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.
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.
I was still wet behind the ears, in my 3-year as a neurology registrar in Johannesburg, when I first used an off-label DMT in MS.
I manage to convince Vivian Fritz, my professor of neurology, to allow us to treat one of her patients with MS with mitoxantrone. This was shortly after the first case series had emerged from Germany.
The patient concerned was a young woman with malignant MS who had one relapse after another and was in our ward for steroids and neurorehabilitation. She had just had a severe spinal cord relapse. She had an EDSS of 8.5 (bed bound with partial loss of hand and arm function). She had had MS for just 2 years. I proposed that she would likely die from her MS if we did nothing to stop her attacks. What had she, and her family, to lose by trying a course of mitoxantrone?
Viv Fritz listened and read the case series. After some reflection, she finally agreed to us trying mitoxantrone in her patient. We went ahead with a course of infusions as per the case series. The patient did so-so; i.e. we managed to stop her having more attacks, but she never got out of a wheelchair. I heard later that she sadly died about 2 years later after she developed septicaemia from an infected pressure sore.
The point I am making about this case is that as a neurology trainee in South Africa I was able to read about a potential innovation in Europe, suggest it to my Professor, argue the case and change our unit’s practice. There were other examples of OLP in SA; it was common in Johannesburg and I suspect it is still happening.
In comparison, OLP is not universal. I have just returned from a short visit to Japan where I found the culture amongst Japanese neurologists to be very similar to parts of the UK in relation to OLP. Very few Japanese neurologists are prepared to stick their heads above the parapet and prescribe off-label DMTs. Why? And what are the potential consequences of not adopting OLP for their patients?
With regards to why I think it is cultural. OLP seems to be more common in cultures that allow individuals to express themselves and challenge the status quo. Japanese neurologists are very deferential and respect their superiors. The same applies to trainees in the UK. For OLP to be widely adopted in Japan and the UK, heads of department, or the ‘neurology establishment’, will have to lead the way.
I am personally in favour of OLP as an engine of innovation. So many of our DMTs in MS have been developed from the insights and actions of individual neurologists who were brave enough, yes brave enough, to give it a go. Larry Jacobs administered intrathecal interferon-beta to his patients based on the hypothesis that MS was due to a virus. Interferons are foremost antiviral agents hence their name. Professor Jacobs saw positive results in a few of his patients and the rest is history. Interestingly, we still don’t know exactly how interferon-beta works. It may be working in MS as an antiviral agent; we just don’t know. Nobody to my mind has disproved the antiviral hypothesis of interferon-beta’s mode of action.
Professor Larry Jacobs; interferon-beta pioneer
Mauch and colleagues tried mitoxantrone, an anti-proliferative chemotherapy agent, on the basis that MS is an autoimmune disease. Mitoxantrone is cell depleting chemotherapy agent and was the first immune reconstitution therapy (IRT) to be licensed. The idea is to simply kill the autoimmune cells responsible for causing MS. It took more than a decade of wider adoption of off-label mitoxantrone prescribing and research before mitoxantrone was eventually licensed as a treatment for MS.
Cyclophosphamide was less fortunate. Cyclophosphamide had been tried in MS for similar reasons as mitoxantrone. Unfortunately, cyclophosphamide was trialled in an era when the MS community didn’t know how to do trials. Cyclophosphamide failed as it was tested in more advanced MS and all the trials were underpowered, i.e. the trials had too few patients to be definitive. I am prepared to bet that if cyclophosphamide was formally tested in early in MS and the trials were adequately powered that it would be shown to a highly-effective DMT.
A more well-known example of OLP and innovation is Professor Alastair Compston’s off-label use of alemtuzumab. It started with Prof. Compston using it in a handful of patients in the early 1990s. Alemtuzumab was being tried in MS based on the same hypothesis as that for mitoxantrone and cyclophosphamide, i.e. MS is autoimmune and that to treat it and potentially cure MS you need to reboot the immune system killing off the autoimmune cells or at least regulating them when the immune system reconstituted itself.
