The following study – a collaboration between research groups in Germany and Norway – is an important contribution to our understanding as to which people may or may not respond to rituximab: ‘Antibodies to ß adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome'.
Jonathan Edwards, Emeritus Professor of Connective Tissue Medicine at University College London, provided these insights to readers of the Phoenix Rising website earlier this week:
I need to look at the paper in detail but I think these are important findings.
The only caveat to flag up is that muscarinic ACh receptor antibodies have a reputation for being a bit of a pain in terms of reproducibility but I would not worry too much about that.
It is good to see dynamic results – i.e. changing with treatment.
It is also great to see the Norwegian/German collaboration bearing fruit.
There is a lot more work to do but this is very promising.
It is hard to answer the question about implications specifically.
However, if it proves possible to select cases for rituximab based on data like this then that makes a huge difference to getting a therapeutic programme of the ground.
One of the most important brakes on the programme is the worry that treatments like rituximab would have to be used hit and miss in a condition that is hard to pin down diagnostically and that may include people for whom this is the wrong approach.
Take away that worry and treating ME by B cell targeting begins to look much more similar to lots of other diseases.
The discussion at Phoenix Rising can be read here:
From Brain, Behavior and Immunity, 21 September 2015.
Antibodies to ß adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome
Loebel M(1), Grabowski P(2), Heidecke H(3), Bauer S(2), Hanitsch LG(2), Wittke K(2), Meisel C(4), Reinke P(5), Volk HD(6), Fluge Ø(7), Mella O(8), Scheibenbogen C(6).
1) Institute for Medical Immunology, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany. Electronic address: firstname.lastname@example.org.
2) Institute for Medical Immunology, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany.
3) CellTrend GmbH, Luckenwalde, Brandenburg, Germany.
4) Institute for Medical Immunology, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany; Labor Berlin GmbH, Immunology Department, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany.
5) Department of Nephrology, Charité University Medicine Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité University Medicine Berlin, Germany.
6) Institute for Medical Immunology, Charité University Medicine Berlin, Campus Virchow, Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité University Medicine Berlin, Germany.
7) Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway.
8) Department of Oncology and Medical Physics, Haukeland University Hospital, and Department of Clinical Science, University of Bergen, Bergen, Norway.
• β adrenergic and muscarinic acetylcholine receptor autoantibodies are elevated in a subset of patients with Chronic Fatigue Syndrome (CFS).
• Elevated autoantibodies in CFS correlate with elevated IgG1-3 subclass levels, thyreoperoxidase and ANA antibodies and T cell activation.
• In CFS patients responding to rituximab treatment, elevated antibody levels detected pre-treatment normalized in the majority of clinical responders post-treatment.
Infection-triggered disease onset, chronic immune activation and autonomic dysregulation in CFS point to an autoimmune disease directed against neurotransmitter receptors.
Autoantibodies against G-protein coupled receptors were shown to play a pathogenic role in several autoimmune diseases. Here, serum samples from a patient cohort from Berlin (n= 268) and from Bergen with pre- and post-treatment samples from 25 patients treated within the KTS-2 rituximab trial were analysed for IgG against human α and ß adrenergic, muscarinic (M) 1-5 acetylcholine, dopamine, serotonin, angiotensin, and endothelin receptors by ELISA and compared to a healthy control cohort (n=108).
Antibodies against ß2, M3 and M4 receptors were significantly elevated in CFS patients compared to controls. In contrast, levels of antibodies against α adrenergic, dopamine, serotonin, angiotensin, and endothelin receptors were not different between patients and controls.
A high correlation was found between levels of autoantibodies and elevated IgG1-3 subclasses, but not with IgG4. Further patients with high ß2 antibodies had significantly more frequently activated HLA-DR+ T cells and more frequently thyreoperoxidase and anti-nuclear antibodies.
In patients receiving rituximab maintenance treatment achieving prolonged B-cell depletion, elevated ß2 and M4 receptor autoantibodies significantly declined in clinical responder, but not in non-responder.
