Geoff’s Narrations
Treatment Takeaways
The Blog
Treatment Takeaways
- “Treatment Takeaways” will now be a feature on the blogs.
- Jen found her way to health via a cytokine panel, a doctor willing to get creative, and a lot of persistence. Cytokine panels can theoretically be ordered by patients. I was having trouble, however, finding one in Quest or Labcorp that was available. Maybe others will have better luck.
- Approved in 2019, Rinvoq is one of nine JAK inhibitors approved for use in the U.S – three of which were approved in the last two years. These drugs work inside the cell to turn off the signals that spark the cell to produce inflammation. They can inhibit the production of many immune factors including most of the interleukins and all the interferons.
- These wide-ranging drugs have been shown to improve the joints in rheumatoid arthritis and psoriatic arthritis, the gut in Crohn’s disease and ulcerative colitis, the spine in ankylosing spondylitis, and the skin in atopic dermatitis.
- Even though Jen’s illness began with an infection, and testing showed that she’d been exposed to multiple pathogens, pathogens weren’t her problem – the immune hyperactivation that the pathogens triggered was. Jen appears to fit into the “hit and run” hypothesis of ME/CFS where a pathogen triggers a long-lasting immune dysfunction.
- Jen’s system simply needed to be reset and once she found the right drug it reset itself amazingly quickly – and then – and here’s the really good part – it has remained reset. Even though she’d been largely bedbound for almost two decades no long-term damage appeared to have been done.
- Jen probably fits a specific subset of ME/CFS patients – those with increased cytokine levels. We know that everyone doesn’t fit this profile because ME/CFS cytokine studies have had such variable results. Plus her results also seem at odds with findings of T and B-cell exhaustion, and studies suggesting that pathogen persistence may be triggering long COVID.
- That’s not surprising- we should expect multiple immune subsets in these diseases.Jen’s story is an example of what precision medicine; that is medicine driven by testing results and not purely by disease status – can achieve.
- Long COVID has triggered interest in powerful immune drugs that never saw the light of day in ME/CFS – and clinical trials are underway. The best hope for rapid movement lies with the rejiggered RECOVER initiative which, with its recent $500 million outlay, has promised to take a more creative approach to long COVID clinical trials. Time will tell – but if the initiative follows through it could fairly quickly provide data on a wide array of drugs.
Jen’s cytokine panel indicated she needed to bring them down.
The Crucial Test
The results from a cytokine multiplex 18-panel test gave Jen the target she needed to find the drug that helped her. These panels typically assess a range of cytokines involved in immune responses and inflammation.
Some of the cytokines commonly included in such a panel are:
- Tumor Necrosis Factor Alpha (TNF-α)
- Interleukin-1 Beta (IL-1β)
- Interleukin-2 (IL-2)
- Interleukin-4 (IL-4)
- Interleukin-6 (IL-6)
- Interleukin-10 (IL-10)
- Interleukin-12 (IL-12)
- Interleukin-13 (IL-13)
- Interleukin-17 (IL-17)
- Interferon Gamma (IFN-γ)
- Interleukin-18 (IL-18)
- Monocyte Chemoattractant Protein-1 (MCP-1)
- Macrophage Inflammatory Protein-1α (MIP-1α)
- Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF)
- Interferon Alpha (IFN-α)
- Interferon Beta (IFN-β)
- CCL3/MIP-1α
- CCL2/MCP-1
Note that a doctor’s prescription is not needed to order this test. (To get an insurance company to pay for it, yes, but not to order it). Finding one may not be so easy, though. Quest Diagnostics says they provide a cytokine panel (but not in my area). An AI search stated that Labcorp does (but I could not find it).
The Drug
Upadacitinib, or Rinvoq, the drug that proved so helpful, is a selective Janus kinase (JAK) inhibitor approved by the US Food and Drug Administration, the European Medicines Agency, and other agencies around the world to treat chronic inflammatory and/or autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, atopic dermatitis, ulcerative colitis, Crohn’s disease.
