Politics, campaigns and information – Page 6

Off-label methotrexate

Prior to interferon-beta being licensed, I used to manage several patients under Prof. W. Ian McDonald who were insistent on being on treated with some form of DMT. The rationale was better to be on something rather than nothing. At the time there was some evidence that methotrexate was effective in MS and as it was relatively safe, so Prof. McDonald acquiesced. In retrospect, I have no idea if these patients responded or not as we didn’t monitor them clinically nor with MRI. How things have changed since then.

As you may be aware there is class 1 evidence that methotrexate works in RA and some evidence that it works in MS as well (see below). I suspect it works rather well and in an era of treat-2-target of NEDA (no evident disease activity) it would seem reasonable in resource-poor settings to try oral methotrexate and if there was breakthrough disease to switch to another agent.

T2T-NEDA changes the dynamic of how we use DMTs; instead of leaving someone on a suboptimal or ineffective therapy we move onto something else. However, T2T-NEDA does mean that resources need to be found to do annual MRI studies or potentially peripheral blood neurofilament levels to monitor for treatment response. This I suspect will be a problem in resource-poor countries, but even then clinicians could fall back onto clinical monitoring, which is better than nothing.

What I am saying is yes, if I was working in a healthcare system with limited access to licensed high-cost therapies I would consider low dose oral methotrexate appropriate as one of the off-label first-line DMTs in active relapsing MS. This is why low dose oral methotrexate is on the Barts-MS essential off-label DMT list for treating MS.

Interestingly, several US neurologists are still using low-dose oral methotrexate for patients in their care who don’t have medical insurance coverage. It is quite interesting to note that we all want to do the best for our patients and adapt our prescribing behaviour to achieve this aim.

This is why when a neurologist in Venezuela recently asked me for advice about how to manage one of her patients with active MS we settled on low-dose methotrexate; in reality, it was the only immunosuppressive or immunomodulator available to her. There was no supply of azathioprine, leflunomide or parenteral cladribine the other 1st-line DMTs on our essential off-label DMT list.

I don’t expect methotrexate to be highly effective, but probably it will fit in the moderate efficacy zone. The important thing is that works in some patients without causing catastrophic health expenditure or ruinous poverty.

Please note the low-dose methotrexate trial in chronic progressive MS (SPMS & PPMS) is the one study that we use as an example to support our length-dependent axonopathy study. Approximately two-thirds of the subjects in this trial had already lost most of their lower limb function (EDSS 6.0 or 6.5), which is why the trial was positive in the upper limbs, but not the lower limbs.

What is needed is for an MS champion to do a trial of low-dose methotrexate vs. an active comparator or to simply collect real-world data on the number of subjects rendered NEDA on the drug. The investigators should also include regular blood sampling to measure peripheral blood neurofilament levels. In fact, we may be able to use an area-under-the-curve analysis of peripheral blood NFL levels to see how effective methotrexate and other off-label DMTs are in the real world.

If you are interested in using methotrexate or other off-label DMTs in resource-poor settings please sign-up to our Grass Roots Off-Label DMT Initiative (GROLDI).

Goodkin et al. Low-dose (7.5 mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis. Ann Neurol. 1995 Jan;37(1):30-40.

Objectives: A randomized, double-blinded, placebo-controlled, clinical trial of low-dose, weekly, oral methotrexate was performed in 60 patients with clinically definite chronic progressive multiple sclerosis (MS) attending a referral-based outpatient MS clinic.

Methods: Study patients were 21 to 60 years old with a disease duration of longer than 1 year. Patients’ Expanded Disability Status Scale scores were 3.0 to 6.5 (ambulatory with moderate disability). Patients were first stratified by Expanded Disability Status Scale scores, 3.0 to 5.5 and 6.0 to 6.5, and then were randomized to receive methotrexate or placebo treatment. Treatment consisted of weekly, oral, low-dose (7.5 mg) methotrexate or identical placebo for 2 years, followed by observation for as long as 1 year. A composite outcome measurement instrument was used and consisted of (1) Expanded Disability Status Scale, (2) ambulation index, (3) Box and Block Test, and (4) 9-Hole Peg Test. Failure of therapy was indicated by a designated change that was sustained for more than 2 months in one or more components of this composite measure.

Results: Significantly less progression of impairment as measured by validated tests of upper-extremity function was observed in the methotrexate treatment group in the absence of clinically significant toxicity.

Conclusion: We conclude that low-dose, weekly, oral methotrexate offers a new, relatively nontoxic treatment option for patients with chronic progressive MS.

Goodkin et al. Low-dose oral methotrexate in chronic progressive multiple sclerosis: analyses of serial MRIs. Neurology. 1996 Nov;47(5):1153-7.

Background: Methotrexate is a platform therapy for managing patients with rheumatoid arthritis. There is anecdotal evidence that it may work in MS.

Methods: We monitored 56 patients with chronic progressive multiple sclerosis (MS) who participated in a clinical trial of weekly, low-dose oral methotrexate with annual gadolinium-enhanced MRIs of the brain (Gd + MRI). Not of these patients had clinical exacerbations during the 8 months preceding study entry. We also monitored 35 of the patients with serial Gd + MRIs every 6 weeks for 6 months.

