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We’re back to the B-cells, and that brings us back to the Charité 3rd International ME/CFS and long COVID Conference. B and T-cells are the two main players in the adaptive or late immune response. They’re the cells we depend on to wipe out infections, and when they go bad, really bad things can happen.

Key players in the adaptive immune response – when B-cells go bad, they can really go bad.

ME/CFS studies have found stressed B-cells, which lack the energy to function normally; immature B-cells that just don’t want to grow up, or go on the attack (high CD24 levels); proliferating B-cells with reduced mitochondrial mass; which appear to be chronically activated by infections; as well as overactive B-cells.

B-cell study is in its infancy in fibromyalgia. Still, Andreas Goebel’s recent preprint suggests fibromyalgia exhibits problems in B-cell tolerance (exaggerated B-cell proliferative responses, enhanced clonal expansion, autoantibody production) that mirror those seen in autoimmune diseases. Plus, a recent gene expression study found highly activated B-cells in FM that were pumping out interferons and inflammatory cytokines at a high rate.

In long COVID, increased levels of activated B-cells, increased plasmablasts (antibody-producing B-cells), and functionally impaired B-cells suggest that B-cells have been chronically turned on (and are suffering for it).

Note that in all these studies, evidence of chronic B-cell activation has emerged. That’s not a great finding given what the IgG transfer studies have found.

New drug – new possibility

The GIST

• The Rituximab study didn’t go so well, but Fluge and Mella haven’t given up yet. At the recent Charite International conference, Fluge presented data on a new B-cell depleting drug called daratumumab.
• Studies suggest that chronically activated B-cells are causing problems in ME/CFS, FM, and long COVID, Indeed, when things go wrong with these major players in the immune response, bad things can happen. B-cell problems play a role in a wide swath of major diseases, including lupus, MS, and rheumatoid arthritis.
• Activated B-cells produce immunoglobulins (IgGs, also known as antibodies), and IgG/antibody transfer studies in ME/CFS, fibromyalgia, and long COVID consistently suggest that something pathogenic has gone awry with their IgG production.
• These findings have prompted attempts to filter out or remove bad B-cells in various ways (Rituximab, cyclophosphamide, immunoadsorption/plasmapheresis, IVIG, daratumumab). The Open Medicine Foundation’s TREATME survey found that IVIG was the most efficacious treatment.
• Convinced that a different B-cell depleter would work better, Fluge and Mella produced a small 10-person pilot trial of daratumumab (Darzalex), which targets a different B-cell than Rituximab, that followed patients for at least a year.
• The results were stark: about half the patients improved dramatically, many reaching a normal level of function, while the other half didn’t improve at all. The improvements began 6-8 weeks after the first injection (no placebo was used here!) and continued to increase over time.
• An analysis suggested that dramatic drops in IgG4 antibodies may have been responsible. High IgG4 levels can lead to an overproduction of collagen, resulting in the excessive growth of connective tissue. That’s an interesting finding given the collagen thickening in the capillaries found in the Wust group’s recent muscle study, which could be impairing blood flow. Indeed, high IgG4 levels can negatively affect the blood vessels in numerous ways, including impairing blood flows.
• While high IgG4 levels were not found at baseline in these patients, high antibody levels aren’t always necessary to cause disease.
• Given the small size of the study and the absence of placebo controls, the authors noted, “No definite conclusions should be drawn before a randomized study has been performed.”  but have applied for a 66-patient, randomized, double-blind, and placebo-controlled ME/CFS study (including long-COVID patients who meet ME/CFS criteria (CCC)). They hope it will be approved shortly.
• Another B-cell depleting study – on Rituximab, of all things – is underway in Japan. Despite the fact that Rituximab failed in ME/CFS, the authors of that study wrote that “our pooled experience supports that some ME/CFS patients seem to respond to rituximab and B-cell depletion“, and noted that the maintenance dose in the large study had been reduced.
• The Japanese study will utilize standard maintenance doses and conduct a range of assessments, including brain, microbiome, immune, and metabolic evaluations, to determine who benefits.