JAK inhibitors work inside the cell to stop it from producing inflammatory molecules.
Approved in 2019, Rinvoq is a relatively new drug. It’s one of nine JAK inhibitors approved for use in the U.S. JAK-inhibiting drugs appear to be a growth field: three were approved in the last two years and other, potentially more potent, drugs are being developed.
These drugs work inside the cell to turn off the signals that spark the cell to produce inflammation. They do this by shutting down enzymes called Janus kinases which trigger the JAK-STAT pathway. This pathway gets activated when an immune factor – a cytokine – lands on a receptor on the outside of a cell. That receptor turns on the JAK-STAT pathway which activates inflammatory genes in the nucleus of the cell, causing it to produce inflammatory molecules.
This pathway is involved in a wide range of inflammatory activities. Rinvoq is able to inhibit the production of many immune factors, including most of the interleukins (IL-2, IL-4, IL-6, IL-7, IL-9, IL-10, IL-12, IL-13, IL-15, IL-21, and IL-23), all the interferons (IFN-α, IFN-β, and IFN-γ), and growth factors (erythropoietin (EPO), thrombopoietin (TPO), and granulocyte colony-stimulating factor (G-CSF)).
Rinvoq is particularly effective at blocking the JAK1 enzyme, but since the 4 JAK enzymes work cooperatively, blocking one may help block others. It demonstrates as well as any drug how one drug can be helpful in so many different diseases. By tamping down inflammation it’s been shown improve the joints in rheumatoid arthritis and psoriatic arthritis, the gut in Crohn’s disease and ulcerative colitis, the spine in ankylosing spondylitis, and the skin in atopic dermatitis.
JAK inhibitors are being trialed in a wide range of disorders including ulcerative colitis, systemic lupus erythematosus, giant cell arteritis, eosinophilic disorders, diabetes, leukemia, alopecia areata and allergic disorders, uveitis, inflammatory rheumatism, etc.
Exactly where in Jen’s body Rinvoq halted the inflammation is an intriguing and important question.
Putting a stop to her cytokine storm worked for Jen.
Immune Suppression Works
One of the first things to know about these drugs is that they are immune suppressants. Despite the fact that Jen’s illness began with an infection, and testing showed that she’d been exposed to multiple pathogens, the pathogens weren’t the problem. If they had been, she likely would have gotten worse. (One of the most common side effects is an increase in upper respiratory infections.)
Instead, she appears to fit into the “hit and run” hypothesis of ME/CFS where a pathogen triggers a long-lasting immune dysfunction. The pathogen probably quickly became irrelevant and, as her attempts with antivirals showed, a treatment dead end. Instead, her testing showed that a hyperactive immune response was her problem.
Jen needed to reset her system, and once she did, it went back to operating normally.
Rapid System Reset – Even after 18 Years
Jen’s system simply needed to be reset, and once she found the right drug, it reset itself amazingly quickly – and then – and here’s the really good part – it has remained reset.
Her case seems reminiscent of Dr. Klimas’s model of ME/CFS as a disease in which a pathogen or toxin or whatever knocks ME/CFS patients’ systems out of their healthy, stable setpoint into a new, unhealthy but still stable setpoint. It takes work to get out of that setpoint – hence the need for the drug – but if you can move it back into its old healthy stable setpoint, you’re back to normal functioning.
Jen’s story suggests that despite her long and very arduous illness, no lasting harm was done – a hopeful conclusion.
The JAK Inhibitor ME/CFS / Long-COVID Connection
Jen’s wasn’t the first time that JAK inhibitors have shown up in long COVID or ME/CFS.