Results: We observed a treatment effect, measured by absolute change in T2-weighted total lesion area (T2W-TLA), in the cohort that completed 6-week scans. We found change in T2W-TLA in this cohort to be significantly related to sustained change in performance on the nine-hold peg test but not to sustained change on the Expanded Disability Status Scale. Gadolinium enhancement of lesions on 6-week and annual scans was uncommon. Prestudy exacerbation frequency appears to be an important consideration in designing future clinical trials in patients with secondary and primary progressive MS.

Currier et al. Low dose oral methotrexate treatment of multiple sclerosis: a pilot study. J Neurol Neurosurg Psychiatry. 1993 Nov;56(11):1217-8.

An 18-month double-blind treatment of multiple sclerosis with low dose oral methotrexate showed it to be well tolerated and suggested effectiveness in exacerbating-remitting MS but not in the exacerbating progressive and chronic progressive stages.

CoI: multiple

Politician G

If I was a politician I would change the way drug regulation works to stimulate repurposing of off-label and unlicensed drugs.

The wider MS community thinks off-label prescribing is accepting second-best. This is not the case. The fact that a drug has a license or a label for a certain indication is because a pharmaceutical company has submitted an application to one of the regulatory authorities and has been given a marketing authorisation. The marketing authorisation allows the pharmaceutical company to advertise and promote the drug in question for a particular indication.

Getting a marketing authorisation is not a simple task; it requires a substantial investment in generating the necessary data, analysing it and submitting it in a form the regulatory authorities require. In fact, regulatory submissions are now so complex that a third-party consulting industry has emerged to help the pharmaceutical industry to do their submissions.

Once a marketing authorisation has been granted it often comes with several post-marketing commitments, in particular, a requirement to collect data on safety in the so-called post-marketing environment. There is no way a pharmaceutical company is going to take on a new drug application and the post-marketing obligations unless the financial incentives are there to do it. I was once told by a senior pharmaceutical representative to cover the regulatory costs and post-marketing commitments for an MS-related DMT, global sales would have to be greater than $150M just to break even. Therein lies the problem!

The upshot of this is that for drugs that are off-patent, have a patent life that is too short for a return on investment or are unlicensed (never been submitted for a license before) there are simply no incentives to license them. These drugs could theoretically be more effective than licensed drugs for a particular disease indication, but without head-2-head studies we can’t tell. A good example of this is the off-label use of rituximab in neuromyelitis optica; it may be good as, or better than, the three new players in the field (eculizumab, satralizumab or inebilizumab) but we may never know.

Another issue is that the regulatory authorities be it the MHRA in the UK, EMA in Europe or the FDA in the US, rely on the pharmaceutical companies for their funding; i.e. by pharma submitting licensing applications or requesting advice (consulting activities) they pay fees, which are used to run the show. This creates a perverse symbiotic relationship between the pharmaceutical industry and the regulatory authorities and explains why these parties work together to actively discourage off-label prescribing.

Off-label prescribing undermines both the activities and survival of the regulatory agencies (turkeys’ don’t vote for Christmas) and challenges the current and very lucrative pharmaceutical business model.

In an ideal world, the regulatory authorities should be funded by the government and be independent of pharmaceutical funding. Regulatory authorities could then be tasked with policing and regulating off-label prescribing; i.e. they could be asked to review the evidence in favour of these drugs and grant these drugs the equivalent of marketing authorisation to support their wider use.

For example, I would envisage the MS community submitting a request to the EMA to review the evidence that rituximab a potential DMT for treating relapsing forms of MS. The EMA would then review the evidence and make a decision whether or not to extend the license of rituximab to cover MS. This would be independent of any pharmaceutical company. I would even envisage the regulators having the power to give a provisional approval with guidance on what data gaps need to be filled for full approval. This would then allow funding agencies and/or healthcare organisations to put out specific calls to the MS community to do the necessary trials to address the regulatory requirements. This would stimulate a robust development path for ‘neglected’ or ‘forgotten’ drugs independent of the pharmaceutical industry.

Even more radical idea would be to create a division within the regulatory authorities to actually review and address unmet medical problems, which off-patent and unlicensed drugs may address, i.e. for the regulators to actually administer grant funds to do drug-repurposing trials. The latter may even be linked to new legislation to tempt pharmaceutical companies to apply for these funds.

Governments could enact legislation to grant unique marketing authorisations for repurposed drugs, similar to the orphan drug act. In a modern economy, it would be relatively easy to police a system where two products of the same drug could be marketed to make sure that a specific product is being prescribed and used for the repurposed indication, but at different prices. In fact, this happened with pregabalin in the UK. The anticonvulsant patent for pregabalin expired earlier than its patent for pain. Pfizer made sure that the NHS prescriptions for pain were of the more expensive branded formulation Lyrica, and not the cheaper generic formulations. The motivation for policing indication-based pricing would be to incentivise the pharmaceutical industry to repurpose off-patent drugs. In other words, they would get their return on investment.

I think the economists, and possibly the pharmaceutical industry, would like the latter solution to the drug repurposing conundrum because it involves a market solution. Repurposing legislation of this type would open up the possibility of doing innovative combination therapy studies using off-patent medication. The latter is urgently needed in the MS space to address add-on neuroprotection trials.

With Brexit looming and the UK about to leave the EMA, I don’t envisage this sort of solution happening anytime soon. Like the orphan drug act, drug repurposing legislation would need to be done at scale, i.e. at an EU level and not a UK level. At the end of the day, the UK market is simply too small with not enough profit margins to make it worthwhile for Pharma to invest the required amount of money to ensure an adequate return on their investment for repurposing a off-patent drug.

