Is Dr. House coming to your MS diagnosis and prognosis?
Dr House is an American television programme about how Dr House and his team diagnose someone to save the day. All entertaining stuff, but I don’t ever remember the programmes showing the re-possession of someone’s house to pay for all the tests performed by the Dr House team to get to the diagnosis. As such, someone comes in with an in-growing toenail but ends up having a spinal tap and a brain biopsy (seems to happen in every episode along with Cardiac Failure and electric shock therapy or is that another medical programme)…and it turns out the individual has a infection caused by being bitten by a mosquito on holiday in Southend due to the bacteria mutating into a fungus that infects mosquitos that is resistant to atheletes foot powder. Course of antibiotics and Dr. House and team save the day. Hurray.
Why is this relevant todays post. Well it is about moving diagnosis and prognosis forward. At present we have a system that has clinical outcomes that define the treatment, either starting as in relapsing MS/active MS or stopping treatment with secondary progression. However, we know the biological processes are occuring in tandem. Should the definition be more refined? This is the basis for the new paper
Pitt D, Lo CH, Gauthier SA, Hickman RA, Longbrake E, Airas LM, Mao-Draayer Y, Riley C, De Jager PL, Wesley S, Boster A, Topalli I, Bagnato F, Mansoor M, Stuve O, Kister I, Pelletier D, Stathopoulos P, Dutta R, Lincoln MR. Toward Precision Phenotyping of Multiple Sclerosis. Neurol Neuroimmunol Neuroinflamm. 2022 Aug 30;9(6):e200025.
The view of how one defines MS has changed over time and was suggested to be active verses non-active (relapses and lesions) in relapsing remission or progressive MS. But we need more refinement. For example opticospinal disease was considered to be MS and was treated as such, but it was realised there is a different pathology and a biomarker is the production of aquaporin-4 antibodies and unlike MS where beta interferons are benefical in this condition it is not…this condition is now called neuromyelitis optica and it has its own treatments that are different from those approved for MS.
So shouldnt we aim to define MS better?
Absolutely, but it becomes more important when you have treatments to make the monitoring worthwhile, so until interferons came around it didnt matter too much if it was called Devics MS (NMO,) becuase there was little you could do and until you had MRI it was difficult to monitor and trials were based on clinical outcomes which was slow,
The more recent change was to define MS as active (Relapses and new lesion formation) in 2013. However, one suspects the need to do this was treamtent driven. This concept became relevant as ocrelizumab was being developed for progressive MS as it was evident from studies with MS and rituximab (done before 2013) that ocrelizumab was most effective in people with “active disease” so without this definition in the heads of the regulators and neuros it would have been more difficult to approve and use ocrelizumab for primary progressive MS in 2017.
Here is an expanded framework for MS classification that is proposed and based on pathologic processes rather than clinical presentation. It is argued that “MS can be described as a combination of multiple, interconnected pathologic processes that present with different degrees of activity at different time points. This approach provides a ground truth about the disease state that clinical observations cannot provide”.
In the paper they say that “While the clinical classification into relapsing-remitting and secondary progressive MS is intuitive, it may obscure individual-level pathologic profiles. For example, MS progression may be driven by chronic lesional inflammation, meningeal inflammation, or inflammation-independent degeneration of denuded axons, which the description “progression” is not able to distinguish. This suggests that additional pathologic axes might provide improved resolution of MS phenotypes”.
It is suggested that the main pathologic axes of MS, which are (1) acute inflammation, (2) chronic parenchymal inflammation, (3) white and gray matter demyelination, (4) axonal degeneration, (5) neuronal loss, and (6) remyelination.
They say “The classification scheme for MS is based on clinical presentation. Recently, the categories of “active” and “nonactive” progressive MS have been introduced. This has been clinically useful because only active progressive, but not nonactive progressive patients respond to MS treatments”…….One could argue that this statement not true as they may respond but not within the scope of a two year trial meansuring leg function”
However, the authors suggest that this “classification system can be further improved by incorporating additional key pathologic processes. This will provide a framework to view MS as a combination of interdependent pathobiological axes that vary in expression between different patients. An advantage of this framework is that it provides a ground truth and overcomes the paradox that clinical categories do not align with specific pathologies. Moreover, by quantifying activity patterns across multiple pathologic axes, patients with MS can be phenotyped according to their activity profiles. This profiling will ultimately allow clinicians to improve prognostication and to administer personalized care, e.g., by determining whether a patient will respond to a specific DMT based on his or her activity profile. Moreover, clinical trials can be better powered by enriching for patients with specific pathobiological features that are predicted to respond to the trial drug.”
Amazing let’s do it
Abstact: The classification of multiple sclerosis (MS) has been established by Lublin in 1996 and revised in 2013. The revision includes clinically isolated syndrome, relapsing-remitting, primary progressive and secondary progressive MS, and has added activity (i.e., formation of white matter lesions or clinical relapses) as a qualifier. This allows for the distinction between active and nonactive progression, which has been shown to be of clinical importance. We propose that a logical extension of this classification is the incorporation of additional key pathological processes, such as chronic perilesional inflammation, neuroaxonal degeneration, and remyelination. This will distinguish MS phenotypes that may present as clinically identical but are driven by different combinations of pathological processes. A more precise description of MS phenotypes will improve prognostication and personalized care as well as clinical trial design. Thus, our proposal provides an expanded framework for conceptualizing MS and for guiding development of biomarkers for monitoring activity along the main pathological axes in MS.
So hurray if the clinical view does incorporate differing pathologies as it is signalling a need for combination therapies to deal with the pathologies. We have been saying this repeatedly for years and years and years.
However, the question arises, with what and how do you monitor people? What can be done differently as a result of such monitoring and are the monitoring tools routine in clinical practise?
Gadolinium enhancement and T2 lesion enhancement are now standard monitoring features anywhere there is an MRI machine. However, we have been talking about atrophy for years but is this a standard outcome measurered,. What about neurofilaments? Do we belive MTR is a reliable measure of myelination or do we need myelin imaging etc. If you see neuronal brain degeneration is it a result of earlier axonal degeneration in the spinal cord, due to earlier demyelination and ineffective remyelination. If you don’t image the cord or do pathology on the brain in addition to the cord to see these differeneces. Are you going to be happy to spend extra time in the scanner whilst they do this should the scanners all be upgraded to 7T to see these differences? Does our budget, your insurance,, the NHS cover the cost of additional monitoring and the additional time spend assessing the monitoring by the neurologist.
Does the Neurological Dr House work in your hospital? I suspect the development of therapies will be the driver for change. It it helps a company to supply a treamtent, I am sure they will help in the development of the monitoring tool.
Anyway, the paper is available open source so please have aread and make comments and maybe one of the authors would like to do a piece on this, because personalised medicine is the way forward.
Disclaimer. These are views of the author and no-body else.