Category: Lab Lessons

the HYPE study

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.

Derfuss et al. Serum Immunoglobulin Levels and Risk of Serious Infections in the Pivotal Phase III Trials of Ocrelizumab in Multiple Sclerosis and Their Open-Label Extensions. ECTRIMS 2019, 

CoI: multiple

Who said anti-CD20 therapies were safe?

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?

Gustavo et al. Infection Risks Among Patients With Multiple Sclerosis Treated With Fingolimod, Natalizumab, Rituximab, and Injectable Therapies. JAMA Neurol. Published online October 7, 2019. doi:10.1001/jamaneurol.2019.3365

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.

Derfuss et al. Serum Immunoglobulin Levels and Risk of Serious Infections in the
Pivotal Phase III Trials of Ocrelizumab in Multiple Sclerosis and Their Open-Label Extensions. ECTRIMS 2019,

MD Here I add this to the bottom of ProfGs post

Evaluating the efficacy and safety of ZytuxTM (Rituximab, AryoGen pharmed) in Iranian multiple sclerosis patients: An observational study. Naser Moghadasi A, Darki A, Masoumi P, Hashemi SN, Ghadiri F. Mult Scler Relat Disord. 2019 Sep 27;36:101419

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

CoI: multiple

A smoking gun?

The big hole in the EBV hypothesis of MS is how does the virus cause the disease at a molecular and immunological level. There are as many theories as thinkers. 

One theory is that EBV infects the CNS and MS is caused by an immune response to the virus in the brain of MSers. MS is then due to bystander damage of the immune cells finding and attacking the EBV infected cells. The evidence that EBV infects the brain is strengthening but is not an accepted fact.  In fact, it remains very controversial.

In the paper below from Francesca Aloisi’s laboratory, it shows that a large number of CD8 T-cells in the brains of MSers are EBV-specific targeting EBV proteins from both the latent and lytic phase of the EBV life-cycle. This is potentially a very important paper but needs to be reproduced. 

The big hole in the EBV-infected brain and CD8+ T-cell hypothesis is why do patients do so well on natalizumab and why does anti-CD20 therapy prevent rebound post-natalizumab? 

If the brain was infected with EBV and you blocked immune surveillance using natalizumab surely you could expect some ill-effects? We don’t see this happening clinically. In fact, we see the opposite; MSers on natalizumab have NEDA, a lot of them see an improvement in disability, they ‘normalise’ brain volume loss, they see a reversal of fatigue and/or sickness behaviour, etc. Surely natalizumab is the one experiment that argues against a direct CNS infection as being the cause of MS? Maybe not. Natalizumab may not stop smouldering MS which is the true disease and this may take many decades to manifest itself.

If MS is due to EBV-specific CD8+ cytotoxic T-lymphocytes attacking the brain of MSers, why does rituximab a drug that takes out predominantly B-cells and not CD8+ cells prevent rebound post-natalizumab? Some have argued that the B-cells are needed to travel to the brain to present antigen to the CD8+ T-cells. I don’t by this there are other professional antigen-presenting cells in the brains of MSers that can do this job. Others quote the new evidence that T-cells need help from B-cells to cross the blood-brain barrier. This does not explain why some of the carry-over PML cases from natalizumab to rituximab (or ocrelizumab) have developed IRIS (immune reconstitution inflammatory syndrome).  In the latter cases IRIS causing T-cells are trafficking to the brain in the absence of circulating B-cells.

So this paper generates more questions than it answers. It does demonstrate that we need to really find-out if EBV is driving MS from within the CNS or from its effects on the immune system in the periphery. These two scenarios require different treatment approaches. However, this should not stop us from exploring both approaches, often it is the experiment that disproves the hypothesis.

It looks as if October 2019 is going to be the month of EBV and MS. 

Serafini et al. Epstein-Barr virus-specific CD8 T cells selectively infiltrate the multiple sclerosis brain and interact locally with virus-infected cells: a clue for a virus-driven immunopathological mechanism. J Virol 2019 (accepted manuscript) DOI: 10.1128/JVI.00980-19

ABSTRACT: Epstein-Barr virus (EBV) is a ubiquitous herpesvirus strongly associated with multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS). Yet, the mechanisms linking EBV infection to MS pathology are uncertain. Neuropathological and immunological studies suggest that a persistent EBV infection in the CNS could stimulate a CD8 T-cell response aimed at clearing the virus but inadvertently causing CNS injury. Inasmuch as in situ demonstration of EBV-specific CD8 T cells and their effector function is missing, we searched for EBV-specific CD8 T cells in MS brain tissue using the pentamer technique.

