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Medscape Medical News > Conference News > IACFS/ME 2025
Research Into ME/CFS Pathology Points to Possible Treatments
Miriam E. Tucker
November 07, 2025
New possibilities for the treatment of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID are emerging as research continues to untangle the complex, multisystem pathophysiology of the two overlapping diseases.
At International Association for Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis (IACFS/ME) 2025, speakers summarized their research into the underlying pathomechanisms of ME/CFS and long COVID and the potential for treatment approaches specifically targeting those identified abnormalities.
“We understand pathophysiology of ME much better than we used to, including the central role of neuroinflammation and the interaction of abnormalities in various systems such as the autonomic nervous system, circulatory, immune system, endocrine, and energy metabolism. Those abnormalities in all those systems continuously feed each other in a vicious cycle that helps to perpetuate the symptoms,” IACFS/ME board member and conference co-organizer Luis Nacul, MD, PhD, told Medscape Medical News.
Abnormalities of the immune system and the nervous system precede the others and therefore are important focuses of both basic and translational research, said Nacul, clinical associate professor at both the London School of Hygiene and Tropical Medicine in London, England, and at the University of British Columbia, Vancouver, British Columbia, Canada.
Any treatment for ME/CFS, including for those diagnosed with long COVID who meet ME/CFS criteria, will likely not work for all patients, nor as monotherapies, noted Nacul, who is currently studying low-dose naltrexone to target neuroinflammation in “post-COVID fatigue syndrome.”
“I think we will need many treatments because a combination may be more appropriate for most patients, and some treatments will be good for some, and other treatments for others. I don’t think there is a magic pill that will be the monotherapy, at least not soon,” Nacul said.
Autoimmunity Is a Major Research Focus and Potential Treatment Target
Carmen Scheibenbogen, MD, director of the Institute for Medical Immunology at Charité Hospital, Berlin, Germany, and Øystein Fluge, MD, PhD, Senior Consultant supervising the ME/CFS research group at the Department of Oncology and Medical Physics, University of Bergen, Haukeland University Hospital, Bergen, Norway, each spoke about their respective work examining the role of autoimmunity in ME/CFS and long COVID and their ongoing research into treatments aimed at quelling those processes. “I believe that autoimmunity is a key pathomechanism in a subgroup of ME/CFS patients, and that we have really made breakthroughs in recent years in understanding of this,” Scheibenbogen said in her introduction.
In a 2018 paper, Scheibenbogen and colleagues reviewed the literature up to that point, finding that autoimmune mechanisms can be linked with ME/CFS at least in a subset of patients, with most of the identified autoantibodies targeting nuclear and neurotransmitter receptors. They also identified multiple complex interactions with evidence of inflammation, associations with Epstein-Barr virus reactivation, autonomic dysfunction including sympathetic overactivity and vascular dysregulation with hypoperfusion, and impaired energy metabolism.
“We think the immune dysregulation is probably at the beginning of this…and we now have clear evidence that several of these dysfunctions are also associated with symptom severity, and altogether these mechanisms can explain the complex clinical symptoms of ME/CFS including post-exertional malaise,” she said.
Scheibenbogen also noted that in the recent landmark Decode ME study of 15,579 patients with ME/CFS and 259,909 control individuals, 29 of the gene variants linked to ME/CFS were related to immune dysregulation, autoimmunity, impaired antiviral immunity, nervous system dysfunction, and mitochondrial function.
Other studies have found evidence of autoantibodies in both ME/CFS and long COVID. In particular, her group has found that G-protein coupled receptor autoantibodies are dysregulated and are correlated with symptoms, including fatigue severity and cognitive impairment.
Scheibenbogen’s team has received funding from the German government for a multipronged clinical trial platform that aims to perform clinical trials of multiple drugs simultaneously, along with comprehensive mechanistic studies. One of these showed significant symptom improvement using immunoadsorption in a majority of 20 patients with post-COVID ME/CFS who had elevated beta-adrenergic receptor antibodies. This approach involves selectively removing immunoglobulins from circulation via extracorporeal adsorption from plasma, similar to dialysis. “They are not fully recovered because we do not get rid of all the antibodies…but it gives us strong evidence that antibodies do play a role in the disease, that they are actually disease-causing,” she said.