We provide evidence that 29.5% of patients with CFS had elevated antibodies against one or more M acetylcholine and ß adrenergic receptors which are potential biomarkers for response to B-cell depleting therapy. The association of autoantibodies with immune markers suggests that they activate B and T cells expressing ß adrenergic and M acetylcholine receptors. Dysregulation of acetylcholine and adrenergic signalling could also explain various clinical symptoms of CFS.
From the Journal of Neurology and Neurobiology, 10 September 2015. Full text available.
The Aerobic Energy Production and the Lactic Acid Excretion are both Impeded in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Family Physician/GPwSI, Soerabaja Research Center, The Netherlands
*Corresponding author: Mark Vink, MD, Family Physician/GPwSI, Soerabaja Research Center Amstel 38, 1096 HH Amsterdam, The Netherlands, E-mail: email@example.com
In this study the muscle bioenergetic function in response to exercise in severe ME was explored to see if the underlying metabolic problem in ME, responsible for the severe difficulties with trivial exercise, and the severe loss of muscle power, could be discovered.
Inorganic phosphate, creatine kinase and lactate were measured in a former Dutch National Field Hockey Champion, who is now a patient bedridden with severe ME, before and 5 minutes after very trivial “exercise”, from which his muscles needed 12 hours to recover.
Inorganic phosphate and creatine kinase were both normal, however, lactate after this trivial exercise was very high, and further testing showed that a second batch of lactic acid was excreted after the same exercise with a 6-fold delay, showing that the lactic acid excretion was impaired and split into two. And this was delayed up to 11- fold by eating closer to the exercise.
This study found that in severe ME, both the oxidative phosphorylation and the lactic acid excretion are impaired, and the combination of these two is responsible for the main characteristic of ME, the abnormally delayed muscle recovery after doing trivial things.
The muscle recovery is further delayed by immune changes, including intracellular immune dysfunctions, and by lengthened and accentuated oxidative stress, but also by exercise metabolites, which work on the sensitive receptors in the dorsal root ganglions, which in severe ME are chronically inflamed, and are therefore much more sensitive to these metabolites, which are produced in high quantities in response to trivial exercise, which for ME patients, due to the underlining metabolic problem, is strenuous exercise. And a similar problem is most likely responsible for the abnormally delayed brain recovery after doing trivial things.
This study also shows that the two metabolic problems are the result of an impaired oxygen uptake into the muscle cells or their mitochondria and in combination with the Norwegian Rituximab studies, which suggest that ME is an autoimmune disease, it is suggestive that antibodies are directly or indirectly blocking the oxygen uptake into the muscle cells or their mitochondria.
From Research Involvement and Engagement, 28 September 2015.
Consulting patients in setting priorities in Myalgic Encephalomyelitis (M.E.) research: findings from a national on-line survey
Nicola Childs(1), Lisa Robinson(1), Sonya Chowdhury(2), Clare Ogden(2) and Julia L. Newton1(3,*)
* Corresponding author: Julia L Newton firstname.lastname@example.org
1) Clinical Academic Office, The Medical School, Newcastle University, Newcastle, UK
2) Action for M.E, 42 Temple Street, Keynsham BS31 1EH, UK
3) Fatigue CRESTA Clinic, Newcastle Hospitals NHS Foundation Trust, Newcastle, UK
Plain English summary
Myalgic encephalitis (M.E.) is a common condition, the cause of which is not known and there are no treatments available. In this study the national patient support group Action for M.E. sought the opinions of their members via an online survey as to what they felt should be future priorities for M.E. research.
Respondents were asked what they considered first, second and third research priorities to be from a list of 13 pre-defined options. Individuals were invited to provide additional free text comments about Action for M.E.’s research priorities in general.
Of the 1144 respondents: 822 had M.E.; 94 were a supporting a member of Action for M.E. ; 66 were carers for someone with M.E.; 26 were professionals with an interest in M.E.; 136 had a family member or colleague with M.E. Individuals selected more than one category as applicable.
