at the base of the pyramid. This will allow us to test our induction-maintenance therapy hypothesis using generic drugs; for example, induction with rituximab followed by leflunomide as maintenance therapy.
Getting rituximab licensed to treat MS could be another strategic objective of our GRAD Initiative (Grass-Roots Affordable DMT Initiative). What do you think? This may appeal to low- and middle-income countries, particularly a country such as India that has a large and burgeoning biosimilars industry.
Please don’t be shy we need #AffordableDMT champions and wider engagement from the MS community. If you would like to get involved please get involved and register your interest. I would also like ideas from the wider community about how we get rituximab licensed as a treatment for MS. If you can’t beat Pharma you might as well join them 😉
It is clear that many MSers on continuous anti-CD20 therapy are concerned about the risk of developing hypogammaglobulinaemia and subsequent infections. Yesterday, I spoke to several neurologists at the O’HAND investigators meeting in Barcelona who informed me that they are considering giving their ocrelizumab-treated patients hyperimmune globulin replacement therapy (HYPE-Ig-RT) when they develop hypogammaglobulinaemia to prevent serious and potentially fatal infections.
The problem I have with this is that HYPER-Ig-RT is expensive and for it to be covered by the NHS we will need to show that it is cost-effective. In response to these discussions Owen Pearson, an MSologist from Swansea, and I came up with the design of the HYPE study below.
The HYPE study
This is a randomised placebo-controlled trial to assess whether or not HYPE-Ig-RT will work, i.e. reduce the risk of serious infection, infections and mortality in MSers on continuous anti-CD20 therapy. Please note we don’t think this study should be limited to ocrelizumab-treated MSers but should be open to any patient on anti-CD20 therapy, including those on rituximab and ofatumumab.
What do you think of the HYPE study? Do we have clinical equipoise?
Please remember for the payers, i.e. NHS England and insurance companies, to pay for HYPER-Ig-RT we need class 1 evidence to make the financial case to them. This study will test the hypothesis that HYPE-Ig-RT will derisk continuous anti-CD20 therapies and prevent some of the infectious complications related to hypogammaglobulinaemia.
What is the risk of serious infections on anti-CD20 therapies?
The following figures put the serious infection risk, i.e. infections requiring hospitalisation, on ocrelizumab in context. The overall figure is 2.24 serious infections per 100 patient-years. In other words for every 45 patients on ocrelizumab for 12 months one patient will be admitted to hospital with a serious infection. However, if you develop low IgG levels (hypogammaglobulinaemia) the risk rises to 5.48 serious infections per 100 patient-years or for every 18 patients on ocrelizumab for 12 months one patient will be admitted with a serious infection. This is why we are now monitoring peripheral blood immunoglobulin levels on an annual basis in all our patients on anti-CD20 therapy.
When I highlighted the risk of hypogammaglobulinaemia and infection in MSers receiving anti-CD20 therapy after ECTRIMS I go a very long email from someone from Roche playing down the risks. The following study is therefore very timely and shows that when comparing interferon-beta, glatiramer acetate, natalizumab, fingolimod and rituximab with each other it is rituximab that comes out worst in relation to infectious complications.
You also need to remember that not all anti-CD20 therapies are made equal and that ocrelizumab is a more potent B-cell depleter than rituximab. We know this based on the infectious complications seen in study subjects with rheumatoid arthritis and lupus and the observation that there is a clear varicella-zoster signal in the ocrelizumab phase 3 programme. In this context, an interesting observation was that there was a lower rate of anti-herpes/anti-virals in the rituximab-treated MSers compared to the other DMTs. This is interesting and raises questions of why this should be? Could it be because rituximab only reduces the CD8+ T-cell counts by about 15% after the first infusion and his little impact thereafter?