I recall attending my first meeting in Cambridge, in late 1993 shortly after arriving in the UK to do my PhD, when Alastair presented the results of his first two patients. At the end of the meeting Professor Newsome-Davis, a senior and well-respected neuroimmunologist said to me that he didn’t agree with this approach. I recall him saying what we really needed was a pair of molecular tweezers and not a sledgehammer to treat autoimmunity. Unfortunately, the molecular tweezers are still the holy grail and without Alastair Compston’s perseverance, alemtuzumab would have never made it to the clinic.
Another example, is Prof. Jonathan Edwards, a rheumatologist at UCLH, who was brave enough to successfully try rituximab as a potential treatment for rheumatoid arthritis (RA). This was a very counterintuitive as the whole world at the time thought RA was a T-cell mediated autoimmune disease. The success of rituximab in RA led to senior executives at Genentech drawing up a list of other autoimmune diseases to try rituximab in. This and other factors subsequently led to Anne Cross trying rituximab in MS. Without a brave clinician trying OLP of an anti-CD20 in RA, we wouldn’t have ocrelizumab and several other me-too anti-CD20s in trials for treating MS.
There are similar stories for dimethyl fumarate, daclizumab, cladribine and some of the other emerging DMTs. Innovation in MS and other areas of healthcare emerge in an environment where OLP is championed and clinicians and their patients are brave enough to test the waters. What has changed?
It seems as if Barts-MS is being criticised, by some UK neurologists, for our compassionate use of off-label subcutaneous cladribine in more advanced MS. I don’t understand this as our position is no different from that of our predecessors mentioned above. We are simply building on a hypothesis that inflammation drives MS disease progression at all stages of the disease. We don’t agree with the 2-staged disease hypothesis of MS, i.e. that MS has an inflammatory phase that is followed by a neurodegenerative phase. The data overwhelming supports the parallel hypothesis that inflammation drives neurodegeneration throughout the course of the disease.
The implications of the parallel hypothesis of MS is that MS is potentially modifiable by anti-inflammatory therapies throughout its course; this even applies to advanced MS, which is why we will be formally testing DMTs in people who are already using wheelchairs for their mobility.
Another implication of the parallel hypothesis of MS, i.e. MS is always both inflammatory and neurodegenerative, is that we need to build a sandwich with an anti-inflammatory therapy, or a combination of anti-inflammatory therapies, at the base and to then use this as a platform on which to build the layers of the sandwich, which includes add-on neuroprotective, remyelination and neuro-restorative therapies.
At the same time we need a holistic approach and to focus on all the other factors that may impact on the health of the brain of someone with MS. This is why we need to proactively manage all of the things that are potentially associated with accelerated ageing in pwMS.
For this reason, I have been proposing for some time that we adopt the marginal gains paradigm when treating MS. Dave Brailsford from the British cycling team is acknowledged as making the marginal gains approach mainstream.
“The whole principle came from the idea that if you broke down everything you could think of that goes into riding a bike, and then improved it by 1%, you will get a significant increase when you put them all together.” Sir Dave Brailsford.
Small changes in many things can have a massive impact on the overall outcome. Prior to Dave Brailsford taking over as head coach of the UK cycling the team, it was in the doldrums. In 1996, prior to adopting the marginal gains philosophy, Team GB was in 12th place in the Olympic Games medal table with two bronze cycling medals. In comparison at the Beijing games in 2008 Team GB won 12 medals from 10 events; 7 gold, 3 silver and 2 bronze medals.
Why can’t we apply marginal gains to the management of MS? If you have MS, you need to ask what you need to do across your disease course to maximise your chances of having a good outcome. This means not only focusing on optimising your MS DMTs but doing all the lifestyle things you can do and more.
For the naysayers, who are criticising Barts-MS for trying to treat people with advanced MS (wheelchair users) and/or active secondary and primary progressive MS, can you imagine what it is like to be told that ‘you are beyond hope and there is no treatment that can help you’? Or ‘there is nothing I can do you for you as you have progressive MS’? This is why it is important to learn how to spread hope and to try and improve everything you possibly can for your patients with MS.