Postmortem brain samples from 12 donors with progressive MS and known HLA class I genotype were analyzed. Brain sections were stained with HLA-matched pentamers coupled with immunogenic peptides from EBV-encoded proteins, control virus (cytomegalovirus, influenza A virus) proteins and myelin basic protein. CD8 T cells recognizing proteins expressed in the latent and lytic phases of the EBV life cycle were visualized in white matter lesions and/or meninges of 11/12 MS donors. The fraction (median value) of CD8 T cells recognizing individual EBV epitopes ranged from 0.5 to 2.5% of CNS-infiltrating CD8 T cells. Cytomegalovirus-specific CD8 T cells were detected at a lower frequency (≤0.3%) in brain sections from 4/12 MS donors. CNS-infiltrating EBV-specific CD8 T cells were CD107a-positive, suggesting a cytotoxic phenotype, and stuck to EBV infected cells.

Together with local EBV dysregulation, selective enrichment of EBV-specific CD8 T cells in the MS brain supports the notion that skewed immune responses toward EBV may contribute to inflammation causing CNS injury.

IMPORTANCE: EBV establishes a lifelong and asymptomatic infection in most individuals and more rarely causes infectious mononucleosis and malignancies, like lymphomas. The virus is also strongly associated with MS, a chronic neuroinflammatory disease with unknown etiology. Infectious mononucleosis increases the risk of developing MS and immune reactivity toward EBV is higher in persons with MS indicating inadequate control of the virus. Previous studies have suggested that persistent EBV infection in the CNS might stimulate an immunopathological response causing bystander neural cell damage. To verify this, we need to identify the immune “culprits” responsible for the detrimental antiviral response in the CNS. In this study, we analyzed postmortem brains donated by persons with MS and show that CD8 cytotoxic T cells recognizing EBV enter the brain and interact locally with the virus infected cells. This antiviral CD8 T cell-mediated immune response likely contributes to MS pathology.

CoI: multiple

Menopause

Is it MS or the menopause?

“I am a woman with MS and have started going through the menopause. My last menstrual period was four months ago and have frequent hot flushes. All of a sudden my MS seems to have worsened. I am more fatigued, my sleep is disrupted, my bladder problems are worse, my mood is all over the place and my walking has deteriorated. Is this my MS or is simply the menopause? “

In my experience, the menopause seems to change things for women with MS. There is little doubt that in healthy women the menopause is associated with a well-defined syndrome or constellation of symptoms. Some women cope very well with the menopause and others don’t. There are several symptomatic treatments that can be prescribed to deal with specific menopausal symptoms or you can take hormone replacement therapy (HRT), which really delays the menopause as it replaces the hormones your ovaries make as they fail. 

Recently there has been a backlash against HRT by the medical community when HRT was shown to increase your chances of developing breast cancer and your chances of having a heart attack or stroke by a similar amount. However, these risks need to be put in the context of the benefits of HRT and the fact that both breast cancer and cardiovascular risks can be derisked with screening. 

It was therefore very reassuring when a very large and definitive meta-analysis showed that the all-cause mortality was not increased by HRT (see below). In other words, the benefits and risks of HRT in terms of life expectancy or survival balance each other off. Based on this I think HRT is safe provided you participate in the national breast cancer and cardiovascular screening programmes.

It is important to realise that the type of breast cancers that occur as a result of HRT is usually hormone-responsive and hence have a better prognosis. In terms of the cardiovascular risks associated with HRT, your GP should make sure these are managed, i.e. if you are a smoker you need to stop smoking or at least go onto safer nicotine replacement therapies, you need to make sure your blood pressure and cholesterol levels are checked and if appropriate screened for diabetes. Your GP will also weigh you and ask about your activity levels and family history. Most UK GPs will plug all this information into one of the online cardiovascular risk calculators to see if you need treatment with a statin. 

All this of the above should happen anyway regardless of whether or not you have MS. What about if you have MS? 

Is the menopause different in women who have MS? 

In my experience, the menopause is likely to cause more problems in MSers because of reduced brain reserve and the presence of many MS-related comorbidities. I suspect a lot of the problems the MSers describes above are due to the menopause interacting with MS, that is both together. 

We now know from several studies that menopause affects the natural history of MS. The menopause seems to be a turning point; the replace rate goes down after the menopause and you are more likely to have worsening disability. One could argue that this could simply be due to ageing rather than the menopause. However, there is compelling data that HRT is anti-ageing and many animal studies showing that oestrogens are neuroprotective. 

HRT in menopausal women reverses many of the symptoms and signs of the menopause, i.e. weight gain, hot flushes, depression, insomnia, dry vagina, hair and skin thinning, loss of breast tissue, urinary symptoms and reduced libido. HRT is anti-ageing when it comes to the skin, brain, reproductive system (vagina and breast) and bone health. The latter is very important for women with MS;  MSers tend to have more fragile bones (osteopaenia) and are more likely to fall and suffer fractures. Therefore anything that improves bone health should help MSers overall.  