So don’t let anyone pull the wool over your eyes that anti-CD20 therapies are not immunosuppressive and are not associated with an infection signal. It is becoming clear to me that continuous dosing with anti-CD20 therapy will result in a cumulative increase in infections and at some stage we are as an MS community are going to have to derisk this problem by using (1) anti-CD20 therapy as an immune-reconstitution therapy (IRT) or as (2) an induction agent or (3) by correcting the immune deficiency by giving immunoglobulin replacement therapy when our patients develop hypogammaglobulinaemia.
I think we need to do the ADIOS study sooner than later. Don’t you?
Question: What is the risk of infections in association with different disease-modifying treatments for multiple sclerosis?
Findings: This nationwide cohort study found that patients with multiple sclerosis are at a generally increased risk of infections, and this risk is partly dependent on the choice of treatment. The rate of infections was lowest with injectable therapies; among newer treatments, use of rituximab was associated with the highest rate of serious infections but less use of herpes antiviral medications compared with fingolimod and natalizumab.
Meaning: Per the results of this study, physicians and patients should be aware of infection risks associated with newer multiple sclerosis treatments and perhaps particularly anti-CD20 therapies.
Importance: Although highly effective disease-modifying therapies for multiple sclerosis (MS) have been associated with an increased risk of infections vs injectable therapies interferon beta and glatiramer acetate (GA), the magnitude of potential risk increase is not well established in real-world populations. Even less is known about infection risk associated with rituximab, which is extensively used off-label to treat MS in Sweden.
Objective: To examine the risk of serious infections associated with disease-modifying treatments for MS.
Design, Setting, and Participants: This nationwide register-based cohort study was conducted in Sweden from January 1, 2011, to December 31, 2017. National registers with prospective data collection from the public health care system were used. All Swedish patients with relapsing-remitting MS whose data were recorded in the Swedish MS register as initiating treatment with rituximab, natalizumab, fingolimod, or interferon beta and GA and an age-matched and sex-matched general population comparator cohort were included.
Exposures: Treatment with rituximab, natalizumab, fingolimod, and interferon-beta and GA.
Main Outcomes and Measures: Serious infections were defined as all infections resulting in hospitalization. Additional outcomes included outpatient treatment with antibiotic or herpes antiviral medications. Adjusted hazard ratios (HRs) were estimated in Cox regressions.
Results: A total of 6421 patients (3260 taking rituximab, 1588 taking natalizumab, 1535 taking fingolimod, and 2217 taking interferon beta/GA) were included, plus a comparator cohort of 42 645 individuals. Among 6421 patients with 8600 treatment episodes, the mean (SD) age at treatment start ranged from 35.0 (10.1) years to 40.4 (10.6) years; 6186 patients were female. The crude rate of infections was higher in patients with MS taking interferon beta and GA than the general population (incidence rate, 8.9 [95% CI, 6.4-12.1] vs 5.2 [95% CI, 4.8-5.5] per 1000 person-years), and higher still in patients taking fingolimod (incidence rate, 14.3 [95% CI, 10.8-18.5] per 1000 person-years), natalizumab (incidence rate, 11.4 [95% CI, 8.3-15.3] per 1000 person-years), and rituximab (incidence rate, 19.7 [95% CI, 16.4-23.5] per 1000 person-years). After confounder adjustment, the rate remained significantly higher for rituximab (HR, 1.70 [95% CI, 1.11-2.61]) but not fingolimod (HR, 1.30 [95% CI, 0.84-2.03]) or natalizumab (HR, 1.12 [95% CI, 0.71-1.77]) compared with interferon beta and GA. In contrast, use of herpes antiviral drugs during rituximab treatment was similar to that of interferon beta and GA and lower than that of natalizumab (HR, 1.82 [1.34-2.46]) and fingolimod (HR, 1.71 [95% CI, 1.27-2.32]).
Conclusions and Relevance: Patients with MS are at a generally increased risk of infections, and this differs by treatment. The rate of infections was lowest with interferon beta and GA; among newer treatments, off-label use of rituximab was associated with the highest rate of serious infections. The different risk profiles should inform the risk-benefit assessments of these treatments.