We can daydream and come up with many potential political solutions for the off-label repurposing issue, but this is not going to help MSers living in resource-poor settings access DMTs anytime soon. So I would please urge you to act local and to help us start our Grass Roots Off-Label DMT Initiative (GROLDI, please sign-up to help) and to remind you of our subcutaneous cladribine protocol, which you can download. There is no reason why we can’t treat MS early and effectively in resource-poor environments.

Barts-MS Essential Off-Label DMT List

*on the 19th WHO Model List of Essential Medicines (April 2015)

CoI: multiple

Catastrophe

Have you heard the term catastrophic health expenditure or CHE before? You should have as many MSers and their families are exposed to catastrophic health expenditure.

CHE occurs when the spending on health exceeds a pre-defined percentage of a person’s or household’s capacity to pay. CHE has a massive impact on MSers’ lives and usually discourages them from using healthcare services and often leads to a reduction in the use of other essential goods and services. In summary, CHE exposes families of MSers to poverty and economic ruin.

In 2014 when I was visiting India on my sabbatical I remember meeting a relatively well-off woman with MS who was having to buy her weekly Avonex (interferon-beta-1a) injection one syringe at a time. She told me that if she couldn’t raise the money from family and friends she would simply miss that week’s injections. Her neurologist told me that she was from quite a wealthy middle-class family and that her MS had devastated their finances. Does this story sound familiar?

If you live in the UK or another country with a socialist healthcare system you are generally protected from CHE by having free access to healthcare and social safety net in the form of unemployment and/or disability benefits. However, if you live in a country with a healthcare system that is based on a fee-for-service private model with substantial out-of-pocket payments it is easy to see how MS can cause CHE.

Iran is a country with substantial out-of-pocket payments for health system financing. The study below shows that about 1 in 25 families with someone with MS encounter catastrophic healthcare costs. Importantly, the brand of DMT, housing, income and health insurance were significantly correlated with catastrophic expenditure. This is one of our motivations for forming a Grass Roots Off-Label DMT Initiative (GROLDI), which promises to lower the costs of treating MS in countries such as Iran by addressing the unacceptable costs of innovator DMTs in countries such as Iran. Iran is not even a good example as the government has at least allowed biosimilars and generics to emerge to try and lower prices of the so-called ‘innovator DMTs’.

Not surprisingly there is a literature of CHE in many low- and middle-income countries, for example, Brazil. Kenya, China, Nepal, Korea and India. But it is also a growing problem in countries such as the USA in the medically uninsured. Over 60% of personal bankruptcies in the USA are triggered by health crises. I sincerely hope you will agree that CHE is another reason why we need to move off-label DMTs up the political agenda and to push-back on Pharma’s influence to prevent off-label prescribing.

I am prepared to bet that if we studied the economic impact of MS worldwide we would find that MS is a common cause of CHE. Is anyone prepared to take on this challenge? How common is CHE in your country and how often is it triggered by someone in the family being diagnosed with MS?

Juyani et al. Multiple Sclerosis and Catastrophic Health Expenditure in Iran. Glob J Health Sci. 2016 Sep 1;8(9):53778.

BACKGROUND: There are many disabling medical conditions which can result in catastrophic health expenditure. Multiple Sclerosis is one of the most costly medical conditions through the world which encounter families to the catastrophic health expenditures. This study aims to investigate on what extent Multiple sclerosis patients face catastrophic costs.

METHOD: This study was carried out in Ahvaz, Iran (2014). The study population included households that at least one of their members suffers from MS. To analyze data, Logit regression model was employed by using the default software STATA12.

RESULTS: 3.37% of families were encountered with catastrophic costs. Important variables including brand of drug, housing, income and health insurance were significantly correlated with catastrophic expenditure.

CONCLUSIONS: This study suggests that although a small proportion of MS patients met the catastrophic health expenditure, mechanisms that pool risk and cost (e.g. health insurance) are required to protect them and improve financial and access equity in health care.

CoI: multiple

HSCT and fake news

I post to manage expectations and counteract fake news.

There is a group of pro-HSCTers going around and saying HSCT is a cure for MS even in MSers with more advanced disease, i.e. it halts and reverses their disability. This is simply not correct and we have no published, peer-reviewed, data to support their position.

The meta-analysis below from Paulo Muraro and colleagues clearly shows that in MSers with SPMS and PPMS having HSCT the ‘majority of study subjects’ continue to progress. This is why most bone marrow transplant units generally don’t treat progressive MS. Even Richard Burt one of the main proponents of treating MS with HSCT stopped transplanting MSers with progressive MS when his BMT unit was still active.

The figure below from the Muraro paper confirms the above; over 60% of the SPMSers and 100% of the PPMSers worsened compared to about 45% of the RRMSers. Why? I suspect it is due to smouldering MS.

HSCT is simply a very potent IRT (immune reconstitution therapy) and is effective at switching off relapses and new focal MRI activity. We have no data to suggest that it impacts on smouldering MS. In fact, we have evidence to the contrary, that the chemotherapy used to deplete the immune system is neurotoxic and some patients actually develop worsening disability as a result of ‘chemo brain’ or acute neurotoxicity associated with the induction protocol. In the Canadian study, which uses myeloablative chemotherapy, treated patients lost more than 2% of their brain volume in year 1. Believe me, this is serious brain volume loss way above what you expect MS to do and is indicative of neurotoxicity. The reason why relapsing MSers cope with the HSCT conditioning is because of reserve and progressive MSers do not, because their MS has already consumed their reserve capacity.