So when it comes to advising my patients with MS about HRT it is a no-brainer. If you have MS and are menopausal the arguments for starting HRT are quite compelling. However, like everything else in medicine is should be about choice and informed consent. What I am finding is that many GP’s are reluctant to prescribe and monitor HRT in my patients because of the ‘hassle factor’. It is easier for them not to prescribe HRT. I deplore this behaviour; in my opinion, every woman living in the UK who is menopausal should have the right to go onto HRT and at the same time they should have the right to say no thanks I want to age naturally, but they need to be given the choice. So don’t take no for an answer and challenge your GP if they refuse to consider you for HRT. 

In my practice, I also see a lot of women using natural HRT products independent of their GPs. Many of these products contain natural oestrogens and hence are working via the same mechanism as HRT. If you go this ‘natural’ HRT route you still need to make sure you enrol in the national screening programmes for cardiovascular disease and breast cancer. 

I suspect this post will generate a lot of questions and discussion. The three papers below are at least some food for thought.

#1 – Menopause and MS

Baroncini et al. Impact of natural menopause on multiple sclerosis: a multicentre study. J Neurol Neurosurg Psychiatry. 2019 Jun 12. pii: jnnp-2019-320587.

Objective: To study the effect of natural menopause on multiple sclerosis clinical course.

Methods: This was an observational, retrospective, multicentre, cohort study. Menopause onset was defined by the final menstrual period (FMP) beyond which no menses occurred for 12 months. We included multiple sclerosis (MS) patients with FMP occurred after 2005 and a recorded follow-up of at least 2 years pre-FMP and post-FMP. We excluded patients with primary progressive course, iatrogenic menopause and with other confounders that could mask menopause onset. We compared relapse-rate and expanded disability status scale (EDSS) scores pre-FMP and post-FMP, searching for possible interactions with age, disease duration, cigarette smoking and nulliparity status.

Results: 148 patients were included (mean observation: 3.5 years pre-FMP and post-FMP). Most patients (92%) received disease-modifying therapies, mainly first-lines. After menopause the annualised relapse rate (ARR) significantly decreased (from 0.21±0.31 to 0.13± 0.24; p=0.005), while disability worsened (increase of mean 0.4 vs 0.2 points after menopause; p<0.001). Older age and long-lasting disease were associated with ARR reduction (p=0.013), but not with disability worsening. Cigarette smokers showed a trend to a higher disability accumulation after menopause (p=0.059).

Conclusion: Natural menopause seems to be a turning point to a more progressive phase of MS. Relapse rate is also reduced after menopause, but this effect could be driven most by ageing and shifting to progressive phase in patients with long-lasting disease. Cigarette smoking could speed up disability progression after menopause.

#2 – HRT and mortality

Manson et al. Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women’s Health Initiative Randomized Trials. JAMA. 2017 Sep 12;318(10):927-938.

IMPORTANCE: Health outcomes from the Women’s Health Initiative Estrogen Plus Progestin and Estrogen-Alone Trials have been reported, but previous publications have generally not focused on all-cause and cause-specific mortality.

OBJECTIVE: To examine total and cause-specific cumulative mortality, including during the intervention and extended postintervention follow-up, of the 2 Women’s Health Initiative hormone therapy trials.

DESIGN, SETTING, AND PARTICIPANTS: Observational follow-up of US multiethnic postmenopausal women aged 50 to 79 years enrolled in 2 randomized clinical trials between 1993 and 1998 and followed up through December 31, 2014.

INTERVENTIONS: Conjugated equine estrogens (CEE, 0.625 mg/d) plus medroxyprogesterone acetate (MPA, 2.5 mg/d) (n = 8506) vs placebo (n = 8102) for 5.6 years (median) or CEE alone (n = 5310) vs placebo (n = 5429) for 7.2 years (median).

MAIN OUTCOMES AND MEASURES: All-cause mortality (primary outcome) and cause-specific mortality (cardiovascular disease mortality, cancer mortality, and other major causes of mortality) in the 2 trials pooled and in each trial individually, with prespecified analyses by 10-year age group based on age at time of randomization.

