Tag: 2018

Rituximab Serum Concentrations and Anti-Rituximab Antibodies During B-Cell Depletion Therapy for Myalgic Encephalopathy/Chronic Fatigue Syndrome

Abstract:

PURPOSE: Previous Phase II trials indicated clinical benefit from B-cell depletion using the monoclonal anti-CD20 antibody rituximab in patients with myalgic encephalopathy/chronic fatigue syndrome (ME/CFS). The association between rituximab serum concentrations and the effect and clinical relevance of antidrug antibodies (ADAs) against rituximab in ME/CFS is unknown. We retrospectively measured rituximab concentrations and ADAs in serum samples from patients included in an open-label Phase II trial with maintenance rituximab treatment (KTS-2-2010) to investigate possible associations with clinical improvement and clinical and biochemical data.

METHODS: Patients with ME/CFS fulfilling the Canadian criteria received rituximab (500 mg/m2) infusions: 2 infusions 2 weeks apart (induction), followed by maintenance treatment at 3, 6, 10, and 15 months. The measured rituximab concentrations and ADAs in serum samples included 23 of 28 patients from the trial.

FINDINGS: There were no significant differences in mean serum rituximab concentrations between 14 patients experiencing clinical improvement versus 9 patients with no improvement. Female patients had higher mean serum rituximab concentrations than male patients at 3 months (P = 0.05). There was a significant negative correlation between B-cell numbers in peripheral blood at baseline and rituximab serum concentration at 3 months (r = -0.47; P = 0.03). None of the patients had ADAs at any time point.

IMPLICATIONS: Clinical improvement of patients with ME/CFS in the KTS-2-2010 trial was not related to rituximab serum concentrations or ADAs. This finding is also in line with a recent randomized trial questioning the efficacy of rituximab in ME/CFS. Rituximab concentrations and ADAs still offer supplemental information when interpreting the results of these trials.

Copyright © 2018. Published by Elsevier Inc.

Source: Rekeland IG, Fluge Ø, Alme K, Risa K, Sørland K, Mella O, de Vries A, Schjøtt J. Rituximab Serum Concentrations and Anti-Rituximab Antibodies During B-Cell Depletion Therapy for Myalgic Encephalopathy/Chronic Fatigue Syndrome. Clin Ther. 2018 Nov 28. pii: S0149-2918(18)30514-9. doi: 10.1016/j.clinthera.2018.10.019. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/30502905

Could disease labelling have positive effects? An experimental study exploring the effect of the chronic fatigue syndrome label on intended social support

Abstract:

Objective: Chronic fatigue syndrome (CFS) patients report limited social support, which can affect symptom severity. Friends are a key source of social support for young adults with CFS, but there is limited research on friends’ responses to the CFS label. We explored the potential benefits or harms of the CFS label for shaping the potential for social support from a friend’s perspective.

Method: 207 university students responded to hypothetical scenarios about a close friend experiencing CFS. Participants were randomly allocated to either the CFS-label or no-label conditions. The potential for social support was operationalised as attitude (sympathetic or hostile), intended treatment support and intended behavioural support.

Results: The CFS label elicited a greater potential for social support, with significantly higher sympathetic responses, lower rejecting responses and greater support for active treatment. These effects were significantly greater in men compared to women. There was no effect on intended behavioural support.

Conclusion: This study suggests the CFS label may increase the potential for social support. Young adults, particularly men, held more supportive attitudes towards their friend when the CFS label was used.

Practical Implications: The effects of labels on the potential for social support need to be considered when evaluating the usefulness of a disease label.

Source: Noble S, Bonner C, Hersch J, Jansen J, McGeechan K, McCaffery K. Could disease labelling have positive effects? An experimental study exploring the effect of the chronic fatigue syndrome label on intended social support. Patient Educ Couns. 2018 Oct 15. pii: S0738-3991(18)30883-8. doi: 10.1016/j.pec.2018.10.011. [Epub ahead of print]  https://www.ncbi.nlm.nih.gov/pubmed/30514660

Prospective Biomarkers from Plasma Metabolomics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Implicate Redox Imbalance in Disease Symptomatology

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease of enigmatic origin with no established cure. Its constellation of symptoms has silently ruined the lives of millions of people around the world. A plethora of hypotheses have been vainly investigated over the past few decades, so that the biological basis of this debilitating condition remains a mystery.