Wes Ely’s big baricitinib (Oluminant) REVERSE LC trial will thoroughly examine a different but similar JAK1 inhibitor. Olumiant and Rinvoq are both used to treat rheumatoid arthritis and skin conditions. The side effects – upper respiratory tract infections, nausea, and increased liver enzymes – are similar as well. While Rinvoq inhibits both JAK1 and JAK 3, Olumiant, which AI reported “had a slightly different efficacy profile”, primarily inhibits JAK1 and JAK2.
The 5-year 500-person NIH-funded study is underway at six universities (Emory University, University of California, San Francisco, University of Minnesota, Vanderbilt University, Yale University, and University of Pennsylvania) in the U.S.
Ely’s interest in baricitinib (Olumiant) dates back to a June 2020 study that used artificial intelligence to tag the JAK1/JAK2 inhibitor as a possible COVID-19 drug. The AI study, interestingly, predicted that Olumiant would suppress both inflammation and the coronavirus. (This is because Olumiant suppresses the kinases the coronavirus uses to propagate.)
Robert Phair has proposed that JAK-STAT inhibitors could block the IFN-a upregulation that may be happening. “WoodyRob” on the Phoenix Rising forums reported that Janet Dafoe recently tweeted that an ME/CFS patient improved on another JAK inhibitor, filgotinib.
A recent study that illuminated the “muscle-brain” connection, and specifically mentioned long COVID, proposed that STAT inhibitors such as ruxolitinib be trialed in long COVID. They believe these drugs could prevent the “muscle dysfunction associated with chronic and infectious diseases.”
Specific Subset
Please note that Jen probably fits a specific subset of ME/CFS patients – those with increased cytokine levels.
We know that everyone doesn’t fit this profile because the ME/CFS cytokine studies have had such variable results. Plus, her results also seem at odds with findings of T and B-cell exhaustion which – according to an AI query – should produce reduced cytokine levels. (The checkpoint inhibitors Avindra Nath proposed to unleash the immune system might have had disastrous results in ME/CFS.) Long-COVID studies and the monoclonal antibody results suggest that the virus, or parts of the virus, may be causing problems as well. In short, a number of different immune dysfunctions could be present.
ME/CFS and long COVID, of course, are heterogeneous diseases and we should expect different subsets to have differing immune profiles. Note how different a panel I had done in 2017 was. I have more low than high levels and only one really high cytokine (IL-2). My immune profile is something like high IL-2 levels, reactivated HHV-6, high IgG 4, and very low NK cell cytotoxicity. My partner’s panel is different from mine.
The Future
All of which calls for precision medicine; that is, medicine driven by testing results and not purely by disease status – which is what Jen received. The heterogeneity found in post-infectious diseases suggests that clinical trials should be accompanied by extensive biological testing to determine which patients most benefit from them and why. The Open Medicine Foundation’s LIFT study is an example of a study that’s doing that.
Thankfully, powerful immune drugs are being considered and tested in long COVID that were never allowed to see the light of day in ME/CFS or fibromyalgia. It makes sense that a powerful drug might be needed to address a powerful disease. Tony Komaroff’s 1996 study, showed, after all, that ME/CFS was significantly more functionally impairing than multiple sclerosis, heart disease, and others. People with these diseases should be able to take a shot at more powerful drugs.
That said, the NIH will still not let researchers apply for ME/CFS clinical trials via its special ME/CFS grant mechanism. (The research center’s grant will allow clinical trials.)
Research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) (R01 Clinical Trials Not Allowed)
Long COVID, though, has sparked more interest in these drugs. Monoclonal antibodies that produced similarly rapid and complete remissions in long COVID indicated that, as with Jen, the right drug in the right patient can produce wonders. At least three small long-COVID monoclonal antibody trials (one by Nancy Klimas) are underway.
IVIG is another drug that has been used with mixed effects in ME/CFS but can work very well in the right patient. An IVIG study is underway in the RECOVER Initiative, but the study unfortunately is not digging into the participants’ biologics. (The Paxlovid trial does, to some extent).