RESULTS: Among 27 347 women who were randomized (baseline mean [SD] age, 63.4 [7.2] years; 80.6% white), mortality follow-up was available for more than 98%. During the cumulative 18-year follow-up, 7489 deaths occurred (1088 deaths during the intervention phase and 6401 deaths during postintervention follow-up). All-cause mortality was 27.1% in the hormone therapy group vs 27.6% in the placebo group (hazard ratio [HR], 0.99 [95% CI, 0.94-1.03]) in the overall pooled cohort; with CEE plus MPA, the HR was 1.02 (95% CI, 0.96-1.08); and with CEE alone, the HR was 0.94 (95% CI, 0.88-1.01). In the pooled cohort for cardiovascular mortality, the HR was 1.00 (95% CI, 0.92-1.08 [8.9 % with hormone therapy vs 9.0% with placebo]); for total cancer mortality, the HR was 1.03 (95% CI, 0.95-1.12 [8.2 % with hormone therapy vs 8.0% with placebo]); and for other causes, the HR was 0.95 (95% CI, 0.88-1.02 [10.0% with hormone therapy vs 10.7% with placebo]), and results did not differ significantly between trials. When examined by 10-year age groups comparing younger women (aged 50-59 years) to older women (aged 70-79 years) in the pooled cohort, the ratio of nominal HRs for all-cause mortality was 0.61 (95% CI, 0.43-0.87) during the intervention phase and the ratio was 0.87 (95% CI, 0.76-1.00) during cumulative 18-year follow-up, without significant heterogeneity between trials.

CONCLUSIONS AND RELEVANCE: Among postmenopausal women, hormone therapy with CEE plus MPA for a median of 5.6 years or with CEE alone for a median of 7.2 years was not associated with risk of all-cause, cardiovascular, or cancer mortality during a cumulative follow-up of 18 years.

#3 – HRT and breast cancer

Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological. Lancet August 29, 2019. DOI:https://doi.org/10.1016/S0140-6736(19)31709-X

Background: Published findings on breast cancer risk associated with different types of menopausal hormone therapy (MHT) are inconsistent, with limited information on long-term effects. We bring together the epidemiological evidence, published and unpublished, on these associations, and review the relevant randomised evidence.

Methods: Principal analyses used individual participant data from all eligible prospective studies that had sought information on the type and timing of MHT use; the main analyses are of individuals with complete information on this. Studies were identified by searching many formal and informal sources regularly from Jan 1, 1992, to Jan 1, 2018. Current users were included up to 5 years (mean 1·4 years) after last-reported MHT use. Logistic regression yielded adjusted risk ratios (RRs) comparing particular groups of MHT users versus never users.

Findings: During prospective follow-up, 108 647 postmenopausal women developed breast cancer at mean age 65 years (SD 7); 55 575 (51%) had used MHT. Among women with complete information, mean MHT duration was 10 years (SD 6) in current users and 7 years (SD 6) in past users, and mean age was 50 years (SD 5) at menopause and 50 years (SD 6) at starting MHT. Every MHT type, except vaginal oestrogens, was associated with excess breast cancer risks, which increased steadily with duration of use and were greater for oestrogen-progestagen than oestrogen-only preparations. Among current users, these excess risks were definite even during years 1–4 (oestrogen-progestagen RR 1·60, 95% CI 1·52–1·69; oestrogen-only RR 1·17, 1·10–1·26), and were twice as great during years 5–14 (oestrogen-progestagen RR 2·08, 2·02–2·15; oestrogen-only RR 1·33, 1·28–1·37). The oestrogen-progestagen risks during years 5–14 were greater with daily than with less frequent progestagen use (RR 2·30, 2·21–2·40 vs 1·93, 1·84–2·01; heterogeneity p<0·0001). For a given preparation, the RRs during years 5–14 of current use were much greater for oestrogen-receptor-positive tumours than for oestrogen-receptor-negative tumours, were similar for women starting MHT at ages 40–44, 45–49, 50–54, and 55–59 years, and were attenuated by starting after age 60 years or by adiposity (with little risk from oestrogen-only MHT in women who were obese). After ceasing MHT, some excess risk persisted for more than 10 years; its magnitude depended on the duration of previous use, with little excess following less than 1 year of MHT use.

Interpretation: If these associations are largely causal, then for women of average weight in developed countries, 5 years of MHT, starting at age 50 years, would increase breast cancer incidence at ages 50–69 years by about one in every 50 users of oestrogen plus daily progestagen preparations; one in every 70 users of oestrogen plus intermittent progestagen preparations; and one in every 200 users of oestrogen-only preparations. The corresponding excesses from 10 years of MHT would be about twice as great.

CoI: multiple

The cause of MS

When I posted the link to our EBV and MS meta-analysis on social media yesterday I was taken to task because of the slow progress we have made in MS prevention. 

https://platform.twitter.com/widgets.js

Can I remind you that science moves steadily and slowly and the biggest problem we have is the slow adoption, or rejection, of innovations or new ideas. 

“The human mind treats a new idea the same way the body treats a strange protein; it rejects it.”
Peter Medawar, Nobel prize laureate, in Physiology or Medicine, 1960.