POST-SCRIPT
In response to a comment, the following figures put the serious infection (requiring hospitalisation) risk on ocrelizumab in context; i.e. how common is this complication. The overall figure is 2.24 serious infections per 100 patient-years. In other words for every 45 patients on ocrelizumab for 12 months 1 patient will be admitted to hospital with a serious infection.
However, if you develop low IgG levels (hypogammaglobulinaemia) the risk rises to 5.48 serious infections per 100 patient-years or for every 18 patients on ocrelizumab for 12 months 1 patient will be admitted with a serious infection. This is why we are now monitoring peripheral blood immunoglobulin levels on an annual basis in all our patients on anti-CD20 therapy.
BACKGROUND:Anti-CD20 monoclonal antibodies such as ocrelizumab, rituximab, and ofatumumab target B-cell lineage. Clinical trials have demonstrated their effect on reducing both magnetic resonance imaging (MRI) active lesion burden as well as clinical activity. Zytux™ (Rituximab, AryoGen Pharmed) used in the present study for multiple sclerosis (MS) patients is basically a biosimilar rituximab. In this observational study, a total of 100 patients receiving Zytux™ were collected to see its effect on the clinical course of the disease.
RESULT: A total of 100 MS patients including 36 males and 64 females participated in the present study. The patients included 20 relapsing remitting MS (RRMS), 20 primary progressive MS (PPMS), and 60 secondary progressive MS (SPMS) patients. Totally, the mean of EDSS score before and after the administration of drug was 5.50 ± 1.04 (ranging from 1 to 7) and 5.11 ± 1.59 (ranging from 0 to 7), respectively, with the difference between them being very significant (p-value: 0.000). Also, the mean of ARR before and after the initiation of the medication was 0.47 and 0.10, respectively, whose difference was also significant (p-value: 0.000). In our study, the greatest effect of Zytux™ was observed in RRMS patients. At the time of injection, 70 patients indicated some reactions including limb pain, skin sensitivity, and throat irritation. One month after the injection, one of the patients suffered from pneumonia and two patients had a urinary tract infection.
CONCLUSION:The observed results revealed that the Zytux™ could have a positive and significant effect on all types of MS
An important highlight of ECTRIMS this year was the data on the safety of the anti-CD20 therapies as a class. It is clear that prolonged, and sustained, B-cell depletion is not safe. Hypogammaglobulinaemia will become a problem with the risk of both common and opportunistic infections.
Stephen Hauser presented the 7-year ocrelizumab safety data and there is a clear uptick in infections in year 7. His poster also included a probable opportunistic infection signal. As of January 2019, there were six potential serious opportunistic infections that had been reported from the ocrelizumab clinical trials.
Systemic Pasteurella infection in a patient with RMS following a cat bite (resolved)
Multisegmental herpes zoster infection in a patient with RMS, treated with intravenous (IV) acyclovir (resolved)
Enterovirus-induced fulminant hepatitis in a diabetic patient with RMS, resulting in liver transplant
Candida sepsis in a patient with PPMS who had stopped OCR treatment 11 months previously and was receiving cancer chemotherapy (resolved)
Viral meningitis in a patient with RMS, cerebrospinal fluid positive for varicella-zoster, treated with IV acyclovir (resolved)
Herpes zoster (monodermatomal) in a patient with RMS treated for a neutropenic fever (not assessed as an opportunistic infection) (resolved)
Continuous anti-CD20 therapy prevents you from forming germinal centres (where B-cells get educated and selected to make antibodies) in lymph nodes and the spleen. In other words, the anti-CD20 therapies result in what I refer to as a functional splenectomy. This causes a scotoma, or blind spot, in your immune system which means you can’t mount a vigorous immune response to new infectious agents or vaccines. In reality, your immune responses are muted.