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Activated B-cells make immunoglobulins (IgGs, aka antibodies); and IgG/antibody transfer studies in ME/CFS, fibromyalgia, and long COVID consistently suggest that something pathogenic has gone wrong with their IgG.

IgG from people with ME/CFS has fragmented mitochondrial and damaged endothelial cells in culture. Mice given fibromyalgia IgG exhibit increased pain response, reduced grip strength, and small nerve fiber damage. Long-COVID IgG has been shown to produce reduced activity, increased pain, dizziness, and sensory stimulation in mice.

These findings have prompted attempts to filter out or remove bad B-cells or their antibodies in various ways (Rituximab, cyclophosphamide, immunoadsorption/plasmapheresis, IVIG, daratumumab). The Open Medicine Foundation’s TREATME survey found that IVIG was the most efficacious treatment.

A different B-cell depleter, cyclophosphamide (red), proves more effective than Rituximab (blue) in ME/CFS.

The Cyclophosphamide Lesson

Probably because it’s too toxic for widespread use, Fluge and Mella’s successful trial of a B-cell inhibiting drug called cyclophosphamide hasn’t gained much attention.

A mustard compound that emerged during research on chemical warfare, cyclophosphamide was originally developed to treat cancer, but it’s also a highly effective B-cell depleter, which depletes different kinds of B-cells than Rituximab.

Note how much better cyclophosphamide performed in ME/CFS than Rituximab did.

Given the huge role B-cell dysregulation plays in many diseases (lupus, multiple sclerosis, Sjogren’s Syndrome, rheumatoid arthritis, type I diabetes, Crohn’s disease, chronic hepatitis, etc.), it wouldn’t be surprising at all if something was off with the B-cells in the ME/CFS/FM/long-COVID suite of diseases.

The mAbs (Monoclonal Antibodies)

It was Fluge and Mella who got the ME/CFS Rutuximab studies going in Norway and it’s back to Norway we go with a new study using a different mAb called daratumumab. Fluge, Mella and Tronstadt now believe they know why the big Rituximab ME/CFS trial failed: it targeted the wrong B cells.

The autoantibody picture is somewhat mixed, but adding IgGs from patients with ME/CFS, fibromyalgia, and long COVID to mice and culture suggests something pathogenic is present.

Rituximab targets CD20 B-cells, which tend to have a shorter lifespan. The authors believe, however, that the autoantibody production found in ME/CFS is likely coming from longer-lived B cells, which daratumumab targets.

They believe that alterations in the levels of “functional autoantibodies”, i.e., autoantibodies that play a positive role in the body, as opposed to “reactive autoantibodies”, autoantibodies that attack the tissues, are in play in ME/CFS and long COVID.

The autoantibody evidence is mixed. The functional autoantibodies believed in play in ME/CFS – those that impact the beta-adrenergic receptors (β1, β2 AdR) and/or muscarinic cholinergic receptors (M3, M4) – are complex and difficult to measure. Some studies suggest they are contributing to the dysautonomia in a subset of people with ME/CFS. Other studies have not found that. Using a sophisticated testing regimen, Hanson’s group recently did not find evidence of upregulated autoantibodies.

It’s possible, though, that autoantibody balances may be more important than single autoantibody levels.

The Daratumumab (Darzalex) ME/CFS Study

https://events.mecfs-research.org/en/events/conference_2025/videos/oystein-fluge-plasma-cell-targeting-daratumumab-mecfs

The goal of the “Plasma cell targeting with the anti-CD38 antibody daratumumab in myalgic encephalomyelitis/chronic fatigue syndrome—a clinical pilot study” study was to wipe out autoantibody-secreting B-cells in an attempt to improve blood flow, reduce preload and hypoxia, and improve symptoms.

Because B-cells they were after can live for decades in the bone marrow or gut wall, the authors hoped that altering levels could produce long-term changes.