I was convinced by the evidence already back in 1999 that EBV was the likely cause of MS. I have been working on EBV ever since and the progress has been very slow. The main reason I left the Institute of Neurology (Queen Square) was to move to a multi-disciplinary institute, that would allow me space and time to work on EBV. However, it takes more than just moving to a new research environment to build momentum around a new research hypothesis. 

I have had more grant applications rejected around the viral hypothesis of MS than I care to count. It is very depressing. Despite this, we are pushing on slowly with our plans to create a trial-ready cohort of people at high risk of MS for exploratory MS prevention studies. Dr Ruth Dobson is doing quite an amazing job at getting this off the ground. We are also pushing forward with our ideas around treating MS with antivirals that target EBV. To say that the funding for doing these trials has been difficult is an understatement, but I am hoping if we can get pilot data we can convince the sceptics to fund definitive trials. 

We are also not the only team working on the EBV hypothesis of MS. Michael Pender in Brisbane, Australia, is doing great things and Atara Bio has taken up the baton in industry. I have recently posted on their preliminary results that were presented at ECTRIMS.

I spend most of my waking day doing MS and a large part of that is thinking about EBV and MS prevention. The main strand of MS prevention is an EBV vaccination study. The vaccine is not in our hands, but the capable hands of Jeff Cohen at the NIH, and hopefully a deep-pocketed Pharma company to commercialise it. Even if we get an effective EBV vaccine developed and launched we will still have to overcome the public resistance to vaccination and to convince public health officials that this is a worthy idea. 

The battles ahead are numerous, but we will get there in the end. We have to. We don’t want the next generation of MSers asking us why we haven’t done anything to prevent MS given the current state of knowledge.

EBV is almost certainly the cause of MS. What are we doing about it?  

Jacobs et al. Systematic review and meta-analysis of the association between Epstein-Barr virus, Multiple Sclerosis, and other risk factors. https://doi.org/10.1101/19007450

Background: EBV infection is thought to play a central role in the development of Multiple Sclerosis (MS). If causal, it represents a target for interventions to reduce MS risk. 

Objective: To examine the evidence for interaction between EBV and other risk factors, and explore mechanisms via which EBV infection may influence MS risk. 

Methods: Pubmed was searched using the terms multiple sclerosis AND Epstein Barr virus, multiple sclerosis AND EBV, clinically isolated syndrome AND Epstein Barr virus and clinically isolated syndrome AND EBV. All abstracts were reviewed for possible inclusion. 

Results: 262 full-text papers were reviewed. There was evidence of interaction on the additive scale between anti-EBV antibody titre and HLA genotype (AP 0.48, p<1×10-4; RERI 3.84, p<5×10-3; S 1.68, p=0.06). Previous IM was associated with increased OR of MS in HLA-DRB1*1501 positive but not HLA-DRB1*1501 negative persons. Smoking was associated with a greater risk of MS in those with high anti-EBV antibodies (OR 2.76) but not low anti-EBV antibodies (OR 1.16). No interaction between EBV and risk factors was found on a multiplicative scale. 

Conclusions: EBV appears to interact with at least some established MS risk factors. The mechanism via which EBV influences MS risk remains unknown.

CoI: multiple

Short- or long-sighted

I saw three patients 9-and-half-years after starting treatment with alemtuzumab as first-line therapy, yesterday. It was a remarkable experience. Only one of the three patients had needed a third cycle of alemtuzumab. All are in long-term remission; i.e. flat-lining on the EDSS, relapse-free and with no MRI activity (NEDA-3). Their EDSS scores yesterday were 1.0, 1.5 and 2.0. All of them are fully functional, with no physical and cognitive restrictions and described themselves as being well. One patient suggested to me she doesn’t have MS anymore. One patient has had ITP and recovered from it. All three patients have normally functioning immune systems with normal total lymphocyte counts. None of them is concerned about infections, travel, vaccinations or secondary malignancies. This is why treating MS with an immune reconstitution therapy, such as alemtuzumab, is so appealing.

I have a dream that this will be the new normal and all people with MS in future will have similar experiences. I sincerely hope the EMA allows people with MS to be treated and managed the same way as these three patients of mine have. I still have had no response from the EMA to my letter below. Maybe they don’t care?

Can anybody tell me from testing their vision if they are short- or long-sighted?