Many years ago we showed that MSers undergoing BMT/HSCT release very high levels of neurofilaments as part of the induction protocol and the levels of neurofilaments released predicted worsening disability. In other words, the chemotherapy caused acute neurotoxicity and resulted in disability worsening. This is one of the reasons why the Rotterdam BMT unit, and many other units, stopped treating progressive MSers. However, if you go to a fee-for-service BMT unit they will treat all-comers. Why? It is called a business and money talks. Don’t be gullible.

What about the anecdotal cases of HSCT curing progressive MS? I can’t say I have seen a single case. All the patients in my practice with progressive MS who have gone abroad to have HSCT have continued to worsen on their return. I am aware of a case of a colleague of mine who had a patient who was in a wheelchair who had HSCT abroad who miraculously got up and walked after having HSCT. My colleague informed me that he had diagnosed this patient as having somatization disorder, a very common MS mimic, that is a psychiatric condition. I am, therefore, sceptical about miraculous anecdotes and I would urge you to be careful before you base your decisions to have HSCT based on anecdotes. What we as an MS community needs is published data on the risks and benefits of HSCT in advanced MS to base our decisions on.

Muraro et al. Long-term Outcomes After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis. JAMA Neurol. 2017 Apr 1;74(4):459-469. doi: 10.1001/jamaneurol.2016.5867.

IMPORTANCE: Autologous hematopoietic stem cell transplantation (AHSCT) may be effective in aggressive forms of multiple sclerosis (MS) that fail to respond to standard therapies.

OBJECTIVE: To evaluate the long-term outcomes in patients who underwent AHSCT for the treatment of MS in a large multicenter cohort.

DESIGN, SETTING, AND PARTICIPANTS: Data were obtained in a multicenter, observational, retrospective cohort study. Eligibility criteria were receipt of AHSCT for the treatment of MS between January 1995 and December 2006 and the availability of a prespecified minimum data set comprising the disease subtype at baseline; the Expanded Disability Status Scale (EDSS) score at baseline; information on the administered conditioning regimen and graft manipulation; and at least 1 follow-up visit or report after transplant. The last patient visit was on July 1, 2012. To avoid bias, all eligible patients were included in the analysis regardless of their duration of follow-up. Data analysis was conducted from September 1, 2014 to April 27, 2015.

EXPOSURES: Demographic, disease-related, and treatment-related exposures were considered variables of interest, including age, disease subtype, baseline EDSS score, number of previous disease-modifying treatments, and intensity of the conditioning regimen.

MAIN OUTCOMES AND MEASURES: The primary outcomes were MS progression-free survival and overall survival. The probabilities of progression-free survival and overall survival were calculated using Kaplan-Meier survival curves and multivariable Cox proportional hazards regression analysis models.

RESULTS: Valid data were obtained from 25 centers in 13 countries for 281 evaluable patients, with median follow-up of 6.6 years (range, 0.2-16 years). Seventy-eight percent (218 of 281) of patients had progressive forms of MS. The median EDSS score before mobilization of peripheral blood stem cells was 6.5 (range, 1.5-9). Eight deaths (2.8%; 95% CI, 1.0%-4.9%) were reported within 100 days of transplant and were considered transplant-related mortality. The 5-year probability of progression-free survival as assessed by the EDSS score was 46% (95% CI, 42%-54%), and overall survival was 93% (95% CI, 89%-96%) at 5 years. Factors associated with neurological progression after transplant were older age (hazard ratio [HR], 1.03; 95% CI, 1.00-1.05), progressive vs relapsing form of MS (HR, 2.33; 95% CI, 1.27-4.28), and more than 2 previous disease-modifying therapies (HR, 1.65; 95% CI, 1.10-2.47). Higher baseline EDSS score was associated with worse overall survival (HR, 2.03; 95% CI, 1.40-2.95).

CONCLUSIONS AND RELEVANCE: In this observational study of patients with MS treated with AHSCT, almost half of them remained free from neurological progression for 5 years after transplant. Younger age, relapsing form of MS, fewer prior immunotherapies, and lower baseline EDSS score were factors associated with better outcomes. The results support the rationale for further randomized clinical trials of AHSCT for the treatment of MS.

Atkins et al. Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial. Lancet. 2016 Aug 6;388(10044):576-85. doi: 10.1016/S0140-6736(16)30169-6.

BACKGROUND: Strong immunosuppression, including chemotherapy and immune-depleting antibodies followed by autologous haemopoietic stem-cell transplantation (aHSCT), has been used to treat patients with multiple sclerosis, improving control of relapsing disease. We addressed whether near-complete immunoablation followed by immune cell depleted aHSCT would result in long-term control of multiple sclerosis.

METHODS: We did this phase 2 single-arm trial at three hospitals in Canada. We enrolled patients with multiple sclerosis, aged 18-50 years with poor prognosis, ongoing disease activity, and an Expanded Disability Status Scale of 3.0-6.0. Autologous CD34 selected haemopoietic stem-cell grafts were collected after mobilisation with cyclophosphamide and filgrastim. Immunoablation with busulfan, cyclophosphamide, and rabbit anti-thymocyte globulin was followed by aHSCT. The primary outcome was multiple sclerosis activity-free survival (events were clinical relapse, appearance of a new or Gd-enhancing lesion on MRI, and sustained progression of Expanded Disability Status Scale score). This study was registered at ClinicalTrials.gov, NCT01099930.