In this study, we investigate whether there is a disturbance in homeostasis of metabolic networks in the plasma of a female 32-patient cohort compared to 19 healthy female controls. Extensive analysis of the 832-metabolite dataset generated by Metabolon®, covering eight biological classes, generated important insight into metabolic disruptions that occur in ME/CFS.

We report on 14 metabolites with differences in abundance, allowing us to develop a theory of broad redox imbalance in ME/CFS patients, which is consistent with findings of prior work in the ME/CFS field. Moreover, exploration of enrichment analysis using www.MetaboAnalyst.ca provides information concerning similarities between metabolite disruptions in ME/CFS and those that occur in other diseases, while its biomarker analysis unit yielded prospective plasma biomarkers for ME/CFS. This work contributes key elements to the development of ME/CFS diagnostics, a crucial step required for discovering a therapy for any disease of unknown origin.

Source:  Arnaud Germain, David Ruppert , Susan M. Levine  and Maureen R. Hanson. Prospective Biomarkers from Plasma Metabolomics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Implicate Redox Imbalance in Disease Symptomatology.  Metabolites 2018, 8(4), 90; doi:10.3390/metabo8040090 https://www.mdpi.com/2218-1989/8/4/90/htm (Full article)

Visual aspects of reading performance in myalgic encephalomyelitis (ME)

Reprinted with the kind permission of ME Research UK.

Abstract:

People with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) report vision-related reading difficulty, although this has not been demonstrated objectively. Accordingly, we assessed reading speed and acuity, including crowded acuity and acuity for isolated words using standardized tests of reading and vision, in 27 ME/CFS patients and matched controls. We found that the ME/CFS group exhibited slower maximum reading speed, and had poorer crowded acuity than controls. Moreover, crowded acuity was significantly associated with maximum reading speed, indicating that patients who were more susceptible to visual crowding read more slowly. These findings suggest vision-related reading difficulty belongs to a class of measureable symptoms for ME/CFS patients.

Publication

Wilson et al, Frontiers in Psychology, 2018 August 17; 9:1468

Authors

Rachel L. Wilson, Kevin B. Paterson, Victoria McGowan and Claire V. Hutchinson

Institution

Department of Neuroscience, Psychology and Behaviour, College of Life Sciences, University of Leicester, Leicester, UK

Funding

This work was funded by an ME Research UK (Grant No. SC036942) to CH and KP. VM was supported by an Economic and Social Research Council (Grant No. ES/L010836/1).

Comment by ME Research UK

Many people with ME/CFS suffer from problems with their eyes and vision, such as oversensitivity to light, troubles with focusing, and dry eyes. Reading can therefore be challenging, particularly for long periods, and pattern glare, headaches and difficulty tracking lines of text are commonly reported. However, before now, the reading performance of ME/CFS patients had not been assessed objectively.

Over the last few years, Dr Claire Hutchinson and her colleagues at the University of Leicester have been looking in depth at some of the vision-related problems associated with ME/CFS, supported in part by grants from ME Research UK.

The group has found that most ME/CFS patients experience a degree of eye pain and sensitivity to bright lights. Using sophisticated eye-tracking techniques, they have also shown that patients struggle to focus on one object and ignore irrelevant information, are slow in shifting attention between objects, are slower than normal and less accurate in their eye movements, and are vulnerable to pattern-related visual stress.

In their latest ME Research UK-funded study, published in the journal Frontiers in Psychology, the Leicester team set out to evaluate what impact ME/CFS has on reading performance. A total of 27 ME/CFS patients and 27 healthy control subjects took part in the research; all had normal vision or corrected-to-normal vision (i.e. they wore spectacles or contact lenses) and none had any history of eye disease.