I highlighted in my hot topics talk on ‘DMTs in RRMS 2019: what remains to be achieved’ about the problems of having a functional splenectomy on anti-CD20 therapies. I recommended that all MSers be vaccinated with the polyvalent pneumococcal vaccine (Pneumovax) and possibly the vaccines for Haemophilus influenzae type B and Meningococcus. In addition, all MSers should have the annual flu vaccine, but with the inactivated component flu vaccine and not the live flu vaccine. In fact, MSers on anti-CD20 therapy should avoid coming into contact with recipients of the live flu vaccine in case it becomes more virulent and infects them. Please note the live flu vaccine is used in the UK in young children and it is recommended that children who have parents or family members at home on immunosuppressive therapies should not have this vaccine.
Another option open to people on longterm anti-CD20 therapy is antibiotic prophylaxis against infections with these encapsulated bacteria. I suspect this may be necessary when MSers develop hypogammaglobulinaemia and recurrent infections, similar to the NMO cases described below. It is clear that anti-CD20 therapies will need annual immunoglobulin levels measured so that if hypogammaglobulinaemia develops MSers can we warned. I suspect immunoglobulin replacement therapy will only be required in the case of recurrent infections, for example, sinus or chest infections; for example, the NMO patient on longterm rituximab who developed bronchiectasis.
I would also recommend that MSers on immunosuppressive therapies wear a medic-alert bracelet that states they are on an anti-CD20 therapy. This would help HCP in an emergency if you are too sick to provide a history. An American colleague told me about one of his ocrelizumab-treated patients, who was fit and well, who died suddenly in the emergency department after presenting with a high temperature and not feeling well. I suspect the cause of death was probably septic shock from one of the encapsulated bacteria discussed above.
The facts that (1) the clinical development programme of ocrelizumab was stopped in rheumatoid arthritis and lupus because of infections and excessive number of deaths, (2) that there is a herpes zoster signal on ocrelizumab, (3) there is blunted vaccine response, in particular to pneumococcus, and (4) ocrelizumab reduces immunoglobulin levels explains why there are infectious complications on ocrelizumab.
So if you are on rituximab, ocrelizumab, ofatumumab or any othe anti-CD20 please be vigilant and take care. On the other side of the coin are the benefits of these treatments and their ease of use and low monitoring burden. As with all DMTs the risks need to be balanced against the benefits.
B-cell depleting anti-CD20 monoclonal antibody therapies have demonstrated promising clinical efficacy in suppressing relapses in individuals with neuromyelitis optica (NMO) and multiple sclerosis (MS). However, uncertainties remain about the optimum treatment schedule. In rheumatological disease, anti-CD20 agents are most often employed for short-term induction therapy and are subsequently replaced by longer-term maintenance therapy. In contrast, repeated cycles of anti-CD20 monoclonal antibody therapy are proposed as maintenance therapy for CNS neuro-inflammatory disorders. Post-marketing surveillance will be essential to fully uncover the long-term safety profile of repeated B-cell depletion. Hypogammaglobulinaemia is a recognised consequence in a proportion of patients treated with medium- to long-term B-cell therapy and may play a role in the increased incidence of infection observed in the anti-CD20 arms of treatment trials. We report 5 cases of serious infection associated with hypogammaglobulinaemia occurring in patients receiving rituximab for NMO. The cases were all female, all had low IgG with variable reductions in IgM and IgA. The cases had a mean treatment duration of 3.1 years, but not all cases had had extensive exposure (treatment duration range 0.5 – 6.2y). We review the evidence relating to hypogammaglobulinaemia following anti-CD20 treatment for neuroinflammatory disorders and propose an algorithm for monitoring and treatment of this recognised complication.
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.
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.
Yes, why can’t we use anti-CD20 therapies as an immune constitution therapy (IRT) or at least adapt the dose based on B-cell reconstitution kinetics? And if we can’t beat the Swedes why can’t we join them?
ADIOS = ADaptIve Ocrelizumab dosing Study
There is mounting evidence from NMO and rheumatology that anti-CD20 therapies can be used as either a maintenance therapy or an immune reconstitution therapy (IRT). Another way of using them is to adjust the dose based on memory B-cell reconstitution (MBR) kinetics.