Spreading the hope is why we are doing the #CHARIOT-MS and #ORATORIO-HAND studies, why we are planning the #SALVAGE-MS study and trying to optimise our MS service, within the confines of the NHS, to adopt a marginal gains approach to managing MS.
I would also like to remind the naysayers that they seem not to have noticed that progressive MS is now modifiable? Ocrelizumab is licensed for active PPMS and Siponimod is licensed for active SPMS in the US and is likely to get an SPMS label in Europe. In addition, there are several other progressive trials underway with a high likelihood of being positive. We are now in an era where progressive MS is treatable.
If you are a naysayer, can I suggest you take off your blinkers, buy a pair of rose-tinted spectacles and smell the roses? Our compassionate use of off-label cladribine has allowed us to collect enough observational data to make the case for doing a trial of cladribine in more advanced MS. We would not have been able to get this point without OLP. For this, we would like to thank our patients and some of our colleagues for their ongoing support and to put DrK on a pedestal for his perseverance and resilience.
We won’t let the critics silence us and distract us from the job at hand; preventing MS (#PreventMS), treating MS early and effectively (#AttackMS, #ThinkCognition) and treating MS in the more advanced stages (#Proximus, #ThinkHand, #Over&Under, #ChariotMS, #OratorioHand, #SalvageMS).
As I write this post I wonder what our colleagues are going to say about our strategy of targeting the intrathecal plasma cell response with an add-on off-label therapy that is currently licensed to treat myeloma (#SIZOMUS)? I suspect the same naysayers will continue to advise their patients to stay away from our centre. At Barts-MS we are proud to practice experimental medicine. Without brave and bold scientists & clinicians and their patients, who are prepared to volunteer for clinical trials using off-label therapies, the innovation cycle, at least in the UK, will grind to halt.
Disclaimer: Please note that off-label prescribing is not a substitute for on-label prescribing unless it is the only way for people living with MS to access DMTs in resource-poor environments.
Jacobs et al. Intrathecal interferon reduces exacerbations of multiple sclerosis. Science. 1981 Nov 27;214(4524):1026-8. Ten patients with multiple sclerosis who were treated with human fibroblast interferon (IFN-B) for 6 months showed a significant reduction in their exacerbation rates compared with their rates before treatment (P < .01). The IFN-B was administered intrathecally by serial lumbar punctures. There was no significant change in the exacerbation rates of ten multiple sclerosis control patients before and during the period of observation. The IFN-B recipients have now been on the study a mean of 1.5 years, the controls, 1.2 years. The clinical condition of five of the IFN-B recipients and one of the control patients has improved, whereas the condition of five of the controls and one of the IFN-B recipients has deteriorated (P < .036). These findings warrant cautious optimism about the efficacy of intrathecal IFN-B in altering the course of multiple sclerosis and support concepts of a viral or dysimmune etiology of the disease.
Mauch et al. Treatment of multiple sclerosis with mitoxantrone. Eur Arch Psychiatry Clin Neurosci. 1992;242(2-3):96-102. Ten multiple sclerosis patients, all with a rapid deteriorating disease profile, were treated with 12 mg/m2 of the cytostatic agent mitoxantrone, administered every 3 months. This dosage is only 25% of what a patient with a solid tumour would normally receive during the same time period. In all treated patients the deterioration was stopped following the initial dosage; in four out of ten patients there was even an immediate improvement of the neurological status. Eight out of nine patients showed an improvement after 1 year as compared with their enrollment status; the other one remained stabile. In correlation with the clinical improvement, the mean P100 latencies of visual evoked potentials showed a reduction after 1 year. However, the changes identified through magnetic resonance imaging were even clearer than those seen clinically. At admission, this group of patients presented with a total of 169 gadolinium (Gd)-enhancing lesions. Only 10 lesions were enhancing in nine patients 12 months after the initiation of treatment. It appears that mitoxantrone accelerates the disappearance of Gd-enhancing lesions and prevents the development of new ones. Minimal side effects such as mild nausea and a slight faintness were evident in six patients and then for only 1-2 days.
