In this December Research 1st e-newsletter, we highlight important advances in the ME/CFS field from 2017. These advances build on promising research and reflect the dynamic momentum occurring on all fronts. Many of these studies are interdisciplinary and have relevance in more than one category. They are not listed in any specific order.

1. Major Collaborative Efforts

The National Institutes of Health (NIH) is now funding a consortium of collaborative centers dedicated to ME/CFS ., This marks an unprecedented commitment by the federal agency to ME/CFS. Although this debilitating disease requires more funding and support, this is undeniably a success for the community. Work at the collaborative centers, funded at $35 million, will play out over the next five years and emphasize integrative approaches to study the multifactorial aspects of ME/CFS. Kick off meetings and planning sessions are underway. The NIH provided an update on the centers and other initiatives on November 28.

., This marks an unprecedented commitment by the federal agency to ME/CFS. Although this debilitating disease requires more funding and support, this is undeniably a success for the community. Work at the collaborative centers, funded at $35 million, will play out over the next five years and emphasize integrative approaches to study the multifactorial aspects of ME/CFS. Kick off meetings and planning sessions are underway. The NIH provided an update on the centers and other initiatives on November 28. The Common Data Elements (CDE) project, a collaboration between NIH and Centers for Disease Control and Prevention (CDC), is a national effort to develop standards for data elements and standardize relevant health information. The CDEs will enhance the precision of patient information and allow for better comparison across studies. Launched in 2017, this effort involves many experts and stakeholders. The CDEs will be open for public comment at the start of 2018 and are intended for broad use in ME/CFS research. SMCI will be incorporating the CDEs into our upcoming National ME/CFS Patient Registry & BioBank, scheduled to launch in early 2018.

(CDE) project, a collaboration between NIH and Centers for Disease Control and Prevention (CDC), is a national effort to develop standards for data elements and standardize relevant health information. The CDEs will enhance the precision of patient information and allow for better comparison across studies. Launched in 2017, this effort involves many experts and stakeholders. The CDEs will be open for public comment at the start of 2018 and are intended for broad use in ME/CFS research. SMCI will be incorporating the CDEs into our upcoming National ME/CFS Patient Registry & BioBank, scheduled to launch in early 2018. The Centers for Disease Control (CDC) recently removed inaccurate information from their CDC webpages on ME/CFS. The CDC is updating the ME/CFS pages for the general public and healthcare providers to reflect the 2015 Institute of Medicine (IOM) report and recommendations from a collaborative Technical Development Working group – this is an important step towards correcting dangerous misinformation and misconceptions and work will continue into the New Year.

on ME/CFS. The CDC is updating the ME/CFS pages for the general public and healthcare providers to reflect the 2015 Institute of Medicine (IOM) report and recommendations from a collaborative Technical Development Working group – this is an important step towards correcting dangerous misinformation and misconceptions and work will continue into the New Year. Major studies are also underway under the guidance of agencies at HHS, with an intramural NIH study and CDC Multi-Site Clinical Assessment of ME/CFS

2. Improved study design creating more definitive conclusions

The theme of subtyping was emphasized universally at presentations and conferences this year. At SMCI’s 2017 Discovery Forum, Dr. Beth Unger (CDC) hypothesized that heterogeneity of individuals with ME/CFS may be the greatest obstacle to identifying the underlying pathobiology. Methodology reviews from 2017 highlight subtyping and other study design elements that will lend additional rigor to the research:

Scheibenbogen et al. recommended the use of standardized case definitions, multiplexing (combining) potential biomarkers together, and patient stratification to increase sensitivity and specificity in ME/CFS research.

Sunnquist et al. compared demographic and survey data of patients diagnosed by either the Institute of Medicine (IOM) criteria or the London criteria for ME and found that the two different case definitions resulted in disparate selection of patients, pointing to the need for a standardized diagnostic protocol.

Stoothoff et al. looked at whether self-reported illness trajectories were correlated with symptomatic and functional differences in study participants. The preliminary findings indicate that patient illness course might prove to be a good subtype classification approach.

3. Immunity/inflammation

ME/CFS has long been considered to have a significant immunological component, but studies focused on deviations in immune function often lack coherence between study groups. Work to better understand immunopathogenic mechanisms figured prominently in 2017. Results pointed to the value of subtyping patient groups and added compelling evidence for researchers to weigh as we drive toward more understanding and treatments:

Montoya et al. found the blood levels of 17 cytokines (immune function signaling proteins), although largely non-differential between patients and controls overall, correlated with patient disease severity, pointing to potential biomarkers and/or a useful subgroup of ME/CFS. 13 of these cytokines are proinflammatory.

Milrad et al. found that poor sleep quality was related to the experience of symptom severity and frequency, as well as levels of circulating pro-inflammatory cytokines, in a sample of women with ME/CFS.

Hornig et al. found distinct immune cytokine signatures in the cerebrospinal fluid samples of classic (reported acute onset of disease preceded by an infection) and atypical (less typical onset and/or development of comorbidities) patient groups presentation, indicating that exposure history before onset and unusual comorbidities may be useful in understanding underlying mechanisms. There were also suggestions of autoimmunity patterns in “classical” ME/CFS.

Clark et al., in contrast to other study results, did not find data to support differences in circulating cytokine protein concentrations and their RNA between cases and controls at rest and before/after commuting or exercise.