Adapting the dose of anti-CD20 therapies using MBR or as IRT has appeal as it will almost certainly be safer in terms of infections, the emergence of hypogammaglobulinaemia and possibly the ability to respond to vaccines. It could also lead to better family planning by being able to expand the treatment-free period safely. Another plus would be cost-saving for the NHS and the other healthcare systems.
We are therefore in the process of designing a new trial to test standard interval dosing (SID) of ocrelizumab vs. adaptive dosing either using an MBR or an IRT protocol. What do you think? If you were on ocrelizumab would you sign up for this study? The advantage for you is that it may make your treatment safer in the long-term and it will potentially save the NHS millions.
Why can’t we use anti-CD20 therapies as immune constitution therapies?
For some years we have been promoting our Barts-MS Essential DMT list to treat people with MS (pwMS) in resource-poor environments. One of the big guns on our list has been rituximab (anti-CD20). One of the problems is that rituximab at a dose of 1g every 6 months is still too expensive to accessible for the vast majority of MSers living in these environments. The good news is that several developments have brought the price of rituximab down.
The Swedes, who are treating more than half their MS population, have data showing that 500mg every 6 months is as good as 1g every 6 months in terms of NEDA, i.e. preventing new relapses and new MR lesions from forming.
Rituximab has come off patent and several cheap biosimilars are now entering the market.
The Swedes are also testing adaptive dosing, i.e. after 2 years of 6 monthly infusions, they are extending the interval between doses to 12 months or more and/or are even beginning to redose rituximab based on peripheral memory B-cell reconstitution. At a recent meeting, I was at one Swedish neurologist is beginning to use rituximab as an IRT (immune reconstitution therapy), i.e. only redosing with rituximab if and when disease activity re-emerges.
I classify anti-CD20 therapies as both a maintenance therapy and an IRT. At the last AAN in Los Angeles, I attended a meeting of like-minded clinical scientists to set-up a trial to test anti-CD20 as a maintenance therapy vs. an IRT. The retreatment arms of the trial were to test redosing based on the reemergence of disease activity or the repopulation of memory B cells. Using anti-CD20 therapies as an IRT has appeal as it will almost certainly be safer in terms of infections, the emergence of hypogammaglobulinaemia and ability to respond to vaccines.
I am therefore very interested in seeing the results of the Swedish experiment of testing rituximab as a maintenance therapy vs. rituximab as an IRT. Just maybe we can get the price of treating MS with rituximab down to affordable levels for low-income countries.
The following is a back of envelope calculations based on the current BNF prices:
Mabthera (Roche) 500mg = £873.15 per 500mg vial Rixathon (Sandoz) = £785.84 per 500mg vial Truxima (Napp) = £785.84 per 500mg vial
Standard dose (1g) Mabthera maintenance regimen: 1g Day 0, 1g Day 14 then 1g 6 monthly indefinitely = £873.15 x 10= £8731.50 for the first 2 years and then £3492.60 annually.
Standard dose (1g) biosimilar maintenance regimen: 1g Day 0, 1g Day 14 then 1g 6 monthly indefinitely = £785.84 x 5 = £7858.40 for the first 2 years and then £3143.36 annually.
Reduced dose (500mg) Mabthera maintenance regimen: 1g Day 0, 1g Day 14 then 1g 6 monthly indefinitely = £873.15 x 10= £4365.75 for the first 2 years and then £1746.30 annually.
Reduced dose (500mg) biosimilar maintenance regimen: 1g Day 0, 500mg Day 14 then 500mg 6 monthly indefinitely = £785.84 x 5 = £3929.20 for the first 2 years and then £1571.68 annually.
Reduced dose (500mg) biosimilar maintenance regimen: 500mg Day 0, 500mg Day 14 then 500mg 6 monthly indefinitely = £785.84 x 5 = £3929.20 for the first 2 years and then £1571.68 annually.