Open letter the EMA sent  on the 20th August 2019

European Medicines Agency
Amsterdam 

Dear Sir/Madam

Alemtuzumab has transformed the MS treatment landscape. It not only provides superior short term efficacy, but a significant number of patients treated with alemtuzumab note improvement in disability. However, its main advantage over other DMTs is that a large proportion of patients go into longterm remission and normalise the rate of their brain volume loss. In regard to the latter, this is unprecedented in comparison to other licensed MS disease-modifying therapies, with the possible exception of haemopoietic stem cell transplantation (HSCT), which is not licensed and hence not widely available to treat patients with MS in Europe.  Alemtuzumab, therefore, is the only realistic alternative to HSCT, which has become a very popular treatment choice amongst people with multiple sclerosis, in particular, ‘digital natives’ who get their information online. As with all DMTs the earlier you use them the more effective they are and the greater the benefit to the individual patient. Alemtuzumab is, therefore, an important treatment option for people with MS; being able to offer alemtuzumab early as a treatment option is an important factor in my clinical practice to dissuade many Britsih patients from travelling abroad for HSCT. 

At our centre, Barts Health NHS Trust, we have now treated over 250 patients with alemtuzumab with over 40% being treated with alemtuzumab first-line. Patients receiving alemtuzumab first-line tend to have more active disease and less favourable baseline prognostic profile. Despite its side effect profile and the need for monthly monitoring, many patients are willing to take on the risks and the burden of monitoring to be treated with the most effective licensed DMT first-line. All our patients are extensively counselled about the risks and benefits of alemtuzumab treatment and sign an informed consent and a patient contract agreeing to the mandatory monitoring programme. We feel the use of alemtuzumab in the correct environment is relatively safe and the adverse events manageable. Not having alemtuzumab for use in early active disease would mean patients having to wait to fail several other, less effective, licensed DMTs prior to accessing alemtuzumab. I firmly believe in the concept that ‘time is brain and spinal cord’ in MS and delaying access to the most effective treatment would limit our ability to optimise the management of MS in patients with more active disease and in those with a poor prognostic profile. In addition, shifting the use of alemtuzumab to a population of patients with more advanced disease would unfavourably change the benefit-risk profile of alemtuzumab and make it less appealing as a  treatment option. 

The real-life data of alemtuzumab clearly supports it as being the most effective DMT on the market and its other attributes in relation to its posology make it a very appealing therapy; for example in women wanting to start or extend their families.  

In summary, limiting alemtuzumab to a third-line, last resort DMT, will severely limit our treatment options for managing this devastating disease. Alemtuzumab offers many patients with MS a real hope of living as normal a life as possible, however, this option does depend on using alemtuzumab early in the course of the disease. I, therefore, appeal to the MS community and the European Medicine Agency to consider these factors when reviewing the benefits and risks of alemtuzumab as a treatment for MS. 

Yours faithfully 

GAVIN GIOVANNONI

CoI: multiple

OVO Study

Finally, after a week or more of thinking and contemplation my opinion about the ofatumumab vs. teriflunomide trial data (ASCLEPIOS I and II); another of my ECTRIMS highlights. 

The result of the ASCLEPIOS I and II are not unexpected and in line with the treatment effects of anti-CD20 therapies with some caveats. 

Novartis summary:

  • Both ASCLEPIOS I and II studies met their primary endpoints in patients with relapsing forms of MS (RMS); overall ofatumumab (OMB157), a subcutaneous, potent, fully-human antibody targeting CD20 positive B-cells, delivered efficacy with a favorable safety profile
     
  • RMS patients on ofatumumab had a reduction in annualized relapse rate (ARR) by 50.5%  (0.11 vs. 0.22) and 58.5% (0.10 vs. 0.25) compared to Aubagio®* (teriflunomide) (both studies p<0.001) in ASCLEPIOS I and II studies respectively
     
  • Ofatumumab showed highly significant suppression of gadolinium (Gd) T1 lesions when compared to Aubagio®, demonstrating a profound suppression of new inflammatory activity
     
  • Ofatumumab showed a relative risk reduction of 34.4% in 3-month confirmed disability progression (CDP†) (p=0.002) and 32.5% in 6-month CDP (p=0.012) versus Aubagio® in pre-specified pooled analyses
     
  • Ofatumumab, if approved, will potentially become a treatment for a broad RMS population and the first B-cell therapy

My interpretation:

Inflammation: relapse rate, focal MRI activity (Gd-enhancing & new T2 lesions) and neurofilament data.

I have made the point that these three markers measure focal inflammation, driven by adaptive immunity, and there is little doubt that ofatumumab is superior in suppressing inflammation compared to teriflunomide. Does this make ofatumumab superior to other very high efficacy DMTs, such as natalizumab, rituximab, ocrelizumab, alemtuzumab and HSCT? I suspect not. To prove this we would need head-2-head studies. I also think there are floor effects on these outcomes, i.e. you can only reduce relapse rates to around 0.1 to 0.2 and no lower. Why? I suspect some relapses are pseudo-relapses and are due to intermittent symptoms in relation to infections, fatigue and possibly hidden symptoms. 