FINDINGS: Between diagnosis and aHSCT, 24 patients had 167 clinical relapses over 140 patient-years with 188 Gd-enhancing lesions on 48 pre-aHSCT MRI scans. Median follow-up was 6.7 years (range 3.9-12.7). The primary outcome, multiple sclerosis activity-free survival at 3 years after transplantation was 69.6% (95% CI 46.6-84.2). With up to 13 years of follow-up after aHSCT, no relapses occurred and no Gd enhancing lesions or new T2 lesions were seen on 314 MRI sequential scans. The rate of brain atrophy decreased to that expected for healthy controls. One of 24 patients died of transplantation-related complications. 35% of patients had a sustained improvement in their Expanded Disability Status Scale score.

INTERPRETATION: We describe the first treatment to fully halt all detectable CNS inflammatory activity in patients with multiple sclerosis for a prolonged period in the absence of any ongoing disease-modifying drugs. Furthermore, many of the patients had substantial recovery of neurological function despite their disease’s aggressive nature.

Petzold et al. Evidence for acute neurotoxicity after chemotherapy. Ann Neurol. 2010 Dec;68(6):806-15. doi: 10.1002/ana.22169.

OBJECTIVE: Chronic neurotoxicity is a recognized long-term complication following chemotherapy in a range of diseases. Neurotoxicity adversely affects patients’ quality of life. The objective of this study is to examine whether there is evidence of acute neurotoxicity.

METHODS: This prospective study included patients with secondary progressive multiple sclerosis (SPMS-BMT, n = 14) and hematological malignancies (HM-BMT, n = 17) receiving chemotherapy as preconditioning for bone marrow transplant. The control groups included SPMS patients matched for demographic and clinical data (SPMS-PL, n = 14) and healthy controls (n = 14). Neurodegeneration was assessed at baseline and longitudinally (months 1, 2, 3, 6, 9, 12, 24, and 36), combining a clinical scale for disability (Expanded Disability Status Scale [EDSS]), a serum protein biomarker for neurodegeneration (neurofilaments, NfH-SMI35), and brain atrophy measures (magnetic resonance imaging).

RESULTS: Disability progression was significantly more acute and severe following chemotherapy compared to placebo. Immediately after starting chemotherapy, serum NfH-SMI35 levels increased in 79% (p < 0.0001) of SPMS-BMT patients and 41% (p < 0.01) of HM-BMT patients compared to 0% of SPMS-PL patients or healthy controls. In SPMS-BMT serum NfH-SMI35 levels were > 100-fold higher 1 month after chemotherapy (29.73ng/ml) compared to baseline (0.28ng/ml, p < 0.0001). High serum NfH-SMI35 levels persisting for at least 3 months were associated with sustained disability progression on the EDSS (p < 0.05). Brain atrophy rates increased acutely in SPMS-BMT (-2.09) compared to SPMS-PL (-1.18, p < 0.05).

INTERPRETATION: Neurotoxicity is an unwanted acute side effect of aggressive chemotherapy.

CoI: multiple

Ask your GP

Should we expect your GP or family doctor to take on more of the day-2-day management of your MS?

In the UK specialist physicians are called consultants because there was always too few of them to get their hands dirty with the day-to-day management of patients with special medical problems. General practitioners used to refer their patients to a specialist for a ‘consultation’ and then get a long letter back with instruction on how to manage their patient. In other words, GPs used to do all the legwork.

In the last 25 years, this has changed. For most long-term conditions, which have become more complicated in terms of their management, the NHS now expects multidisciplinary teams to manage these patients. This has changed the relationships between specialists and GPs and not necessarily in a positive way for patients. For example, we have to rely on GPs to prescribe and help monitor specialist medicines. Not all GPs feel comfortable doing this. If the medicine is off-label they often refuse to prescribe it. There are two reasons for this, (1) why should they pay for an off-label medicine and (2) why should they take on the risks of off-label prescribing. To overcome this we have to put in place so-called shared-care guidelines, which are designed to protect the GPs. Under a shared-care guideline, we have to start and monitor the new medication for the first few months, before the GP takes over the prescribing. The paperwork involved in prescribing drugs under a shared-care guideline is not trivial and takes many meetings and months to get in place, which is why we rely so heavily on our neuroscience specialist pharmacist. Neurologists don’t have the time or space in their job plans to take this on. Notice my use of management speak to delegate this task to our pharmacist.

Because we now see most of our MSers once or twice a year for MS-related problems some rarely see their GPs and hence fall through the cracks, i.e. they are not being routinely monitored for comorbidities (diabetes, hypertension, hypercholesterolaemia, etc.). This causes problems for MSers because MSologists and MS HCPs are not trained and do not have the time to screen for and manage comorbidities.

To implement the marginal gains philosophy into routine MS practice we are going to have to change the way we work with GPs and other community-based HCPs to make the management of MS and all its problems seem seamless to MSers. At the moment it isn’t. A large number of my patients have problems navigating the complexity of the NHS to get the care they need; this is not only community-based services but the services we provide within a secondary care environment.

