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Research Digest 29/05/20

Welcome to the 48th Emerge Australia Research Digest, where you will find summaries of some of the latest research and information about ME/CFS, with links to the complete articles.

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Autoimmunity-related Risk Variants in PTPN22 and CTLA4 are Associated with ME/CFS with Infectious Onset

Authors: Steiner S, Becker S C, Hartwig J, Sotzny F, Lorenz S, Bauer S, Löbel M, Stittrich A B, Grabowski P, Scheibenbogen C

Single nucleotide polymorphisms (SNP) in various genes have been described to be associated with susceptibility to autoimmune disease. This study analysed five immune gene SNPs which have been associated with autoimmune diseases such as type 1 diabetes, rheumatoid arthritis and Graves’ disease. It further examined the association between these SNPs and the onset of infection-triggered ME/CFS.

This study included 305 ME/CFS patients (diagnosed according to the Canadian Consensus Criteria) and 201 healthy controls. There was a significantly greater frequency of two SNPs (PTPN22, rs2476601 and CTLA4, rs3087243) in ME/CFS patients compared to the controls. Both genes play a key role in regulating B and T cell activation. However, the associations were only found in ME/CFS patients who reported an acute onset of disease with an infection.

This study provides further evidence that there is a genetic predisposition for ME/CFS, and that autoimmunity may be a factor for at least a subset of patients.

A Systematic Review of Neurological Impairments in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome Using Neuroimaging Techniques

Author: Maksoud R, du Preez S, Eaton-Fitch N, Thapaliya K, Barnden L, Cabanas H, Staines D, Marshall-Gradisnik S

This is the first systematic review to collect and evaluate the literature related to neurological changes in ME/CFS patients, as measured by neuroimaging techniques. Fifty-five studies were reviewed that used neuroimaging techniques to assess neurological or cognitive differences in adult ME/CFS patients compared to healthy controls. Four different neuroimaging techniques were used in the review studies: magnetic resonance imaging (MRI), functional MRI, PET scans, and magnetic resonance spectroscopy. 

The review found evidence that people with ME/CFS exhibit autonomic disruption as well as changes in white matter and functional connectivity, but results were inconsistent across the studies reviewed. However, the authors report that the research did show “consistent examples of altered brain health, e.g. an increase in neuroinflammation suggestive of a neuroimmune mechanism and reduced functional efficiency”.

Of the 55 papers in this review, 43 used the Fukuda criteria to classify ME/CFS patients. The authors propose that because the broader Fukuda criteria selects a heterogeneous patient group, this could go some way to explaining the variability in results both within and between studies. 

Further research is required to understand neurological involvement in ME/CFS pathology with larger sample sizes and stricter diagnostic criteria.

Intravenous Cyclophosphamide in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. An Open-label Phase II Study

Author: Rekeland I G, Fosså A, Lande A, Ktoridou-Valen I, Sørland K, Holsen M, Tronstad K J, Risa K, Alme K, Viken M K, Lie BA, Dahl O, Mella O, Fluge O

These authors have hypothesised that ME/CFS could be an autoimmune condition, possibly involving B cells and autoantibodies. They note that ME/CFS patients on their oncology ward who underwent cancer treatment with cyclophosphamide showed ME/CFS-related improvements. Cyclophosphamide is an immunosuppressant which is used in chemotherapy as well as in the treatment of autoimmune conditions. These authors have previously undertaken an unsuccessful Phase III trial with Rituximab, a monoclonal antibody which targets B-cells.

This study was a Phase II open-label clinical trial with 40 ME/CFS patients (diagnosed according to the Canadian Consensus Criteria) to determine the viability of cyclophosphamide as a treatment for ME/CFS. Fifteen of the participants had previously received Rituximab. Participants received six intravenous infusions of cyclophosphamide at four-week intervals. Patient follow-up was originally intended to last for 18 months but was extended to four years. The primary outcome measures were overall response rate and change in fatigue scores. Secondary outcome measures included response duration, physical function and mean number of steps taken in a 24-hour period. Human Leukocyte Antigen (HLA) genotyping was also undertaken to determine if genetic predisposition towards autoimmunity plays a role in treatment response. 

In terms of the primary outcome, 55% (20 out of 40) of patients reported significant improvement in fatigue with similar improvements also reported in secondary outcome measures.  In addition, at the four-year follow-up mark, 68% (15 out of 22) of those who had responded to the treatment had maintained their improvement (which the authors labelled “remission”). Further, an association was found between two HLA risk alleles and better outcomes following treatment.

However, adverse reactions were common and ranged from mild (nausea to constipation) to serious (requiring hospitalisation). The authors concluded that toxicity of cyclophosphamide in ME/CFS patients is moderate, with only a few serious adverse events. The adverse events together with the absence of blinding and a control group in this trial means that the results should be treated with caution.

Overall, the results showed that cyclophosphamide may be a feasible treatment for ME/CFS patients with an acceptable toxicity profile and a future randomised trial is warranted.

Thirty-five-year-old Living in Aged Care Reveals What Life is Like Inside During this Pandemic

Author: Wooding, K

Ketra Wooding is a 35-year-old woman living with severe ME/CFS who was forced into an aged care facility after spending three months in hospital.

Living among people who are about 50 years older than she is, Ketra’s feeling of isolation is compounded by the COVID-19 lockdown rules. Ketra describes her hopes for enough NDIS support to allow her to live independently at home, and access to telehealth services so she can consult with health professionals.

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