And this findings points to the potential use of drugs that target autoantibody-producing cells. Her team is now seeking further funding to perform a study comparing intravenous treatment with the anti-CD20 antibody ublituximab and the anti-CD19 antibody inebilizumab against placebo. Both are already on the market for treating autoimmune diseases. “Autoantibody-targeting therapies hold promise as effective treatment for the autoimmune subset of long COVID and ME/CFS,” she concluded.
Fluge introduced his talk by saying “We have been working for 20 years on the assumption that, in a subset of patients, ME/CFS may be an autoantibody-mediated disease…Even though many patients remain ill for decades or lifelong, I think it is, in principle, reversible. There are usually no signs of obvious lasting organ damage if the patient recovers.”
Based on evidence that ME/CFS is a variant of an autoimmune disease with roles for B cells, plasma cells, and functional autoantibodies, Fluge’s team had previously studied both rituximab, which targets CD20 on B cells, and cyclophosphamide, which inhibits the action of B cells. Cyclophosphamide was deemed too toxic, while a phase 3 randomized placebo-controlled trial of rituximab did not achieve its primary endpoint of reduction in fatigue scores at 2 years, primarily attributed to heterogeneity of the study sample.
Now, he’s investigating the anti-CD38 monoclonal antibody daratumumab, currently approved for treating multiple myeloma and amyloidosis. In a recent pilot study, subcutaneous daratumumab in 10 patients with ME/CFS was well tolerated and was associated with significant improvement in physical function in six patients at 12-24 months.
The responders showed significantly greater reductions in serum immunoglobulin G than the four nonresponders and had higher natural killer cells at baseline. “But due to the very low numbers in the study, this could be coincidental,” Fluge noted, adding “we should not make any conclusions before we have seen a double-blind, randomized study.”
In fact, such a study has been initiated, a phase 2, randomized, double-blind, placebo-controlled trial of daratumumab vs placebo injections in 66 patients with ME/CFS. “This study has no public funding, and no support from the pharmaceutical industry. But if this randomized trial is positive, we will need some kind of pharmaceutical interest [to proceed],” he noted.
Meanwhile, a new phase 2, placebo-controlled, double-blind rituximab trial has been launched in Japan by Wakiro Sato, MD, PhD, chief of Section of Research and Development Strategy, Translational Medical Center, National Center of Neurology and Psychiatry, Tokyo, Japan. A total of 30 adults with ME/CFS will receive either rituximab or placebo for 24 weeks, then will be switched. The primary endpoint is the proportion of patients showing improvement on Performance Status scores by more than one point at 24 weeks. Secondary endpoints will include time spent standing/sitting/supine, fatigue levels at rest and during exertion, quality of life, grip strength, brain imaging, and immune markers.
Sato said he hopes to take the lessons from the earlier rituximab trials forward by identifying the subgroups of patients in whom the drug is effective. And more objective measures will be assessed. “The focus is exploratory…the findings will be incorporated into protocols for subsequent higher-stage trials,” he told Medscape Medical News.
He added that patients in the trial will be allowed to continue treatments they’ve already been taking, such as supplements, gastrointestinal medications, and traditional medicines while receiving rituximab. “This approach closely mirrors real-world clinical practice. Enrollment is proceeding smoothly, so I expect results come in a few years.”
Ion Channels and Low-Dose Naltrexone
Sonya Gradisnik-Marshall, PhD, of the National Centre for Neuroimmunology and Emerging Diseases, Griffith University, Gold Coast, Queensland, Australia, discussed recently-published findings from her group’s study of low-dose naltrexone in nine individuals with long COVID. Dysfunctional Transient Receptor Potential Melastatin 3 (TRPM3) ion channels are associated with the pathophysiology of long COVID due to reduced calcium (Ca2+) influx, negatively affecting cellular processes, she explained.
The study showed low-dose naltrexone treatment restored TRPM3 ion channel function in natural killer cells, with no significant difference following treatment in TRPM3 currents assessed by electrophysiology between the patients with long COVID and healthy control individuals. “Overall, our findings support low-dose naltrexone as a potentially beneficial treatment for long COVID patients by restoring TRPM3 ion channel function and reestablishing adequate Ca2+ influx necessary for homeostatic cellular processes,” she concluded.
To read the full article go to https://www.medscape.com/viewarticle/research-me-cfs-pathology-points-possible-treatments-2025a1000uuu