Moreau et al. Preliminary evidence from magnetic resonance imaging for reduction in disease activity after lymphocyte depletion in multiple sclerosis. Lancet 1994 Jul 30;344(8918):298-301. The central nervous system lesions of multiple sclerosis (MS) can be detected by magnetic resonance imaging (MRI) and the initial perivascular inflammatory component is distinguished by the presence of gadolinium enhancement. To assess the effect of systemic lymphocyte depletion on disease activity, seven patients with MS received a 10-day intravenous course of the humanised monoclonal antibody CAMPATH-1H (anti-CDw52). With some variations in the protocol, enhanced cerebral MR images were obtained monthly for 3-4 months before and at least 6 months after treatment. 28 enhancing areas were detected on the first series of 7 scans; 51 additional active lesions were identified on 18 scans before treatment; 15 were detected on 20 scans done over the next 3 months, but only 2 active lesions were seen on 23 scans during follow-up beyond 3 months. The difference in lesion incidence rate before and after treatment varied and the rate ratio was significantly reduced in only three patients. Collectively, in a “meta-analysis”, the rate ratios were 0.15 [corrected] (95% CI 0.09-0.24) for all seven patients and 0.24 (0.14-0.42; p < 0.001) with exclusion of the patient whose scanning schedule differed. The effect of CAMPATH-1H on disease activity provides direct, but preliminary, evidence that disease activity in MS depends on the availability of circulating lymphocytes and can be prevented by lymphocyte depletion. It is too early to say anything about the clinical results of treatment with this agent.
Edwards et al. B-lymphocyte depletion therapy in rheumatoid arthritis and other autoimmune disorders. Biochem Soc Trans. 2002 Aug;30(4):824-8. B-lymphocyte depletion therapy is being explored in a wide range of autoimmune disorders. In many, there is early evidence for efficacy, and immunosuppression has not been a major problem. The mechanism of action is unclear but appears to be consistent with the lowering of autoantibody levels, where relevant antibodies are quantifiable. An interesting finding is the persistence of clinical improvement for periods of 1 year or more after B-lymphocyte return, which supports the concept that stochastic generation of rare pathogenic B-lymphocyte subsets may be a rate-limiting step in pathogenesis.
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.
What are the most important outstanding research questions for people with MS?
Depending on how long you have been following this blog you may or may not be aware of the COMBAT-MS study. This is a study that is funded by the US government as part of the Patient-Centered Outcomes Research Institute (PCORI).
COMBAT-MS is a US-Swedish initiative for a hybrid study between a traditional retrospective cohort and a structured prospective cohort study. COMBAT-MS (clinicaltrials.gov NCT03193866) aims to recruit up to 3,700 MS patients at all of Sweden´s seven university clinics (serving about 50% of the total population) who are starting their first MS therapy or switching therapies. By doing the same structured follow-up with annual disability scorings, MRIs and patient-reported QoL outcomes the COMBAT-MS study will generate high quality, real-world long-term efficacy outcomes. This will help the MS community sort out which drugs work or don’t work in a real-world setting. To address safety concerns, COMBAT-MS will obtain data from Swedish national healthcare registries, as well as from Kaiser Permanente Southern California. By combining these resources, COMBAT-MS will be able to address major risks, such as cancer, as well as transient treatable concerns like recurring bladder infections and bothersome skin rashes. So, which of the approved MS drugs will be the winner?
I will be attending the annual COMBAT-MS stakeholder meeting for an update this week and have been asked to give a talk on ‘Identifying and addressing research questions of high importance to patients’. I could simply use the MS Society’s James Lind Alliance Top 10 list (below) or ask you the Barts-MS Blog readers to add to, or critique, this list for my talk this Thursday. Please note that this list below was published in 2013 and what was a priority then may not be a priority today.
The following is this week’s programme; any comments to help me prepare my talk would be much appreciated. I was invited onto this trial as a stakeholder because I am considered a patient advocate and for my role in formulating and promoting an ‘Essential Off-label DMT‘ list. To fulfil my role as a patient advocate I need your help. Thank you.
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.
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.
