Primary progressive MS: the forgotten many

Have you been treated like a second-class citizen by your MS service because you have primary progressive MS (PPMS)? What should be done to improve the lot of people with PPMS?

Why can’t primary progressive multiple sclerosis (PPMS) be diagnosed and treated earlier? 

People with PPMS have drawn the short straw. They present on average ten years later than people with relapse-onset disease and take much longer to get diagnosed. Across Europe, the diagnostic delay from symptom onset to diagnosis is over four years. In addition, there is only one licensed treatment for PPMS, and that is ocrelizumab. In most countries, ocrelizumab is only licensed for active PPMS. Some countries restrict access based on age, and others don’t cover the costs of its use for PPMS.  

A picture of ‘forgotten many’ created by Gemini

Active PPMS refers to pwPPMS, who have Gd-enhancing or acquired new T2 lesions on their MRI scans. In my experience, MRI activity can only be demonstrated in about 1 in 20 pwMS; therefore, most pwPPMS are not on a DMT and have to be left to face the natural history of the disease, which, given sufficient time, causes significant disability in the majority of pwPPMS. Saying this there are several trials recruiting patients with PPMS, and hence, we have the option of offering them a clinical trial. Often pwPPMS, once diagnosed, don’t have annual monitoring MRI scans. This creates problems when looking for new MRI lesions. Often the diagnostic or baseline scan is done many years ago, so when you rescan them, you can’t use the older scan for comparative reasons. The current recommendation is if their baseline scan is more than three years old then you need to start the clock again. This means pwPPMS who may have active disease have to wait another year or two to access ocrelizumab. As ‘time is brain and spinal cord’ this wait can come with a high cost to the individual with PPMS. 

However, the MS mantra of “diagnose early, treat early, flip the pyramid” must be frustrating to hear if you have PPMS. I know that some neurologists and MS stakeholders think PPMS is a different disease. However, when you use a biological definition of MS, PPMS is MS and is part of the spectrum, which we are beginning to refer to as MS spectrum disorder. For more information on this topic, please read “Is primary progressive MS a different disease?” (2-Sept-2022). 

So, what can be done about the problems facing pwPPMS? I have thought about this a lot over the years, and apart from population screening to identify people at risk of MS or in the presymptomatic phase, there is little that can be done apart from educating general practitioners and other specialists to #ThinkPPMS to speed up referral and the diagnosis of PPMS.

At our centre, we have pioneered the use of spinal fluid neurofilament levels for disease activity monitoring and off-label subcutaneous cladribine to treat people with MS who have been left behind, and this includes pwPPMS. As a result of this, we have a large number of pwPPMS who have been treated with cladribine. I am sure we have helped slow down their disability worsening, but we have done little to date to address the problem of treating PPMS at a broader level. Our CHARIOT-MS trial of oral cladribine in more advanced MS may shift the dial if positive. I am aware that in other countries, off-label rituximab is often used in a similar way to treat PPMS. Are any of you on off-label rituximab? 

The problem with population screening is that we don’t have a reliable method of detecting presymptomatic MS. There are MS risk calculators and MS polygenic risk scores, but neither are good enough to pass the UK National Screening Committee’s (UK NSC) criteria for viability, effectiveness and appropriateness of a population screening programme. For those of you interested in population health, I urge you to read the UK NSC’s criteria for population screening. It is clear that if you apply this to MS, we are decades away from having anything meaningful that can be used for MS screening and presymptomatic diagnosis. 

As a neurologist who diagnoses and looks after pwPPMS, I feel it is important to spread hope, i.e., to make pwPPMS feel that they are not forgotten or neglected. This is why PPMS trials are so important, as well as educating them about the holistic approach to managing MS and the value of marginal gains. 

A poster designed and created by Gemini

If you have PPMS, I would like to hear your thoughts about these issues. Have you been treated like a second-class citizen by your MS service? What should be done to improve the lot of pwPPMS? How can we improve the diagnostic delays for pwPPMS? 

UK NSC’s criteria for population screening

The condition…

1. The condition should be an important health problem as judged by its frequency and/or severity. The epidemiology, incidence, prevalence and natural history of the condition should be understood, including development from latent to declared disease and/or there should be robust evidence about the association between the risk or disease marker and serious or treatable disease.

