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In search of the autoantibody, or biomarker...

Posted by Maddison on 04 Nov 2011 at 11:58 GMT

Having read this very important study it seems clear that either an autoimmune and/or immune modulating effect is responsible for the observed response. Whilst it is clear as far as one can be sure, that the results genuinely reflect proof of response, it is clear that there remains doubt in the minds of those that consider the disease to be psychiatric; albeit a view that itself is based only on subjective findings.

Therefore the two major problems in researching this terrible disease have always been, accuracy of diagnosis, and an objective clinical measure of response, or biomarker as it were.

The first of these problems can be minimized by the use of the Canadian Criteria as opposed to more general criteria such as Oxford or Fukuda. As was observed in the present article, it was a non-Canadian Criteria patient that significantly responded to placebo. Therefore for those that wish to repeat this research a serious caution should be made in this respect.

Coming to a biomarker, one of the most confusing aspects of ME/CFS has been, how can patients feel so much pain and inflammation yet routine markers such as sed rate and CRP are almost always normal? This is also the main source of disbelief in those that wish to deny a physical aspect of the disease. One possible explanation could be that the focus of inflammation is small, possibly affecting sensory neurons, such that symptoms are disproportionate to quantum of inflammation.
However, markers of inflammation are notoriously inaccurate even in classical inflammatory disease[1]. It is well accepted that flares of SLE are rarely reflected by CRP, and recent findings have suggested that this is not because of a failure to produce CRP, but of the production of anti-CRP autoantibodies[2]. These autoantibodies are also described in the anti-phospholipid syndrome even in the absence of SLE[3], a syndrome that has been linked somewhat to ME/CFS[4]. Additionally this antibody has also been linked with the disease process. With regard to sedimentation rates, abnormalities of red cell deformability, production of stomatocytes, (possibly explanations for the deficits in blood flow so often seen in patients) could account for low readings[5]. In other words, are low levels of ESR and CRP truly reflective of low levels of inflammation, or are they actually, ironically, a result of the very inflammation of the disease.

Therefore to avoid confusion in both patient selection and those that call for objective findings it would appear wise that an exhaustive search for biological markers is made in future studies. Whilst Dr Fluge and colleagues measured routine markers, RNase-L in the present study, do they intend to measure other perhaps less routine parameters in future studies? If so may I humbly suggest that possibly anti-CRP-autoantibodies, Serum Amyloid A, CH50 total complement be considered for selection, and possibly repeat VO2 max stress testing be added as an objective measure of treatment effect. Furthermore, given that post-exertional symptoms are a hallmark of ME, inflammatory markers could be measured both before and after stress testing.

1.The Many Myths of Erythrocyte Sedimentation Rate and C-Reactive Protein, Wolfe F., The Journal of Rheumatology August 1, 2009 vol. 36 no. 8 1568-1569.
2. CRP and Anti-CRP Autoantibodies in Systemic Lupus Erythematosus, Sjöwall C. et al, Current Rheumatology Reviews, 2005, 1, 81-89
3. Autoantibodies against C-reactive protein: clinical associations in systemic lupus erythematosus and primary antiphospholipid syndrome. Figueredo MA et al, J Rheumatol. 2006 Oct;33(10):1980-6.
4. Anticardiolipin Antibodies in the Sera of Patients with Diagnosed Chronic Fatigue Syndrome. Hokama et al, Journal of Clinical Laboratory Analysis 23 : 210–212 (2009).

5 Erythrocyte Oxidative Damage in Chronic Fatigue Syndrome. Richards RS et al, Archives of Medical Research 38 (2007) 94-98

No competing interests declared.

RE: In search of the autoantibody, or biomarker...

bobrobert replied to Maddison on 04 Mar 2013 at 10:20 GMT

Dear Dr Fluge,

I read with interest your paper last year on rituximab therapy of Chronic Fatigue Syndrome. I was disappointed to read however that you have failed to find any biomarker to distinguish patient from control, or responder with non-responder.

In this regard, I have come across a number of biomarkers that have shown promise. These are listed below.

1. Serum Tryptase - Tryptase is released from mast cells. Such inflammation, even when extensive, will not result in increases of ESR or CRP. Certainly from my testing, this has been shown to be positive in patients diagnosed with ME/CFS, and also correlates to flares in symptoms. Additionally mast cell mediated inflammation would correlated strongly with symptoms flaring on physical and emotional stress as well as the high prevelence of food and chemical sensitivities in this group of patients. Mast cell mediated inflammation has also recently be hypothesised to be linked with Multiple Sclerosis, albeit elevation in tryptase is limited to the CSF. Possibly the success of interferon therapy in some patients with ME/CFS is therefore linked with these findings, interferon being the most effective treatment against mast cell disorders as a whole.

2. Transferrin saturation - This has been shown to be routinely positive in patients, but not controls.(1) This is not due to haemochromatosis, but I would hypothesise it to be caused by either inflammation (transferrin being a reverse acute phase reactant), or a hitherto unknown deficit in tissue oxygenation driving down serum hepcidin levels thus increasing iron uptake by the intestinal mucosa. This test has the advantage that it will exclude anorexic patients from cohorts. Unusually, even young menstruating female ME/CFS patients are positive for elevated transferrin saturation, thus making this marker very robust.

3. CH50 - elevated total hemolytic complement. Little research has been conducted on this marker in ME/CFS, possibly due to difficulty in sample collection. However, in isolated instances it has shown to be highly elevated, possibly only during relapse/symptom flare.

4. Finally, whilst not a marker as such, there appears to be a large percentage of ME/CFS patients who are negative for EBV and CMV antibodies. Since these antibodies should be present in over 95% of the population, it would raise the question whether a certain subset of ME/CFS patients cannot make antibody to these viruses. Perhaps these patients should be treated with IVIG?

(1)Primary haemochromatosis: a missed cause of chronic fatigue syndrome?, Neth J Med. 2002 Dec;60(11):429-33.

No competing interests declared.