Adaptive dose (500mg) biosimilar maintenance regimen: 500mg Day 0, 500mg Day 14 then 500mg 6 monthly for 2year and then 500mg approximately every 12 months = £785.84 x 5 = £3929.20 for the first 2 years and then £785.84 annually (the latter may be lower if redosing is done using peripheral B cell reconstitution).
Please note these figures are the list price and don’t include discounts, VAT nor the infusion costs. In reality, these costs could come down with central, say NHS, purchasing power. Unfortunately, they are still too high to help pwMS in low-income countries. Just maybe getting MS and anti-CD20 therapies onto the WHO Essential Medicines List may bring down the costs by creating political pressure on the Pharma industry or innovations in making cheap biosimilars may also help.
The Caveat
There is one major caveat I have about putting up anti-CD20 as the solution for MS is that we may be getting it wrong. I personally don’t think relapses and focal MRI activity are the disease we call MS; these markers are an inflammatory response to what is causing the disease. Therefore I suspect we may be lulling ourselves into a false sense of security with anti-CD20 therapies and ignoring what is really driving the disease, i.e. what is causing the end-organ damage in MS.
Do we know what is driving the slowly expanding lesion? What is causing the extensive cortical lesions in MS, which we can’t see on conventional MRI? What is driving the progressive brain volume and grey matter loss in MS? Don’t we need to go beyond NEDA as a treatment target? I know some would argue we have done this already, which is why so many MSers want HSCT as a first-line treatment option.
Should your vaccine status be checked and updated before you start treatment?
As part of our programme to derisk disease-modifying therapies (DMTs) for pwMS in our service, we are reviewing our vaccination policy. One issue that has emerged is the possible need to boost immunity to certain types of bacteria that are known to pose a risk in patients on long-term immunosuppression, in particular B cell depleters, such as rituximab, ocrelizumab and ofatumumab. Why?
Chronic B-cell depletion essentially prevents B-cells mounting an adequate antibody response to new antigens. It does this by preventing the formation of so-called germinal centres in the spleen and/or lymph nodes. In other words patients on longterm anti-CD20 therapy behave, from an immunological perspective, if they have had a functional splenectomy. This put patients with longterm B cell depletion at risk of hypogammaglobulinaemia (low immunoglobulin levels) in the future and predisposes them to infections caused by so-called encapsulated bacteria; these include pneumococcus, meningococcus and Haemophilus Influenzae.
When you review the rheumatoid arthritis literature in relation to longterm rituximab (anti-CD20) therapy both these problems have been documented. How do the rheumatologists deal with these problems? They appear to routinely monitor immunoglobulin levels and they proactively vaccinate their patients prior to starting long-term anti-CD20 therapy.
It seems pretty obvious to me, reading the rheumatology literature, that before you start long-term anti-CD20 therapy you should have your vaccination status checked and we should start vaccinating patients against pneumococcus, meningococcus and Haemophilus Influenzae B. In fact, pneumococcal vaccine is already recommended, if possible, for all patients before starting immunosuppressive treatments. It is clear for anti-CD20 therapies that the vaccines will need to be given prior to starting treatment (see Nguyen paper below).
We also recommend doing baseline immunoglobulin levels on all patients before starting treatment as a reference and then to start checking levels from year 3 onwards. I say year 3 because in the ocrelizumab trials we only saw a significant drop in IgM and IgA levels over 2 years and IgG levels were stable. Based on the rituximab data a drop in IgG levels is, therefore, only likely to emerge after 2 years of treatment.
I would be interested to know if any of you had your vaccine status discussed before you started maintenance immunosuppression?
BACKGROUND: Rituximab, a chimeric monoclonal antibody against CD20, is increasingly used in the treatment of B-cell lymphomas and autoimmune conditions. Transient peripheral B-cell depletion is expected following rituximab therapy. Although initial clinical trials did not show significant hypogammaglobulinaemia, reports of this are now appearing in the literature.