The Canadian review below on the potential role of the GP or family physician in managing spasticity is refreshing. I see no reason why GPs can’t be upskilled to take on the day-to-day management of many of the symptomatic problems faced by MSers. Spasticity is just one of the symptoms that can be tackled, why can’t they take on bladder, bowel & sexual dysfunction, anxiety, depression, pain, sleep disorders, social isolation, falls prevention, bone health, immunosuppression, diet, smoking, addiction, etc.

What are your experiences with your GP managing your MS compared to your neurologist or MS nurse specialist? Do you think the communication between your MS service and GP could be improved? Do you agree with applying the marginal gains philosophy to the management of your MS?

Milligan et al. Demystifying spasticity in primary care. Can Fam Physician. 2019 Oct;65(10):697-703.

OBJECTIVE: To raise awareness of spasticity in primary care and clarify how to identify, diagnose, and manage it effectively and efficiently in patients with pre-existing neurologic conditions.

SOURCES OF INFORMATION: PubMed was searched for articles published from 1970 to May 2018 using the terms spasticity, spasticity in physical disability, spasticity in mobility impairment, and spasticity with family medicine or primary care. Other relevant guidelines and resources were reviewed and used.

MAIN MESSAGE: Spasticity is a common secondary complication in conditions such as spinal cord injury, multiple sclerosis, stroke, cerebral palsy, and other neuromuscular physical disabilities and can have a negative effect on health and quality of life. Factors such as inconsistent definition, poorly understood mechanism, and relatively low prevalence make spasticity seem like a daunting condition to manage. Furthermore, its variable presentation and effect on a patient’s quality of life, and its range of treatments with varying levels of evidence, can make treatment challenging in primary care and in other clinical settings. Family physicians play an important role in recognizing and inquiring about spasticity and its changes, triggers, and effects on function. Ruling out reversible causes is important. Many management strategies can be instituted by family physicians.

CONCLUSION: Managing spasticity might be unfamiliar to many practitioners. It is important for physicians to understand spasticity and the potential treatment options available to improve quality of life. The current review provides concise information on the clinical relevance of spasticity in primary care and how to assess and manage it effectively and efficiently in those with chronic neurologic conditions.

CoI: multiple

Inequality

Prof G why the sudden and recent fixation with inequality?

There is overwhelming evidence that many health outcomes, including life expectancy, infant mortality, obesity, cancer survival rates, suicide, addiction and many more are linked to the level of economic inequality within society. In short, greater economic inequality leads to worse health outcomes.

Inequality does not necessarily refer to poverty, but relative poverty in society. For example, somebody in the lowest decile of the income distribution of a rich country such as the UK may not be considered poor by international standards, but relative to other people in the UK they are poor.

If you are interested in understanding more about this can I suggest you read Danny Dorling’s book “Injustice: Why social inequality still persists”. In this book, he uses the example of not be able to go on a family holiday as been a good indicator of the ‘have-nots’. The corollary is being able to afford an annual family holiday in modern Britain defines you as being one of the ‘haves’.

Why inequality results in poor health outcomes is complex. Michael Marmot argues in “The Health Gap: The Challenge of an Unequal World” that it causes chronic stress that results in poor outcomes. Please note stress is a biological response and can be measured; when people are stressed they produce excessive cortisol (a steroid) that then triggers a biological cascade that drives many disease processes and behavioural responses. The implications of this are that at a population level stress is bad and to improve outcomes you need population-based interventions to reduce stress. The latter is easier said than done when you have at least half the political establishment pushing a neoliberal (market) agenda that has been shown to increase inequality.

How does this relate to MS? At the moment we are not sure if inequality affects MS outcomes, but we suspect it does. Many comorbidities associated with inequality, such as smoking, obesity, hypertension, diabetes, stroke and myocardial infarction are associated with a worse MS prognosis. In addition, healthcare literacy and healthcare utilization are also linked to inequality and this is very relevant to MS.

To address this data gap we are starting a programme of work in the UK to investigate inequality and whether or not it is impacting on MS practice, MS outcomes and access to MS services. Although we started this at Barts-MS the main body of work will be done under one of the MS Academy workstreams we have defined as part of our ‘Raising the Bar’ initiative. Please note this is not just about defining and measuring inequality in MS Service provision and use, but implementing service change to make sure no MSers are left behind.

I note many commentators on this blog don’t like us highlighting political issues and would prefer us to focus on science. I would argue healthcare is politics and politics is health. If you are an HCP you can’t practice your trade without getting involved with politics or at least having a position on political issues.

The one positive outcome for me from the Brexit debacle is that it has made me realise that I didn’t have the background knowledge to have an informed opinion on Brexit and the reasons for Brexit. As a result of the self-exploration Brexit triggered (see Medium post), I have become an amateur economist, behavioural psychologist and geopolitician. All this has changed my worldview. This is why we have launched our #ThinkSocial campaign to raise awareness and make sure every HCP working in the MS space understands how inequality impacts on their patients and rather than accepting the status quo they should do something about it.

CoI: multiple

O’HAND

I am very excited and proud to be attending and speaking at the first European Oratoria-HAND, or O’Hand, study investigator meeting in Barcelona. With Chariot-MS, the O’HAND study is the culmination of more than 4 years of work and campaigning for Barts-MS.