Please note that I don’t consider peripheral blood neurofilament levels (pbNFL) to be a neurodegenerative marker in the context of MS. All the data I have seen to date indicates that it is linked to focal inflammatory activity. Clearly more needs to be done in progressive MS with pbNFL to understand what it means in inactive or smouldering MS. 

End-organ damage: disability progression and brain volume data

I was disappointed with how ofatumumab did against teriflunomide in delaying disability progression and reducing the relative loss of brain volume. This will be ofatumumab’s Achille’s heel. Why? It is clear that MS the disease is not focal inflammation; I have made the point that based on the Prentice criteria, both relapse and focal MRI activity don’t predict disability outcomes in natural history studies and placebo arms of clinical trials. If focal inflammation was MS then relapses and focal MRI activity would predict outcome whether or not you are on a DMT. The point I making here may be a philosophical one, but it a very important one. 

In comparison, sustained or confirmed disability progression has to be MS and is based on the pathological correlates that define MS (demyelination, neuroaxonal loss and gliosis). 

Why did ofatumumab do so poorly on these metrics relative to teriflunomide? It could be that teriflunomide is the outlier and this opinion is based on several observations. 

  1. Teriflunomide is the only DMT to have a consistent effect on disability progression; i.e. both teriflunomide phase 3 placebo-controlled trials were positive on this outcome. In addition, the treatment effect or impact of teriflunomide on disability progression has always been greater than what you would expect from its impact on relapses. For the tuned-on readers, you would have noticed the same disconnect between relapses and disease progression was observed in the ponesimod vs. teriflunomide trial. 
  2. Teriflunomide also has a significant effect on brain volume loss compared to placebo, which again is out of proportion to its impact on relapses (see picture below). 
  3. Teriflunomide is more effective when used 2nd and 3rd line. Teri is the only DMT to show the latter and this observation was seen in both phase 3 studies, which makes it likely to be a real, and a very important, finding. 
  4. Teriflunomide is a broad-spectrum antiviral agent, which may be part of its mode of action in MS. Could teriflunomide be targeting the viral cause of MS independent of its effects on the immune system’s response to that virus? This needs more study, but teriflunomide is the outlier, or exception, that disproves the dogma. 

Is ofatumumab being underdosed? 

Ofatumumab is being given at a dose of 20mg subcutaneously monthly. This dose was chosen to keep B-cells depleted, but not severely depleted, so as to allow rapid repopulation of peripheral B-cells numbers if ofatumumab is stopped. In other words, B-cell depletion is relatively mild compared to ocrelizumab 600mg every 6 months. With ocrelizumab, it takes 6 months or longer to start to see B-cell reconstitution. 

I don’t buy this argument. The repopulation kinetics with ofatumumab are based on relatively short-term dosing studies in which deep tissue and in bone marrow B-cell depletion is likely to be relatively modest. I suspect with long-term dosing with ofatumumab deep tissue and bone marrow B-cell depletion is more likely and hence the B-cell repopulation kinetics will mimic that of rituximab and ocrelizumab. 

I also think rapid B-cell repopulation is likely not to be relevant as the new B-cells will almost certainly be bone marrow-derived naive B-cells and not memory B-cells. 

The question I have is the 20mg per month of ofatumumab sufficient to penetrate the CNS and clear the intrathecal of CNS resident B-cell follicles? 

At the AAN this year Stephen Hauser presented data indicating that when it comes to disability progression, not relapse rate or MRI activity, the extent of exposure to ocrelizumab is very important.

The greater the ocrelizumab exposure the more effective it was at delaying disability progression. This could be related to deep tissue (peripheral) and end-organ (central) B-cell depletion. There is mounting evidence that the B-cells and plasma cells within the brain and spinal cord of MSers are driving some of the slow-burn we see clinically and on MRI (smouldering MS). What I am saying is that ocrelizumab could be superior to ofatumumab when it comes to scrubbing the brain clean of pathogenic B-cell follicles. Therefore it more important than ever to test this hypothesis in a head-2-head study of ocrelizumab vs. ofatumumab (OVO study) or  the DODO study comparing double-dose (1200 mg) vs standard-dose (600 mg) ocrelizumab (DODO study) to see if the higher dose of ocrelizumab has a bigger impact on the intrathecal B cell response than the standard dose. 

I would suggest these studies include next-generation MRI and other biomarkers to test the CNS penetration hypothesis. If these studies are positive, i.e. ocrelizumab is superior to ofatumumab and double-dose ocrelizumab is superior to single-dose ocrelizumab, it will not only tell us a lot about how anti-CD20 therapies work in MS, but it may answer the question of whether or not we need to target the intrathecal or CNS B-cell response in MS. The latter hypothesis is being tested by our group in two studies at present. We would love to add a third and fourth study to the portfolio. If you work for Novartis or Roche please tell the powers that we are really, really, interested in doing both the OVO and the DODO studies.