METHODS: We performed a retrospective review of patients previously treated with rituximab that were referred to Clinical Immunology with symptomatic or severe hypogammaglobulinaemia. Patient clinical histories, immunological markers, length of rituximab treatment and need for intravenous immunoglobulin replacement therapy (IVIG) were evaluated. An audit of patients receiving rituximab for any condition in a 12-month period and frequency of hypogammaglobulinaemia was also carried out.
RESULTS: We identified 19 post-rituximab patients with persistent, symptomatic panhypogammaglobulinaemia. Mean IgG level was 3.42 ± 0.4 g/l (normal range 5.8-16.3 g/l). All patients had reduced or absent B-cells. Haemophilus Influenzae B, tetanus and Pneumococcal serotype-specific antibody levels were all reduced and patients failed to mount an immune response post-vaccination. Nearly all of them ultimately required IVIG. The mean interval from the last rituximab dose and need for IVIG was 36 months (range 7 months-7 years). Of note, 23.7% of 114 patients included in the audit had hypogammaglobulinaemia.
CONCLUSION: With the increasing use of rituximab, it is important for clinicians treating these patients to be aware of hypogammaglobulinaemia and serious infections occurring even years after completion of treatment and should be actively looked for during follow-up. Referral to clinical immunology services and, if indicated, initiation of IVIG should be considered.
OBJECTIVE: To evaluate the initial serological responses to pneumococcal vaccination with the 13-valent protein-conjugated pneumococcal vaccine (PCV13) followed by the 23-valent polysaccharide pneumococcal vaccine (PPV23) among patients with rheumatoid arthritis (RA) treated with biological disease-modifying antirheumatic drugs (bDMARD) according to dosing and intervals between immunizations.
METHODS: Investigator-initiated clinical trial. Patients with RA receiving bDMARD were randomized (1:1:1) to immunization with single dose PCV13 followed by PPV23 after 16 or 24 weeks, or double dose PCV13 followed by PPV23 after 16 weeks. A comparison group of patients with RA treated with conventional synthetic (cs)DMARD received single dose PCV13 followed by PPV23 16 weeks later. Pneumococcal antibodies were collected before and 4 weeks after each vaccination. The primary endpoint was the proportion of participants responding to ≥ 6/12 pneumococcal serotypes 4 weeks after both vaccinations.
RESULTS: Sixty-five participants receiving bDMARD and 35 participants receiving csDMARD were included. After PPV23 vaccination, 87% (95% CI 0.76-0.94) and 94% (95% CI 0.77-0.99), respectively, of participants treated with bDMARD and csDMARD had reached the primary endpoint. There was no significant difference in primary endpoint between the 3 randomization arms. The response for rituximab-treated participants was 25% compared to ≥ 89% in participants treated with bDMARD with other mode of action.
CONCLUSION: The early serological response to prime-boost vaccination with PCV13 followed by PPV23 was very similar among participants receiving bDMARD and csDMARD. However, notable differences in response were observed according to individual bDMARD. It is important to consider the RA treatment when planning pneumococcal vaccination in patients with RA.
PURPOSE OF REVIEW: Rheumatoid arthritis (RA) patients experience increased infectious disease-related morbidity and mortality, and vaccinations represent an important element in their care. However, vaccine immunogenicity can be affected by disease-modifying antirheumatic drug (DMARD) therapy, such that vaccine choice and timing can be clinically challenging. We review the indications, safety, and immunogenicity of vaccines in the setting of RA.
RECENT FINDINGS: Recent recommendations highlight the use of influenza, pneumococcal, and shingles vaccines in RA patients. Studies suggest influenza and pneumococcal vaccines are underutilized, but well tolerated in RA patients and generally immunogenic during DMARD use with the exception of rituximab. Though data for other nonlive vaccines are more limited, hepatitis B virus and human papilloma virus vaccines also appear well tolerated and immunogenic in this population. Live vaccines for shingles and yellow fever remain contraindicated in some RA patients; however, limited data suggest they might be well tolerated in certain individuals.
SUMMARY: The review updates rheumatologists on the optimal use and timing of routine vaccinations in the care of RA.