However, our #ThinkHand campaign will only be considered a true success if we get a positive outcome from one of our studies and a DMT gets licensed to protect, or delay loss of, hand and arm function in people with more advanced MS. These trials have the potential to change the field and make more advanced MS modifiable. Many cynics think we are wasting our time. But if you have MS and you lose your lower limb function you become dependent on your hand and arms to maintain your independence. In other words, your arms become your legs.

The following is my presentation from the meeting, which you can download from my bespoke SlideShare site.

O’HAND Eligibility Criteria

Ages Eligible for Study:	18 Years to 65 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Inclusion Criteria:

EDSS score at screening and baseline >= 3.0 to 8.0, inclusive
Disease duration from the onset of MS symptoms:

Less than 15 years in patients with an EDSS at screening > 5.0 Less than 10 years in patients with an EDSS at screening <= 5.0

Documented history or presence at screening of at least one of the following laboratory findings in a cerebrospinal fluid specimen: Elevated IgG index or one or more IgG oligoclonal bands detected by isoelectric focusing
Screening and baseline 9-HPT completed in > 25 seconds (average of the two hands)
Ability to complete the 9-HPT within 240 seconds with each hand at screening and baseline
Patients previously treated with immunosuppressants, immunomodulators, or other immunomodulatory therapies must undergo an appropriate washout period according to the local label of the immunosuppressant/immunomodulatory drug used
For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use adequate contraceptive methods during the treatment period and for 6 months after the final dose of ocrelizumab. Adherence to local requirements, if more stringent, is required.
For female patients without reproductive potential: Women may be enrolled if post-menopausal unless the patient is receiving a hormonal therapy for her menopause or if surgically sterile

Exclusion Criteria:

History of relapsing-remitting or secondary progressive MS at screening
Confirmed serious opportunistic infection including: active bacterial, viral, fungal, mycobacterial infection or other infection, including tuberculosis or atypical mycobacterial disease
Patients who have or have had confirmed or a high degree of suspicion of progressive multifocal leukoencephalopathy (PML)
Known active malignancy or are being actively monitored for recurrence of malignancy
Immunocompromised state
Receipt of a live-attenuated vaccine within 6 weeks prior to randomization
Inability to complete an MRI or contraindication to Gd administration.
Patients requiring symptomatic treatment of MS and/or physiotherapy who are not on a stable regimen. Patients must not initiate symptomatic treatment of MS or physiotherapy within 4 weeks of randomization.
Contraindications to mandatory premedications for infusion-related reactions, including:

uncontrolled psychosis for corticosteroids and closed-angle glaucoma for antihistamines

Known presence of other neurologic disorders
Pregnant or breastfeeding, or intending to become pregnant during the study and 6 months after last infusion of the study drug
Lack of peripheral venous access
Significant, uncontrolled disease, such as cardiovascular, pulmonary, renal, hepatic, endocrine or gastrointestinal, or any other significant disease that may preclude patient from participating in the study
Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study
History of alcohol or other drug abuse
History of primary or secondary immunodeficiency
Treatment with any investigational agent within 24 weeks prior to screening (Visit 1) or 5 half-lives of the investigational drug (whichever is longer), or treatment with any experimental procedure for MS
Previous treatment with B-cell targeting therapies
Any previous treatment with bone marrow transplantation and hematopoietic stem cell transplantation
Any previous history of transplantation or anti-rejection therapy
Treatment with IV Ig or plasmapheresis within 12 weeks prior to randomization
Systemic corticosteroid therapy within 4 weeks prior to screening
Positive serum hCG measured at screening or positive urine β-hCG at baseline
Positive screening tests for hepatitis B
Any additional exclusionary criterion as per ocrelizumab (Ocrevus®) local label, if more stringent than the above
Lack of MRI activity at screening/baseline if more than 650 patients without MRI activity have already been enrolled, as defined by T1 Gd+ lesion(s) and/or new and/or enlarged T2 lesion(s) in the screening, to ensure that at least 350 patients with MRI activity will be randomized

Eligibility Criteria for Open-Label Extension Phase:

Completed the double-blind treatment phase of the trial or have received PDP OCR in the FU1 phase, and who, in the opinion of the investigator, may benefit from treatment with Ocrelizumab. Patients who withdrew from study treatment and received another disease-modifying therapy (DMT) or commercial ocrelizumab will not be allowed to enter in the OLE phase.
Meet the re-treatment criteria for ocrelizumab
For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use adequate contraceptive methods during the treatment period and for 6 months after the final dose of ocrelizumab. Adherence to local requirements, if more stringent, is required.
For female patients without reproductive potential: Women may be enrolled if post-menopausal unless the patient is receiving a hormonal therapy for her menopause or if surgically sterile

CoI: I am the principal investigator on the O’Hand study

Walking the talk

This post has been moved to Prof G’s Medium Account.

What’s in a name?

You will have noticed that a lot of discussion on this blog has recently been devoted to the topic of secondary progression or smouldering MS or whatever else you want to call it. At the moment there is no standard terminology for describing the scenario of someone with MS who is NEDA-2 (no relapses and no activity on MRI) who is getting worse. The getting worse could be overt, i.e. worsening EDSS, or a more subtle deterioration, which can only be detected using more sensitive outcome measures, or asymptomatic.

Can you let us know which term you prefer?

