The difference between religion, a belief system, and science, an experimental system, is that you can falsify the latter, but not the former. So when KoL (key opinion leaders) say they believe something they don’t really mean it literally. What they are really stating is a hypothesis that needs to be interrogated.
So when I say that relapses and focal MRI activity are not MS, but are occurring in response to the cause of MS I am stating a hypothesis that needs to be falsified. Underpinning science are philosophical constructs on which to test hypotheses. One such construct, or system, is the Prentice criteria for defining a so-called surrogate endpoint in clinical medicine.
According to the Prentice criteria for a surrogate endpoint to be considered as a substitute for the disease (or is the disease), it requires that (1) the baseline measurement of the endpoint is predictive of outcome, (2) changes in the measurement of the endpoint over time is predictive of outcome and (3) changes in the measurement of endpoint in response to a therapy is also predictive of outcome (Prentice, 1989). I would add a fourth criterion that (4) the measurement of the endpoint should predict outcome independent of treatment, i.e. it should behave in the same way whether a subject is on placebo or active treatment.
When you apply these four criteria to relapses and/or focal MRI activity (new and/or enlarging T2 lesions or Gd-enhancing lesions) they don’t predict disability outcomes. This is why I state that the real MS is smouldering MS and the focal inflammatory activity is the immune system’s response to what is causing the disease. Suppressing the immune system’s response to the cause of MS may modify the course of MS, but it does not stop MS from smouldering away.
The analogy I use is one put forward way back in 1994 to Ed Thompson my supervisor when I was a PhD student. I subsequently felt confident enough to present it at a European Charcot Foundation meeting in Lausanne under the title of ‘The yin and yang of inflammation in multiple sclerosis’. I subsequently published the hypothesis as a book chapter in 2004 (see below).
It is interesting that my ideas, or hypotheses, about MS from 25 years ago haven’t changed very much. This is called cerebral stagnation. Maybe it is time to move on?
The primary neurodegenerative hypothesis (1994): Although multiple sclerosis is a clinically heterogeneous disease it can be viewed as an inflammatory neurodegenerative disease with the clinical spectrum or phenotype determined by the presence or absence of focal inflammation, similar to that which occurs in infectious diseases, e.g. leprosy. The underlying neurodegenerative component of the disease may or may not be ongoing but it is modified by superimposed focal inflammatory events. The focal inflammation may be an appropriate host response directed at an unidentified aetiological agent or an inappropriate autoimmune response. These focal inflammatory events are responsible for clinical attacks and MRI disease activity. Although damaging in themselves the focal inflammation provides the biological substrate in the form of trophic and growth factors which promote repair and clinical recovery. Inhibiting the focal inflammatory events, e.g. with generalised immunosuppression, would reduce the relapse rate and MRI activity and remove the important trophic and growth factor support provided by the inflammatory infiltrates, but it may not affect the underlying primary neurodegenerative processes. This strategy would simply convert relapsing-remitting disease into non-relapsing progressive disease. There is evidence from infectious diseases that this phenotypic variability is linked to genetic susceptibility.
Why use leprosy as an analogy? Leprosy is an infectious disease caused by a bacterium with a well-defined set of antigens that can be used to interrogate the adaptive immune systems responses to antigens. Depending on the immune response you get a different clinical picture. If you a brisk inflammatory response you get tuberculoid leprosy and it presents with very inflamed lesions. On the other side of the spectrum, you get lepromatous leprosy that is more of a smouldering disease with low-grade inflammation. Between these two extremes, you get a grey zone that is referred to as borderline subtypes. Interestingly people can convert from having lepromatous to tuberculoid leprosy if the shift their immune response to a so-called type 1 immune response that is driven by a cytokine called interferon-gamma.
Primary progressive MS is lepromatous MS and relapsing-remitting MS is tuberculoid MS and the SPMS sits in the middle. Interestingly, gamma interferon may have the same effect in MS as it does in leprosy. We know that an early trial of gamma-interferon had to be aborted as it triggered relapses. I hypothesise that if you treat PPMS with gamma-interferon you would convert it to RRMS. Unfortunately, this is an experiment that is unlikely to occur but happens naturally when you get a viral infection. Interestingly, infections are a common trigger of relapses. These clinical observations are congruent with the ‘Leprosy Hypothesis of MS‘.
Panitch et al. Treatment of multiple sclerosis with gamma interferon: exacerbations associated with activation of the immune system. Neurology. 1987 Jul;37(7):1097-102.
We treated 18 clinically definite relapsing-remitting MS patients with recombinant gamma interferon in a pilot study designed to evaluate toxicity and dosage. Patients received low (1 microgram), intermediate (30 micrograms), or high (1,000 micrograms) doses of interferon by intravenous infusion twice a week for 4 weeks. Serum levels of gamma interferon were proportional to dose and no interferon was detected in CSF. Seven of the 18 patients had exacerbations during treatment, a significant increase compared with the prestudy exacerbation rate (p less than 0.01). Exacerbations occurred in all three dosage groups and were not precipitated by fever or other dose-dependent side effects. There were significant increases in circulating monocytes bearing class II (HLA-DR) surface antigen, in the proliferative responses of peripheral blood leukocytes, and in natural killer cell activity. These results show that systemic administration of gamma interferon has pronounced effects on cellular immunity in MS and on disease activity within the CNS, suggesting that the attacks induced during treatment were immunologically mediated. Gamma interferon is unsuitable for use as a therapeutic agent in MS. Agents that specifically inhibit gamma interferon production or counteract its effects on immune cells should be investigated as candidates for experimental therapy.