The top five research priorities identified were: disease processes to achieve a better understanding of the causes of M.E.; more effective treatments; faster and more accurate diagnosis; clinical course of M.E.; outcomes and natural history; and severely affected patients. Least popular priorities were: sleep; economic research towards identifying the cost of ME; and psychological aspects. Much of the free text comments emphasised the importance of funding biomedical research into disease processes to achieve a better understanding of the causes of M.E. Three themes were identified in relation to this topic: accurate diagnosis and awareness; risk factors and causes; drug development and curative therapies.
In conclusion; individuals affected by M.E. have clear views regarding priorities for research investment. These have informed Action for M.E.’s ongoing research strategy and ultimately will inform national and international research priorities.
The aim of this work was to involve patients in setting future priorities for myalgic encephalomyelitis (M.E.) research.
A national on-line survey was developed collecting structured and unstructured data. Respondents were asked what they considered Action for M.E.’s first, second and third research priorities to be from a list of 13 pre-defined options. Individuals were also invited to provide any additional free text comments about Action for M.E.’s research priorities in general. A total of 1144 individuals completed the on-line survey. Respondents were asked to indicate if: they had M.E. (n = 822; 90.4 %); were a supporting a member of Action for M.E. (n = 94; 10.3 %); carer for someone with M.E. (n = 66;7.3 %), professional with an interest in M.E. (n = 26;2.9 %); or had a family member or colleague with M.E. (n = 136;15 %). Individuals were able to select more than one category as applicable.
The top five research priorities identified by the respondents were: disease processes to achieve a better understanding of the underlying pathology of M.E.; more effective treatments; faster and more accurate diagnosis; clinical course of M.E.; outcomes and prognosis; and severely affected patients. The lower research priorities identified were: sleep; economic research towards identifying the cost of ME for individuals and society; and psychological aspects. Much of the unstructured data provided by respondents emphasised the importance of funding biomedical research into disease processes to achieve a better understanding of the underlying pathology of M.E. Three themes were identified in relation to this topic: accurate diagnosis and awareness; risk factors and causes; drug development and curative therapies.
Individuals affected by M.E. have clear views regarding the most important priorities for research investment. These tended to focus on disease processes to achieve a better understanding of the underlying pathology of M.E. and have been used to inform Action for M.E.’s ongoing research strategy.
From the Journal of Investigative Medicine – high impact case reports, 27 September 2015.
Mitochondrial Myopathy in Follow-up of a Patient With Chronic Fatigue Syndrome
Fernando Galán, AOPT(1,*), Isabel de Lavera, PhD(2), David Cotán, PhD(2), José A. Sánchez-Alcázar, AOPT(2)
1) University of Seville, Seville, Spain
2) Universidad Pablo de Olavide-Consejo Superior de Investigaciones Científicas-Junta de Andalucía, Seville, Spain
*Fernando Galán, Department of Medicine, Medical School, University of Seville, Internal Medicine Service, University Hospital Virgen Macarena, Avda. Doctor Fedriani s/n, Seville 41009, Spain. Email: email@example.com
Symptoms of mitochondrial diseases and chronic fatigue syndrome (CFS) frequently overlap and can easily be mistaken.
We report the case of a patient diagnosed with CFS and during follow-up was finally diagnosed with mitochondrial myopathy by histochemical study of muscle biopsy, spectrophotometric analysis of the complexes of the mitochondrial respiratory chain, and genetic studies.
The results revealed 3% fiber-ragged blue and a severe deficiency of complexes I and IV and several mtDNA variants. Mother, sisters, and nephews showed similar symptoms, which strongly suggests a possible maternal inheritance. The patient and his family responded to treatment with high doses of riboflavin and thiamine with a remarkable and sustained fatigue and muscle symptoms improvement.
This case illustrates that initial symptoms of mitochondrial disease in adults can easily be mistaken with CFS, and in these patients a regular reassessment and monitoring of symptoms is recommended to reconfirm or change the diagnosis.