Important X-Post from Ralf Wittenbring – about an antibody for reducing plasma cells
Has the right drug for ME/CFS been found? Daratumumab in a pilot study
Imagine you suffer from ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome), a condition that causes extreme fatigue and exhaustion, often following infections such as COVID-19. Many sufferers can barely cope with their daily lives. Now there’s a small study that offers hope: The drug daratumumab, which is normally used for cancer, could significantly improve symptoms in some patients. But be careful, it’s only a pilot study—so it’s not definitive proof yet.
Ralf Wittenbrink’s (@RWittenbrink) thread on X summarizes this well. It’s based on a blog post by Cort Johnson and the actual study. I’ve turned it into an overview, with explanations for laypeople but also enough detail for doctors. Let’s go through it step by step.
The Problem with B Cells in ME/CFS and Long COVID
Studies on ME/CFS (chronic fatigue syndrome) have found stressed B cells (a type of immune cell that produces antibodies). These cells lack enough energy to function normally, or they are immature and don’t grow properly. Sometimes they are overactive, as if constantly stimulated by infections.
In long COVID (long-lasting symptoms after COVID-19), elevated levels of activated B cells and plasmablasts (cells that produce antibodies) indicate that the immune system is out of sync. These B cells produce IgG (immunoglobulin G, the most common antibodies). And here’s where it gets interesting:
When IgG from ME/CFS patients is given in lab tests or to mice, it causes problems such as damaged mitochondria (the cells’ energy powerhouses), injured endothelial cells (cells in the blood vessels), or pain and weakness.
This indicates autoantibodies – antibodies that attack the body’s own body. Researchers have therefore attempted to remove these harmful B cells, for example, with medications such as rituximab or cyclophosphamide, or procedures such as immunoadsorption (filtering antibodies from the blood).
Read more in Prof. Carmen Scheibenbogen’s X-Post: Study summary by Prof. Scheibenbogen.
The pilot study on daratumumab
The study is called “Plasma cell targeting with the anti-CD38 antibody daratumumab in myalgic encephalomyelitis/chronic fatigue syndrome – a clinical pilot study.” The goal was to destroy B cells that produce autoantibodies. This should improve blood flow, reduce oxygen deficiency (hypoxia), and alleviate symptoms.
These B cells can survive in the bone marrow or intestine for years, so the researchers hoped for long-term effects. Ten female patients participated. They received four injections of daratumumab (1800 mg) at weeks 0, 2, 4, and 6. The last four received additional maintenance doses at weeks 14, 22, and 30.
Before the injections, they received medications to combat side effects: dexamethasone (a cortisone), cetirizine (for allergies), paracetamol (pain reliever), and montelukast (for inflammation). The patients were observed for 12 to 24 months.
The full study can be found here: Fluge et al. (2025) Frontiers in Medicine.
Prof. Øystein Fluge’s lecture is also worth watching: Biological treatment strategies (with English subtitles), shared by @Sissel777 on X: Post by Sissel Sunde.
Results: Impressive, but not for everyone
Six out of ten patients experienced significant improvement. Their SF-36 physical function score (a quality of life questionnaire) rose from 32 to 78 – from severely limited daily functioning to almost normal.
In the end, five even had scores around 88, meaning hardly any limitations. They managed over 10,000 steps a day!
The improvement began after 6-8 weeks and lasted. For the other four, nothing changed.
Biologically: In those who improved, IgG levels (antibodies in the blood) decreased by 54%, especially IgG4 (a subclass) by 65%.
In those who did not improve, the decrease was only 40% and 29%, respectively.
Here is a graphic from the study showing the progression:
And another one on step count:
More graphics in the thread: Entire thread by Ralf Wittenbrink.
Another post by Prof. Scheibenbogen: Presentation on the daratumumab pilot study.
What does this mean? And next steps
Daratumumab is mostly used for cancer (such as multiple myeloma), but case reports show success in autoimmune diseases. Researchers are now starting tests with lower doses in long-COVID patients with higher levels of NK cells (natural killer cells, part of the immune system).
But: It’s a small, open-label study without a placebo control. The authors themselves say: No final conclusions will be drawn until a randomized study is available. They are planning one with 66 patients, including long-COVID cases, who meet ME/CFS criteria.
This sounds promising for integrative medicine approaches – i.e., as a complement to conventional medicine, perhaps off-label. But always discuss it with your doctor and weigh the risks!