Reading performance was assessed using two standardised tests, the Minnesota Reading Acuity Chart and the Radner Rate of Reading Chart, which between them produced the following measures:

  • Reading acuity (the smallest print size that can be read without significant mistakes),
  • Maximum reading speed (not limited by print size),
  • Average reading speed, and
  • Critical print size (the smallest print size that can be read at maximum speed).

As expected, the maximum reading speed was significantly slower in ME/CFS patients than in control subjects, and patients also tended to have a slower average reading speed. However, reading acuity and critical print size were not different between the two groups, indicating that the reading difficulties were not due to an inability to make out smaller print.

Furthermore, ME/CFS patients and control subjects performed similarly on a vocabulary test, showing that the differences in reading performance between the two groups were unlikely to be due to cognitive problems.

The researchers also looked at uncrowded visual acuity for individual words and letters (identifying a word or letter on its own) and crowded visual acuity (identifying a target letter surrounded by other letters), using the logMar Crowded Test.

While uncrowded visual acuity appeared to be similar in patients and controls, ME/CFS patients did have greater problems with visual crowding and performed less well on that test. Furthermore, those individuals who were more susceptible to visual crowding were also shown to read more slowly.

These findings build on a considerable body of work from Dr Hutchinson and her team in which they have detailed and explored the vision-related symptoms associated with ME/CFS. While many people with he illness know full well how difficult it can be to read comfortably, particularly for long periods, this is the first time these problems have been assessed objectively in a laboratory setting.

As the researchers conclude, ‘identifying and treating vision-related symptoms of ME/CFS could provide a means of improving the everyday lives of patients’.

________________

ME Research UK commissions and funds high-quality scientific (biomedical) investigation into ME/CFS. 

 

Hyperintense sensorimotor T1 spin echo MRI is associated with brainstem abnormality in chronic fatigue syndrome

Abstract:

We recruited 43 Chronic Fatigue Syndrome (CFS) subjects who met Fukuda criteria and 27 healthy controls and performed 3T MRI T1 and T2 weighted spin-echo (T1wSE and T2wSE) scans. T1wSE signal follows T1 relaxation rate (1/T1 relaxation time) and responds to myelin and iron (ferritin) concentrations. We performed MRI signal level group comparisons with SPM12. Spatial normalization after segmentation was performed using T2wSE scans and applied to the coregistered T1wSE scans.

After global signal-level normalization of individual scans, the T1wSE group comparison detected decreased signal-levels in CFS in a brainstem region (cluster-based inference controlled for family wise error rate, PFWE= 0.002), and increased signal-levels in large bilateral clusters in sensorimotor cortex white matter (cluster PFWE < 0.0001). Moreover, the brainstem T1wSE values were negatively correlated with the sensorimotor values for both CFS (R2 = 0.31, P = 0.00007) and healthy controls (R2= 0.34, P = 0.0009), and the regressions were co-linear.

This relationship, previously unreported in either healthy controls or CFS, in view of known thalamic projection-fibre plasticity, suggests brainstem conduction deficits in CFS may stimulate the upregulation of myelin in the sensorimotor cortex to maintain brainstem – sensorimotor connectivity. VBM did not find group differences in regional grey matter or white matter volumes. We argued that increased T1wSE observed in sensorimotor WM in CFS indicates increased myelination which is a regulatory response to deficits in the brainstem although the causality cannot be tested in this study. Altered brainstem myelin may have broad consequences for cerebral function and should be a focus of future research.

Source: Barnden LR, Shan ZY, Staines DR, Marshall-Gradisnik S, Finegan K, Ireland T, Bhuta S. Hyperintense sensorimotor T1 spin echo MRI is associated with brainstem abnormality in chronic fatigue syndrome. Neuroimage Clin. 2018;20:102-109. doi: 10.1016/j.nicl.2018.07.011. Epub 2018 Jul 11. https://www.ncbi.nlm.nih.gov/pubmed/30497131

Evaluation of four clinical laboratory parameters for the diagnosis of myalgic encephalomyelitis

Abstract:

Background: Myalgic encephalomyelitis (ME) is a complex and debilitating disease that often initially presents with flu-like symptoms, accompanied by incapacitating fatigue. Currently, there are no objective biomarkers or laboratory tests that can be used to unequivocally diagnosis ME; therefore, a diagnosis is made when a patient meets series of a costly and subjective inclusion and exclusion criteria. The purpose of the present study was to evaluate the utility of four clinical parameters in diagnosing ME.