The Norwegian B-cell depletion saga from Oystein Fluge.

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The Study

The small study followed 10 female ME/CFS patients who received daratumumab injections (1,800 mg) at weeks 0, 2, 4, and 6, with added maintenance treatments at weeks 14, 22, and 30 for the last four patients.

Image by Niels-W.-C.-J.-van-de-Donk,-Maarten-L

Prior to the first injection, dexamethasone 10 mg orally, cetirizine 10 mg orally, paracetamol 1 g orally, and montelukast 10 mg orally were given. Two days after the injections, they received dexamethasone 4 mg orally. If patients experienced no adverse reactions to the first daratumumab injection, dexamethasone 10 mg, cetirizine 10 mg, and paracetamol 1 g were administered prior to the next injection.

They were followed for at least 12 months, and in some cases for 24 months.

Results

The results were impressive. Six out of ten patients experienced “marked improvement”: i.e. SF physical function score more than doubled (!). The improvement from 32 to 78 translates to going from having major difficulties with moderate activities or self-care tasks to a level of functioning that’s close to normal (!). It got even better. By the end of the study, five of the six improvers ended up with a mean SF-36 PF of 88 (range 80–95) – indicating they had “almost no physical limitations”. Five of the responders were able to maintain a mean step count above 10,000/24 h for some weeks at a time.

The improvements began 6-8 weeks after the first injection (no placebo here!) and increased over time.

The patients who didn’t improve showed no changes at all. There was no guessing who did or did not improve; either a patient did really well or did not improve at all.

Surprise Impact

Biologically, the study aimed to reduce serum IgG levels. Patients who improved had a more pronounced reduction in IgG antibodies (54%) than those who did not (40%). Most interestingly, it was the smallest subclass of IgG antibodies, IgG4, which decreased the most in those who improved. IgG4 antibodies were reduced by 65% in responders but only by 29% in non-responders.

IgG1 vs IgG4 antibodies. (Rumo Berlin, CC BY-SA 4.0 via Wikimedia Commons)

These seemed a bit odd as IgG4 is also the only IgG antibody class that has not been linked to the beta-adrenergic (β1, β2) and muscarinic (M3, M4) autoantibodies these researchers were aiming at. Only one ME/CFS/long-COVID study has highlighted high IgG4 levels.

Yet, this preliminary study suggested that daratumumab may have achieved its good work by knocking down IgG4 antibodies.

I’m particularly interested in IgG4 because I have consistently very high IgG4 levels, which can drive tissue inflammation and fibrosis. In IgG4-related disease (IgG4-RD), the tissue inflammation often also drives mast cell production, which then interacts with IgG4 to produce more inflammation.

Indeed, high IgG4 levels can cause an overproduction of collagen and growth of the extracellular matrix, resulting in the excessive growth of the connective tissue. That’s an interesting finding given the collagen thickening in the capillaries found in the Wust group’s recent muscle study, which could be impairing blood flow. High IgG4 levels can negatively affect the blood vessels in numerous ways including impairing blood flows.

Of course, IgG4 antibody levels do not need to be high to drive disease. Even low levels of highly specific autoantibodies can produce major effects (myasthenia gravis, Graves disease) in some diseases. Antibodies can also have localized effects that are not reflected in serum samples. Note that high IgG4 levels were not found at baseline in these patients, but reducing IgG4 may have played a key role in the patients’ recoveries.

Higher NK cell numbers at baseline were associated with a better response.

While daratumumab is usually used in cancer, the authors noted a series of case studies suggesting it can be highly effective in autoimmune patients who have not responded to treatment. Because those studies suggest that the first daratumumab injection may be the most important one, they’re beginning a new series of tests using fewer doses in four long-COVID ME/CFS patients (with higher baseline NK cell levels).

Given the small size of the study and the absence of placebo controls, the authors noted, “No definite conclusions should be drawn before a randomized study has been performed.”  but have applied for a 66-patient, randomized, double-blind, and placebo-controlled ME/CFS study (including long-COVID patients who meet ME/CFS criteria (CCC)). They hope it will be approved shortly.