References and further links
Fluge et al. (2025) Frontiers in Medicine (Link to study)
Cort Johnson (2025) Health Rising Blog (Link to blog post)
Possible laboratory values as inclusion criteria
From the pilot study on daratumumab in ME/CFS, several laboratory values and biomarkers can be derived that could serve as potential inclusion criteria for future studies or off-label applications.
The study is small (n=10), open-label, and without placebo control, so these conclusions are preliminary and evidence-based on correlations with clinical response.
I’m focusing on NK cells, IgG levels, IgG subclasses, and autoantibodies, as mentioned in your question.
Specific autoantibodies such as GPCR autoantibodies (e.g., against G protein-coupled receptors) are not explicitly tested or mentioned as a criterion in the study, but general screening for autoantibodies is relevant.
The study indirectly suggests that patients with higher baseline NK cell levels may be more likely to respond, while lower levels correlate with lack of response. IgG reduction (especially IgG4) is more pronounced in responders, suggesting a role for pathogenic antibodies.
NK cells as a potential predictor
The study shows a significant correlation between baseline NK cell counts (CD16/56-positive) and clinical improvement.
Responders had a mean baseline value of 238 × 10^6/L (range 136–383), while non-responders had only 97 × 10^6/L (range 80–115). The correlation with the maximum increase in the SF-36 Physical Function Score is Spearman’s rho of 0.77 (p=0.012).
After daratumumab, NK cells decline sharply (below or near the lower normal range of 59–533 × 10^6/L), with slow recovery after 5–9 months.
The authors discuss that low baseline NK cell counts could be a marker for lack of response and plan follow-up studies with patients who have higher NK cell counts (e.g., in long-COVID ME/CFS).
Suggested inclusion criteria: Patients with NK cell counts >150 × 10^6/L to increase the likelihood of response. This could be causally related to intact immune surveillance, which better controls pathogenic B cells.
3. IgG levels and subclasses
Baseline serum IgG was a mean of 9.9 g/L (range 6.8–13.2 g/L), which is within the normal range. The maximum relative reduction during treatment was 48% (range 22–62%), greater in responders (54%) than non-responders (40%). After 5 months, the mean reduction was 5.5 g/L, followed by an increase.
For subclasses: IgG1 reduction was 44% (50% responders, 34% non-responders). IgG4 was particularly notable: a 60% reduction overall (65% responders, 29% non-responders). This suggests that a greater depletion of IgG4-producing plasma cells is associated with improvement.
Suggested inclusion criteria: Normal or slightly elevated baseline IgG levels (e.g., >8 g/L), with a focus on the IgG4 subclass >0.5 g/L, as the reduction correlates most strongly with this subclass. Elevated total IgG could indicate chronic B cell activation, which the study considers to be the target.
4. Autoantibodies and Screening
The study screened for common autoantibodies: 8/10 patients had no positive findings. One had positive anti-TPO (thyroid peroxidase antibodies, with normal thyroid function), one had positive ANA (antinuclear antibodies), anti-CCP IgG, and ribosomal P IgG. Protective antibodies (e.g., against diphtheria, tetanus, SARS-CoV-2) remained stable.
Specific ME/CFS-associated autoantibodies such as those against GPCRs (e.g., muscarinic or beta-adrenergic receptors) were not tested. However, the study hypothesis is based on pathogenic autoantibodies from B cells that impair blood flow and endothelium.
Proposed inclusion criteria: Negative screening for classic autoimmune markers (e.g., ANA <1:160, anti-TPO <35 IU/ml) to rule out other diseases, but positive evidence for ME/CFS-specific autoantibodies (e.g., via commercial tests for GPCR antibodies) could be considered, as the study targets antibody-induced pathology. Reference is made in the discussion to IgG transfer studies demonstrating ME/CFS IgG damage.
5. Further patient characteristics and implications
All patients were female, mean age 38 years, disease duration 12 years, with a defined onset (mostly post-infectious).
No long-COVID cases.
Responders showed significant improvement in SF-36 and DSQ-SF, with >10,000 steps/day.
So for whom might this expensive drug be useful:
Patients with baseline NK cells >200 × 10^6/L and IgG reduction potential as criteria for testing daratumumab off-label.
But: Only pilot data, randomized trial with 66 patients planned.
Reference: Flights (2025) Front Med https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2025.1607353/full
Google CENSORSHIP!
Google censors my homepage quite a bit, sometimes I am not even able to find my articles on Google. So please sign up for the newsletter and share it with friends or via Facebook and use the search function on my website. Follow me on Twitter, where I also announce important articles.
