voner
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this is from a discussion @Jonathan Edwards and I had. I thought other people might find something of interest here.....
dr. edwards,
For decades now, I keep reading that what we need for advances in the field of ME/CFS is the definition of biomarkers and having these biomarkers well quickly advance of funding and give clinicians the ability to correctly diagnose patients.
sometimes I buy this, and then at other times the more practical side of me says this is a load of crap (meaning it might be nice to have biomarkers, but it's not necessary in order to move forward).
you come from experience in a field – rheumatoid arthritis – where a good clinical differential diagnosis is considered essential for the diagnosis of rheumatoid arthritis and maybe that is backed up by some testing results. At least that's how I think that's how you understand it?
-so how did the field of rheumatoid arthritis get research funding in lieu of definitive biomarkers?
-Do you think it was because many of the patients display physical manifestations and not just patient reported symptoms?
and in addition,
how was the clinical diagnosis definitions developed for rheumatoid arthritis?
do you know how clinicians got educated on the disease?
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Interesting question, voner.
I guess that for RA we had shedloads of 'biomarkers' from the nineteenth century on because we had pathological and x-ray findings. By 1950 we had immunological findings. So by 1965, when people really started trying to understand RA, there were all sorts of things we could measure objectively and relate to hypotheses:
Pathology from tissues, which could be got from biopsy, surgical synovectomy or joint replacement.
X-rays showing characteristic erosion of bone.
Raised ESR, CRP, low haemoglobin, high platelets, and various other signs of inflammation.
Rheumatoid factor antibodies, and some others like ANA and the anti-CCP.
Anyone trying to study the disease could limit themselves to cases with a positive rheumatoid factor and be pretty sure they were studying cases all with the same basic cause. When genetics came along those cases were studied for tissue type genes because (to everyone's surprise) a genetic link to tissue type had already been found in ankylosing spondylitis. When cytokines were discovered they could be studied in these cases.
It took much longer than it should have done for us to piece it all together but now there is no need for us to miss the same clues. The problem may be that the clues are going to be different this time.
By 'biomarker' I would really just mean some objective finding in terms of tissue structure or blood chemistry or anything that might help identify a common cause for some symptoms. Once you have a marker, even if it is for only 20% of cases, you can look at links or correlations, maybe to patterns of symptoms. We might discover that POTS or brain fog is specifically linked to some biological measurement and work on that.
You might say that we already have measurable things, like low cortisol etc. but a biomarker really needs to be something that one can be fairly sure is part of a cause rather than an effect. So, to be simplistic, a heel sore is not a good biomarker for MS because you know it is caused by the immobility of MS rather than the other way around.
The diagnostic criteria for RA were developed on the basis of just asking 'experts' which patients they thought really had RA and working backwards. it was not a very high powered exercise and it made no significant difference to sorting the disease out. The important breakthrough was when Moll and Wright noted that RA could be separated from 'spondarthritis' by certain telltale clinical signs. That explained why there was a group without rheumatoid factor antibodies. But criteria were only ever relevant to standardisation of recruitment to drug trials really. They did not move the science forward.
Clinicians got educated in the disease because after the second world war and the discovery of penicillin all the infectious disease doctors were looking for work and since they knew about rheumatic fever they moved on to some boring chronically disabled people with what was called rheumatoid arthritis. And immunology was trendy so a few people actually thought RA might be interesting. In the 1970s a few rheumatologists started educating each other in immunology and a few thousand more jumped on the bandwagon. Most of the others never learnt any immunology but they liked the meetings paid for by drug companies. And John Vane had just got a Nobel prize for discovering how aspirin worked. So a few of us like Tiny Maini and I actually tried to work out what was going on, and in the end we got a pretty good idea and discovered that TNF inhibitors and rituximab and IL-6 inhibitors were good treatment.
What we need to know for ME is what pathway needs blocking with treatment (not necessarily with a drug). We need to find a clue to what pathways are critical.
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