New Rituximab Study Underway

A new 30-person Rituximab study is underway in Japan. One might ask, “Why?” Fluge and Mella’s six-year update of the 2017 151-person double-blinded Norwegian Rituximab study found no evidence that Rituximab had positive effects.

Yet Fluge and Mella’s followup study also stated that “our pooled experience supports that some ME/CFS patients seem to respond to rituximab and B-cell depletion“, and provides some reasons why the big Rituximab study may have gone bust.

Patient heterogeneity is probably always going to be high on anyone’s list as we don’t know how to biologically target patients for drug trials, but the authors also noted the lower maintenance doses of rituximab used than in the previous phase II studies. (I read somewhere that funding was an issue in that.)

The Japanese speaker did not explain why they chose to do another Rituximab study, but the new study will adhere to traditional maintenance doses and focus on exploring Rituximab’s effect on the gut microbiome, the brain (both SPECT and MRI), the immune system (flow cytometry, B-cell repertoire, a couple of autoantibodies), and metabolomics. If it is successful in at least some patients, it may help tell us which patients are more likely to benefit.

• As a side note, a case report just appeared on a person with a diagnosis of ME/CFS and later multiple sclerosis who responded well to Rituximab after other treatments had failed.

The Past is Not Necessarily Prologue

New drug – new possibility.

Some people will probably look at Fluge and Mella’s two successful small Rituximab studies and then the big Rituximab study that bombed and throw up their hands and assume the same pattern will occur with daratumumab.

Time will tell what happens with daratumumab, but consider that it affects B-cells differently, that Fluge/Mella and the Norway team picked it because they feel they know more about the B-cell situation in ME/CFS now, that another B-cell depleting drug (cyclophosphamide) appears to be helpful, and finally, that this is how science proceeds.

It’s a pity that it proceeds so slowly for ME/CFS, but perhaps it’s not surprising that the first try at a B-cell drug didn’t go so well.

Conclusion

Studies including IgG (antibody) transfer experiments suggest problems with the B-cells exist in ME/CFS, fibromyalgia and long COVID, and many B-cell depleting efforts (monoclonal antibodies, plasmapheresis, immunoadsorption, IVIG) are being tried in these diseases.

A small open-label study found that a B-cell depleter called daratumumab (which affects B-cells differently than Rituximab) was either highly effective or did nothing at all. By the end of the study, half the patients reported on physical functioning questionnaires that had “almost no physical limitations”.

While it’s not clear how daratumumab achieved its effects, its significant reduction of IgG4 antibodies suggests that IgG4 antibodies may play a major role in ME/CFS. While the baseline levels of IgG4 antibodies were not high, these antibodies can lead to an overproduction of collagen, resulting in excessive growth of connective tissue. That’s an interesting finding given the collagen thickening in the capillaries found in the Wust group’s recent muscle study, which could be impairing blood flows.

Last month, the authors applied for a 66-patient, randomized, double-blind, placebo-controlled study of daratumumab in ME/CFS.

A smaller Japanese Rituximab study, which will use higher maintenance doses than did the big Rituximab study, is underway. It will feature numerous exploratory analyses in an attempt to understand both Rituximab’s effects and what’s happening in ME/CFS.

Check out the first blog on the 2025 Charité ME/CFS and long COVID Conference

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After doing some digging – the light bulb went on.

When I first saw daratumumab, I thought, “Oh boy, another B-cell depleting drug – and from Norway! Don’t they know when to give up?”.

But then I started digging. I found that the big Rituximab study may have had some problems (low maintenance dose), that Fluge and Mella had demonstrated that B-cell depletion could be effective, that daratumumab affects different B-cells than Rituximab, and that the pilot study had yielded very good results. Plus, there were all these studies suggesting that something had gone wrong with the B-cells in ME/CFS. FM and long COVID…Now I was excited.

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