Methods: In the present study, we utilized logistic regression and classification and regression tree analysis to conduct a retrospective investigation of four clinical laboratory in 140 ME cases and 140 healthy controls.

Results: Correlations between the covariates ranged between [− 0.26, 0.61]. The best model included the serum levels of the soluble form of CD14 (sCD14), serum levels of prostaglandin E2 (PGE2), and serum levels of interleukin 8, with coefficients 0.002, 0.249, and 0.005, respectively, and p-values of 3 × 10−7, 1 × 10−5, and 3 × 10−3, respectively.

Conclusions: Our findings show that these parameters may help physicians in their diagnosis of ME and may additionally shed light on the pathophysiology of this disease.

© The Author(s) 2018

Source: Kenny L. De Meirleir, Tatjana Mijatovic, Krishnamurthy Subramanian, Karen A. Schlauch and Vincent C. Lombardi. Evaluation of four clinical laboratory parameters for the diagnosis of myalgic encephalomyelitis. Journal of Translational Medicine201816:322
https://doi.org/10.1186/s12967-018-1696-z Received: 1 September 2018, Accepted: 14 November 2018, Published: 21 November 2018 https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-018-1696-z (Full article)

Erythrocyte Deformability As a Potential Biomarker for Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is arguably the last major disease we know almost nothing about. It is a multi-systemic illness of unknown etiology affecting millions of individuals worldwide, with the capacity to persist for several years. ME/CFS is characterized by disabling fatigue of at least 6 months, accompanied serious fatigue and musculoskeletal pain, in addition to impaired short-term memory or concentration, and unrefreshing sleep or extended post-exertional. While the etiology of the disease is still debated, evidence suggest oxidative damage to immune and hematological systems as one of the pathophysiological mechanisms of the disease. Erythrocytes are potent scavengers of oxidative stress, and their shape changes appreciably in response to oxidative stress and certain inflammatory conditions including obesity and diabetes. The shape of erythrocytes change from biconcave discoid to an ellipsoid due shear flow in microcapillaries that provides a larger specific surface area-to-volume ratio for optimal microvascular perfusion and tissue oxygenation establishing the importance not only of total hematocrit but also of the capacity for large deformations in physiology. Clinically, ME/CFS patients show normal arterial oxygen saturation but nothing much is known about microvascular perfusion. In this work, we tested the hypothesis that the erythrocyte deformability in ME/CFS is adversely affected, using a combination of biophysical and biochemical techniques.

We tested the deformability of RBCs using a high-throughput microfluidic device which mimics blood flow through microcapillaries. We perfused RBCs (suspension in plasma) from ME/CFS patients and from age and sex matched healthy controls (n=9 pairs of donors) through a high-throughput microfluidic platform of 5µm width and 3-5 µm height. We recorded the movement of the cells at high speed (4000 fps), followed by image analysis to assess the following parameters: entry time (time required by the cells to completely enter the test channels), average transit velocity (velocity of the cells inside the test channels) and elongation index (ratio of the major diameter before and after deformation in the test channel). We observed that RBCs from ME/CFS patients had higher entry time (~12%, p<0.0001), lower average transit velocity (~17%, p<0.0001) and lower elongation index (~14%, p<0.0001) as compared to RBCs from healthy controls. Taken together, this data shows that RBCs from ME/CFS patients have reduced deformability. To corroborate our findings, we also measured the erythrocyte sedimentation rate (ESR) for these donors which show that the RBCs from ME/CFS patients had lower (~40%, p<0.01) sedimentation rates.