What about teriflunomide?

Don’t forget that the implications from the ponesimod vs. teriflunomide and ofatumumab vs. teriflunomide trials are quite profound. Teriflunomide is quite a remarkable DMT and we need to explore its antiviral effects in MS in more detail and understand what it is doing in MS independent of its rather weak anti-inflammatory effects. This is why I have proposed using teriflunomide as a maintenance therapy post-induction. In my ECTRIMS hot topic presentation, I called the trial the iTeri study (see slide show above). 

If you work for Genzyme-Sanofi please tell the powers that be that we are really, really, interested in an induction-maintenance trial with both teriflunomide (iTeri study) and a second with your BTK inhibitor (iBruT study).

CoI: multiple

Derisking anti-CD20 therapy

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.

  1. Systemic Pasteurella infection in a patient with RMS following a cat bite (resolved)
  2. Multisegmental herpes zoster infection in a patient with RMS, treated with intravenous (IV) acyclovir (resolved)
  3. Enterovirus-induced fulminant hepatitis in a diabetic patient with RMS, resulting in liver transplant
  4. Candida sepsis in a patient with PPMS who had stopped OCR treatment 11 months previously and was receiving cancer chemotherapy (resolved)
  5. Viral meningitis in a patient with RMS, cerebrospinal fluid positive for varicella-zoster, treated with IV acyclovir (resolved)
  6. 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. 

Image from Family Doctor

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. 

Tallantyre et al. Secondary Antibody Deficiency and infection following B-cell depletion for CNS neuroinflammation. ECTRIMS Online Library. Oct 25, 2017; 199742; EP1722

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.

CoI: multiple

Genius

My #ECTRIMS2019 highlight #3 is the elevation of fatigue to be the first secondary outcome measure in a clinical trial. Was this genius or a marketing coup? I would have loved to be a fly on the wall when the steering committee of the OPTIMUM study made the decision to bump fatigue to the top of the secondary outcomes.

If you have MS you know that the most troubling symptom the majority of MSers complain about is fatigue. Therefore for a DMT to be able to claim it reduces fatigue is a big deal. I suspect MSers will find the promise of fatigue reduction a very compelling reason to choose one DMT over another.

The Oral Ponesimod Versus Teriflunomide In Relapsing MUltiple Sclerosis (OPTIMUM) study was positive. Compared to teriflunomide ponesimod reduced the relative annualised relapse rate (ARR) by 30.5% (P<0.0003) and 3-month CDP (confirmed disability progression) by 17% (not significant).

If you recall this study was one of the studies we asked the Crowd to predict the results of. In fact, they were almost spot-on; they predicted that ponesimod would reduce the ARR and CDP compared to teriflunomide by 33.8% (interquartile range=24.5-44.3%) and 21.2% (interquartile range=10.0-25.0%), respectively. My interpretation is that the Crowd did very well; well done!

Please note that I will be contacting the winners of the #ECTRIMS competition very soon. There will two awards one for the OPTIMUM study and a second award for the ASCLEPIOS I & II studies.

When it comes to the S1P wars ponesimod is setting itself up very nicely to go head-2-head with newer entrants, i.e. siponimod and ozanimod. In my opinion, the safety profile of ponesimod is reasonably good, the lack of need for 1st-dose monitoring will put it alongside ozanimod in the S1P Me-Too wars. The question everyone is now asking ‘Will fatigue be the trump card?’. What do you think?

CoI: multiple

Real Life

After my #1 highlight #ECTRIMS2019 post, I was sent an email by Antoinio Scalafari, a like-minded colleague, to remind me of their real-life data at Imperial College on alemtuzumab in clinical practice. It mirrors the trial experience and needs a platform for discussion (see below).

In parallel, I heard via the MS grapevine that the MS community does not appreciate me questioning the ethics of the DELIVER-MS and TREAT-MS Trials. Why not? These are pragmatic trials to compare escalation therapy with the strategy of flipping the pyramid (high-efficacy therapy first-line).

Giovannoni. Do we have equipoise when it comes to how we treat active multiple sclerosis? Lancet Neurol. 2019 Jul 30. pii: S1474-4422(19)30227-3. doi: 10.1016/S1474-4422(19)30227-3.

Don’t I have a right to an opinion? I finish my commentary with a simple question for the trialists: ‘The real litmus test for the investigators of the DELIVER-MS and TREAT-MS trials is the question they should all ask themselves: “If I had multiple sclerosis, how would I want to be treated?” Given the evidence, patients deserve the choice of being treated with a high-efficacy DMT first-line’.

Why shouldn’t MSers with active MS not have the option of being treated with alemtuzumab, or for that matter HSCT?

CoI: multiple

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