Nguyen, T. et al. propose a mechanism for the reduction of natural killer (NK) cell cytotoxicity in ME/CFS based on study evidence that impaired functioning of the protein TRPM3 (an ion channel) impacts intracellular Ca 2+ concentrations and changes the activity threshold for sufficient NK cell activity.

concentrations and changes the activity threshold for sufficient NK cell activity. Theorell et al. evaluated the phenotype and function of cytotoxic lymphocytes and did not find evidence of diminished NK cell function in ME/CFS patients as compared to controls, conflicting with results from a number of previous studies.

Halpin et al. suggest a subgroup from a study of ME/CFS and Gulf War Illness (GWI) patients had reactivation of multiple herpesviruses based on a statistically significant increase in Immunoglobulin G (IgG) antibodies to Epstein-Barr virus (EBV), HHV-6, VZV, and human nuclear dUTPases (a virus-encoded enzyme) relative to control subjects.

Loebel et al. published data that does not support a pathogenic role of EBV reactivation in CFS. The enhanced IgG response against an EBNA-6 repeat sequence may point to a potential antigenic mimicry and requires further studies

Nguyen, C.B. et al. compared neuroendocrine, gene expression, immune, and clinical markers in blood samples from adolescent CFS patients and healthy controls. The researchers found a different gene expression pattern in patients that indicates impaired B cell differentiation and increased viral immune response and inflammation.

4. Neuroendocrine Biology

ME/CFS falls under the classification of a neurological disorder and increasing evidence supports the involvement of the nervous system and the relevance of neuroinflammation. Direct measurement of the human brain is limited by our physiology – it is difficult to get a good picture of what is occurring inside our skull. Studies published in 2017 utilized inspired methodologies for quantifying neurological disturbances in individuals with ME/CFS:

Baraniuk & Shivapurkar measured cerebrospinal fluid microRNA (small, non-coding RNA molecules that influence gene expression) before and after exercise in CFS, Gulf War Illness (GWI), and control subjects. They found significant differences in levels after exercise between the groups, pointing to separate mechanisms for post-exertional malaise in these diseases.

Finkelmeyer et al. found abnormalities in grey and white matter in certain brain areas of CFS patients using magnetic resonance imaging (MRI) and the novel method of voxel-based morphometry (VBM).

5. Energy System Defects

Elevated oxidative stress levels, which impact mitochondrial energetics, have been well documented in patients and the body of evidence points to irregularities in various metabolic pathways. Researchers have also been probing the hypothesis that mitochondrial dysfunction in immune cells could be driving problems with immune system functioning in ME/CFS patients. Metabolomics (the large-scale study of metabolites) has emerged as a powerful tool to advance the study of cell energetics in ME/CFS:

Germain et al. conducted metabolic pathway analysis in a discovery (method building) cohort of ME/CFS patients. The data highlighted disturbances in fatty acid and lipid metabolism and found 35 metabolites are significantly altered in patients.

Tomas et al. assessed several parameters of cellular energetics (particularly, patterns in oxidative phosphorylation and glycolysis) in CFS patients and healthy controls. The results from their study of immune cells in blood samples supports the hypothesis of a hypometabolic response under both resting and high energy demand contexts.

6. Gut microbiome

ME/CFS is associated with gastrointestinal disturbances and dysbiosis of the microbiome has emerged as a strong study area of interest. Recent research into the gut microbiome explored alterations in gut microbiome composition in ME/CFS and the possibility that these differences disrupt the bidirectional communication between the brain and gut:

Nagy-Szakal et al. study findings bolstered previous work indicating intestinal dysbiosis in ME/CFS. The authors indicate that dysbiotic features that are uniquely ME/CFS associated may be masked by disturbances arising from the high prevalence of IBS comorbidity in ME/CFS.

Giloteaux et al. (2016) published findings of reduced overall microbial diversity in patient gut microbiomes and a proinflammatory environment, potentially leading to damage of the intestinal lining. The authors suspect these conditions might influence immune system function in ME/CFS patients.

7. Epigenetics

Research into a heritable component of ME/CFS has looked at the possibility that gene variants and epigenetics (modifications in gene expression) underlie ME/CFS pathophysiology, such as deficiencies in cell energy production and differential immune functioning. Genetic screening techniques hope hold promise to clarify this influence in disease onset and progression:

De Vega et al. found differences in DNA methylation (a mechanism that impacts gene expression) in immune cells from blood samples of a female cohort of ME/CFS patients in the SolveCFS BioBank that correlated with quality of life scores and glucocorticoid sensitivity. The authors noted that immune cell subtyping and epigenetic data might help reveal biological pathways in ME/CFS.

8. Clinical Research

It was recently reported that the Phase 3 clinical trial of rituximab in ME/CFS patients did not demonstrate clinical efficacy in the study group. However, the negative result does not discount the potential for benefit in an appropriately identified subgroup.

Hodges et al. looked at VO 2 (maximum amount of oxygen an individual can use during peak exercise) as a measure of fatigue across ME/CFS, multiple sclerosis and healthy control groups during a repeated exercise test. The results showed that a repeated cardiovascular test is required to notably distinguish ME/CFS from healthy controls and Multiple sclerosis (MS)MS patients, and suggests this protocol should be used in future studies.

___________________________________

The research and discovery process is multifaceted and costly. The Solve ME/CFS Initiative is committed to accelerating progress and, despite our modest budget, we have made great strides to fund innovative science and discovery projects in biologics, capacity building, and ME/CFS infrastructure development. We are currently operating five SMCI-Directed research projects with prestigious partners at seven universities and biotech companies and funding ten Ramsay Award Program research teams from twelve universities in seven countries, across four continents.