To understand the basis for differences in deformability, we investigated the changes in the fluidity of the membrane using a lateral diffusion assay using pyrenedecanoic acid (PDA), and observed that RBCs from ME/CFS patients have lower membrane fluidity (~30%, p<0.01). Apart from the fluidity, Zeta potential measurements showed that ME/CFS patients had lower net negative surface charge on the RBC plasma membrane (~18%, p<0.0001). Higher levels of reactive oxygen species (ROS) in RBCs from ME/CFS patients (~30%, p<0.008) were also observed, as compared to healthy controls. Using scanning electron microscopy (SEM), we also observed changes in RBC morphology between ME/CFS patients and healthy controls (presence of different morphological subclasses like biconcave disc, leptocyte, acanthocyte and burr cells; area and aspect ratio; levels of RBC aggregation). Despite these changes in RBC physiology, the hemoglobin levels remained comparable between healthy donors and ME/CFS patients. Finally, preliminary studies show that RBCs from recovering ME/CFS patients do not show such differences in cellular physiology, suggesting a connection between RBC deformability and disease severity.

Taken together, our data demonstrates that the significant decrease in deformability of RBCs from ME/CFS patients may have origins in oxidative stress, and suggests that altered microvascular perfusion can be a possible cause for ME/CFS symptoms. Our data also suggests that RBC deformability may serve as a potential biomarker for ME/CFS, albeit further studies are necessary for non-specific classification of the disease.

Source: Saha, A. K., Schmidt, B. R., Wilhelmy, J., Nguyen, V., Do, J., Suja, V. C., Nemat-Gorgani, M., Ramasubramanian, A. K., & Davis, R. W. (2018).Erythrocyte Deformability As a Potential Biomarker for Chronic Fatigue Syndrome. Blood, 132(Suppl 1), 4874. Accessed November 28, 2018. https://doi.org/10.1182/blood-2018-99-117260.

Interferon-γ and CXCL10 responses related to complaints in patients with Q fever fatigue syndrome

Abstract:

Approximately 20% of patients with acute Q fever develop Q fever fatigue syndrome (QFS), a debilitating fatigue syndrome. This study further investigates the role of C. burnetii-specific IFNγ, but also IL-2, CXCL9, CXCL10, and CXLC11 production in QFS patients. C. burnetii-specific IFNy, IL-2, CXCL9, CXCL10, and CXCL11 production were tested in ex vivo stimulated whole blood of QFS patients who recovered from their complaints (n = 8), QFS patients with persisting complaints (n = 27), and asymptomatic Q fever seropositive controls (n = 10).

With the exclusion of one outlier, stimulation with C. burnetii revealed significantly higher IFNy and CXCL10 production in QFS patients with persisting complaints (medians 288.0 and 176.0 pg/mL, respectively) than in QFS patients who recovered from their complaints (medians 93.0 and 85.5 pg/mL, respectively) (p = 0.041 and 0.045, respectively). No significant differences between groups were found for C. burnetii-specific IL-2, CXCL9, and CXCL11 production.

These findings point towards a difference in cell-mediated immunity in QFS patients with persisting complaints compared to those who recovered from their complaints. Such a difference may aid to eventually diagnose QFS more objectively and might serve as an indicator of its underlying etiology.

Source: Raijmakers RPH, Jansen AFM, Keijmel SP, Schoffelen T, Scholzen A, van der Meer JWM, Joosten LAB, Netea MG, van Deuren M, Bleeker-Rovers CP. Interferon-γ and CXCL10 responses related to complaints in patients with Q fever fatigue syndrome. Eur J Clin Microbiol Infect Dis. 2018 Jul;37(7):1385-1391. doi: 10.1007/s10096-018-3265-z. Epub 2018 May 26. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6015096/ (Full article)

VIDEO: Dr Jonathan Kerr, Mourne Country Hotel, Newry

This is the recording of Dr. Jonathan Kerr’s lecture at the Mourne Country Hotel, Newry on 30th October 2018. Dr. Kerr, BSc, MBBCh, MD, PhD, FRCPath, is a researcher who became interested in ME/CFS after studying the consequences of Parvovirus B19 infection and finding that some of those infected went on to develop CFS. Formerly of St. George’s University of London, he is presently working as an Associate professor in the School of Medicine and Health Sciences at Universidad del Rosario, Bogotá, Colombia. The lecture was organised by Hope 4 ME & Fibro NI.