2. All the cost-effective primary prevention interventions should have been implemented as far as practicable.

3. If the carriers of a mutation are identified as a result of screening the natural history of people with this status should be understood, including the psychological implications.

The test ….

4. There should be a simple, safe, precise and validated screening test.

5. The distribution of test values in the target population should be known and a suitable cut-off level defined and agreed.

6. The test, from sample collection to delivery of results, should be acceptable to the target population.

7. There should be an agreed policy on the further diagnostic investigation of individuals with a positive test result and on the choices available to those individuals.

8. If the test is for a particular mutation or set of genetic variants the method for their selection and the means through which these will be kept under review in the programme should be clearly set out.

The intervention …..

9. There should be an effective intervention for patients identified through screening, with evidence that intervention at a pre-symptomatic phase leads to better outcomes for the screened individual compared with usual care. Evidence relating to wider benefits of screening, for example, those relating to family members, should be taken into account where available. However, where there is no prospect of benefit for the individual screened then the screening programme should not be further considered.

10. There should be agreed evidence based policies covering which individuals should be offered interventions and the appropriate intervention to be offered.

The screening programme …. 

11. There should be evidence from high quality randomised controlled trials that the screening programme is effective in reducing mortality or morbidity. Where screening is aimed solely at providing information to allow the person being screened to make an 'informed choice' (such as Down’s syndrome or cystic fibrosis carrier screening), there must be evidence from high quality trials that the test accurately measures risk. The information that is provided about the test and its outcome must be of value and readily understood by the individual being screened.

12. There should be evidence that the complete screening programme (test, diagnostic procedures, treatment/ intervention) is clinically, socially and ethically acceptable to health professionals and the public.

13. The benefit gained by individuals from the screening programme should outweigh any harms, for example from overdiagnosis, overtreatment, false positives, false reassurance, uncertain findings and complications.

14. The opportunity cost of the screening programme (including testing, diagnosis and treatment, administration, training and quality assurance) should be economically balanced in relation to expenditure on medical care as a whole (value for money). Assessment against this criteria should have regard to evidence from cost benefit and/or cost effectiveness analyses and have regard to the effective use of available resource.

Implementation criteria…. 

15. Clinical management of the condition and patient outcomes should be optimised in all health care providers prior to participation in a screening programme.

16. All other options for managing the condition should have been considered (such as improving treatment or providing other services), to ensure that no more cost effective intervention could be introduced or current interventions increased within the resources available.

17. There should be a plan for managing and monitoring the screening programme and an agreed set of quality assurance standards.

18. Adequate staffing and facilities for testing, diagnosis, treatment and programme management should be available prior to the commencement of the screening programme.

19. Evidence-based information, explaining the purpose and potential consequences of screening, investigation and preventative intervention or treatment, should be made available to potential participants to assist them in making an informed choice.

20. Public pressure for widening the eligibility criteria for reducing the screening interval, and for increasing the sensitivity of the testing process, should be anticipated. Decisions about these parameters should be scientifically justifiable to the public.

References

Department of Health, Screening of pregnant women for hepatitis B and immunisation of babies at risk. London: Dept of Health, 1998 (Health Service Circular : HSC 1998/127).

Wilson JMG, Jungner G. Principles and practice of screening for disease. Public Health Paper Number 34. Geneva: WHO, 1968.

Cochrane AL. Holland WW. Validation of screening procedures. Br Med Bull. 1971, 27, 3.

Sackett DL, Holland WW. Controversy in the detection of disease. Lancet 1975;2:357-9.

Wald NJ (Editor). Antenatal and Neonatal screening. Oxford University Press, 1984.

Holland WW, Stewart S. Screening in Healthcare. The Nuffield Provincial Hospitals Trust, 1990.

Gray JAM. Dimensions and definitions of screening. Milton Keynes: NHS Executive Anglia and Oxford, Research and Development.

Angela Raffle/Muir Gray Screening Evidence and Practice, Oxford University Press 2007.

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General Disclaimer

Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Queen Mary University of London or Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you have problems, please tell your healthcare professional, who will be able to help you.