Non-relapsing SPMS
Inactive SPMS
Hidden SPMS
Hidden progression
Silent progression
Progression independent of relapses (PIRA)
Smouldering MS
Worsening MS
Festering MS

I personally don’t like the use of secondary progression in the term. This excludes MSers with a primary progressive course who have the same pathology and entrenches the dogma that relapse-onset MS and PPMS are different and separate diseases.

Hidden is another term that I don’t like; what is hidden for some MSers may not be hidden for other MSers. For example, cognitive impairment only becomes a problem when you stress your brain. Some MSers may be in a life stage when cognitive stressors are rare and others may stress or test their cognitive abilities on a daily basis.

The term PIRA seems to have the lead at the moment and is being used more and more in abstracts and meetings. Worsening MS is a catch-all phrase that by definition can occur in the presence or absence of relapses and hence according to the Lublin classification you can have active-worsening and inactive-worsening MS. Please note that according to Lublin the worsening has to be overt, i.e. captured using an objective outcome measure.

I like smouldering MS because it creates a visual analogy of what is happening to the brain and spinal cord of MSers. In other words, the flames or relapses and focal MRI activity have been quelled, but the embers continue to burn. It also implies that the embers can fire-up and reignite the flames at any stage. I have a potential conflict in that the term ‘smouldering MS’ may have been used first on this blog and hence we have a vested interest in this term being selected.

What do you think?

CoI: multiple

For English PPMSers

“I love deadlines. I like the whooshing sound they make as they fly by” Douglas Adams, Hitchhikers Guide to the Galaxy.

There is one deadline that happened quitely earlier this month. NHS England turned on the blueteq form ocrelizumab treatment for PPMSers living in England; they did at the last possible timepoint dictated by the law. The good news is that the requirements for someone with PPMS to be treated are relatively simple. All that is required from us is the following:

1. Confirmation the patient has a diagnosis of early PPMS with active disease, defined by the appearance of new lesions confirmed by two MRI studies taken at least 6 months apart OR one or more gadolinium enhancing lesions on one MRI over the last three years.

2. EDSS score <= 6.5

3. A decision agreed at an MS multi-disciplinary team (MDT) meeting.

4. Recording of all the above in the patient’s records (for audit purposes).

This has been a long time coming and I want to thank all my colleagues who signed-up to the open letter we sent to the Chief Medical Officer (see below). I suspect the letter may have helped find a funding solution. It is clear that when there is a will there is a way.

I am also beginning to realise that NHSE is actually on the side of the patient and contrary to my previous perceptions NHSE want patients to access effective treatments. The problem is they have limited budgets and are beholden to the Department of Health and the political system of the day.

We may have won one battle, but the war continues. PPMSers in Scotland still have no access to ocrelizumab. How can we live in a country, with a socialist healthcare system, that allows your place of abode to dictate your access to treatment? If there is anything we can do to help PPMSers living in Scotland please let us know.

Open Letter

Professor Dame Sally Davies
Chief Medical Officer
Department of Health
Room 114, Richmond House
79 Whitehall
London SW1A 2NS
Email:CMOweb@dh.gsi.gov.uk

24 September 2018

Dear Dame Sally

Ocrelizumab for the Treatment of Primary Progressive Multiple Sclerosis

We are writing to you as concerned healthcare professionals for help. We are neurologists, nurse specialists and allied healthcare professionals who specialise in multiple sclerosis (MS). Although patients with the relapsing-remitting type of MS have access to many disease-modifying treatments no treatments until now have been licensed for those with the primary progressive type of MS (PPMS). In its final appraisal document [FAD ID938] NICE has not recommended the first available licensed treatment ocrelizumab, for treating early PPMS.

The problem with NICE’s appraisal determination (FAD) is that the price for ocrelizumab had already been set for treating relapsing-remitting MS (RRMS, FAD TA533), but this price was considered not cost-effective for the treatment of PPMS based on its efficacy in the PPMS trial. As there are currently no licensed treatments for PPMS ocrelizumab had to be compared with best supportive care or no treatment. In comparison, when NICE appraised ocrelizumab for RRMS it was compared to all the other licensed disease-modifying therapies (DMTs).

We have been told that Roche had then agreed to lower the price for ocrelizumab so that it would be cost-effective for the PPMS indication. If this was accepted it would mean ocrelizumab having two NHS prices, a higher price for the treatment of RRMS and a lower price for the treatment of PPMS. Apparently, the Department of Health is not prepared to support differential pricing, despite having a mechanism with the blueteq system for tracking prescribing for the PPMS and RRMS indications.

NICE’s decision in association with the Department of Health’s Rules means an irrational decision has been made. It also creates inequity. People with PPMS who are prepared to pay for ocrelizumab privately will be able to receive the therapy, potentially in an NHS institution. Similarly, those who are fortunate may be able to move and be treated with ocrelizumab in another country where ocrelizumab is covered for the PPMS indication as other UK and EU countries have different decision-making processes.

We would appreciate it if you could review the Department of Health’s position on differential pricing as a solution for people with PPMS being treated with ocrelizumab? We are convinced that there must be a solution that will allow our patients with PPMS to be appropriately treated under the NHS.

Despite the pharmaceutical company conceding to the NICE target and the drug receiving a European license, it is now the government who is preventing patients receiving appropriate treatment for their MS simply due to a rule, arguably an irrational rule, created by the Department of Health.

We look forward to hearing from you.

Yours sincerely

Concerned NHS HCPs.

CoI: multiple