Besides these studies, two stem cell studies, Xiflam (a novel small molecule inhibitor and anti-inflammatory), the ensitrelvir antiviral (Henrich), HIV drugs (tenofovir disoproxil/emtricitabine and Selzentry (Putrino), anakinra and immunoadsorption are being trialed.
Long COVID is opening up treatment possibilities for post-infectious diseases.
These are nice starts, but we need much more. The NIH and the RECOVER Initiative (gulp) are where we once again have to look for rapid progress. The story of the RECOVER Initiative is not done, but thus far, its ponderous, top-down, uncreative approach appears to have displayed in brilliant colors all the shortcomings of the NIH.
After a horrific start that ate up hundreds of millions of dollars, the clinical trials section of the Initiative appears to have made a turnaround, however. Pledging to engage in small, research-intensive trials, and to use platform trials, RECOVER could fairly quickly provide patients the data they need to get their doctors to try many new treatment options. Time will tell, but if the RECOVER Initiative can switch gears, the future looks bright.
As that’s happening, Jen’s case study, when published, will provide a powerful reminder that when the right drug meets the right patient, miracles can happen and should spur doctors to do the appropriate testing and try the appropriate drugs.
Jen’s case is also a reminder of the important role that genetic studies can and should play in these illnesses. Family studies can provide powerful insights into these diseases, yet despite a heritability study which found evidence that ME/CFS runs in families, I’ve never seen an ME/CFS family study. That’s the kind of study that occurs as a matter of course in other diseases. On that note, it was good to hear that the ME/CFS Roadmap Initiative spurred the formation of a genetics group at the NIH, that Ian Lipkin’s group is doing its own GWAS study, and of course, that the DeCodeME study is underway.
Publishing Jen’s story was just the start. Next came digging into it and trying to figure out what it meant.
Donation Drive Update
Thanks to the over 100 people who have supported Health Rising thus far!
Presenting Jen’s remarkable story was only the beginning. Next came digging into it and trying to understand what it meant for ME/CFS, long COVID, etc. Why? Because that’s what we do – we put on our thinking caps and dig, dig, dig. If you find that more comprehensive approach to these illnesses helpful, please support us in a manner that works for you.
Super interesting Cort and congrats to Jen! Just curious if you’re going to try Rinvoq? , since you have high IL2 . I have the same as you high IL2 – CD5 elevation with high HHV6 and EBV. Do you know if her doctor was a Rheumatologist or ME/CFS specialist ? Also wondering if this would improve sleep ?
You do good work Cort. However, it would be good if you perhaps could probe some of the researchers a bit harder. You mention Klimas – again. She’s been talking about immune dysfunction and trials with immunomodulators for YEARS, with very little to show for it. Why? Can you probe a bit harder?
Was the basis for her theories flimsy? Is funding an issue? Were her theories good but haven’t been supported by her research over the past few years?
I am always willing to keep an open mind, but what’s going on? I would be delighted if my skepticism on Klimas has been misplaced, and she delivers meaningfully on her promise!
The likes of PolyBio seem to be able to move with some urgency…
And on the positive front, Simmaron said their initial results on their rapamycin trial are ‘very promising’
https://www.bbc.com/future/article/20241119-long-fatigue-the-exhaustion-that-lingers-after-an-infection?fbclid=IwY2xjawGt2D5leHRuA2FlbQIxMQABHbrhc5yPJnWZj57RK0qlbog1S937C9CwIfqBnuRHk-_gxAaMKXaZ-L_NgQ_aem_e7P4_hZw6DQXiCaBkeWrNQ
I just spent an hour in annoying AI ‘voice jail’ trying to get a live agent to talk to at Quest Diagnostics. After trying several numbers I found a number that can at least lead to voice mail with the right navigation, which was to say I was a physician and request ‘supplies’. It’s 1-866-697-8378. I’m hoping to somehow access the cytokine panel from Canada, perhaps through the mail. Or make a trip down there one day if I’m well enough (ironic!).