Manuel
Senior Member
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๐๐ก๐ ๐๐ฌ๐ ๐จ๐ ๐๐๐-๐๐๐๐ ๐๐ง๐ก๐ข๐๐ข๐ญ๐จ๐ซ๐ฌ ๐ข๐ง ๐๐ฒ๐๐ฅ๐ ๐ข๐ ๐๐ง๐๐๐ฉ๐ก๐๐ฅ๐จ๐ฆ๐ฒ๐๐ฅ๐ข๐ญ๐ข๐ฌ ๐๐ง๐ ๐๐จ๐ง๐ ๐๐๐๐๐: ๐๐๐ฆ๐ฉ๐จ๐ซ๐๐ซ๐ฒ ๐๐๐ง๐๐๐ข๐ญ๐ฌ ๐๐ง๐ ๐๐ข๐ฆ๐ข๐ญ๐๐ญ๐ข๐จ๐ง๐ฌ ๐ข๐ง ๐๐ง๐๐๐๐ญ๐ข๐จ๐ฎ๐ฌ-๐๐๐ฌ๐๐ ๐๐๐ฌ๐๐ฌRecently, the use of JAK-STAT pathway inhibitors has been proposed as a possible โcureโ for myalgic encephalomyelitis (ME) and long COVID. The JAK-STAT pathway is a key intracellular mechanism in the regulation of the immune response. Although this strategy may offer important benefits, it also presents significant risks, especially if MS has a chronic infectious basis.
๐๐๐ฏ๐๐ง๐ญ๐๐ ๐๐ฌ: ๐๐จ๐ง๐ญ๐ซ๐จ๐ฅ ๐จ๐ ๐๐ง๐๐ฅ๐๐ฆ๐ฆ๐๐ญ๐ข๐จ๐ง ๐๐ง๐ ๐๐ฆ๐ฆ๐ฎ๐ง๐ ๐๐ฒ๐ฉ๐๐ซ๐๐๐ญ๐ข๐ฏ๐ข๐ญ๐ฒ.Innate immunity is the body's first line of defense against infection, but in some cases, this response can become overactive, contributing to chronic inflammation and tissue damage. However, the reality in ME and long COVID is not that innate immunity is overactive per se, but that this overactivation is a consequence of poor infection control due to malfunctioning of adaptive immunity, related to genetic predisposition, such as HLA-II. The inability of adaptive immunity to adequately control chronic or latent infections leads to overcompensation by innate immunity.
JAK-STAT inhibitors (such as Filgotinib and Rinvoq) act by blocking the signaling of certain cytokines that are critical to the innate immune response. This can have several beneficial effects:
๐๐๐๐ฎ๐๐๐ ๐๐ง๐๐ฅ๐๐ฆ๐ฆ๐๐ญ๐ข๐จ๐ง: by inhibiting the JAK-STAT pathway, the production of inflammatory mediators that perpetuate tissue damage and symptoms of both diseases, such as pain, fatigue and cognitive dysfunction, may be reduced. ๐๐จ๐ง๐ญ๐ซ๐จ๐ฅ ๐จ๐ ๐๐ฆ๐ฆ๐ฎ๐ง๐ ๐๐ฒ๐ฉ๐๐ซ๐๐๐ญ๐ข๐ฏ๐ข๐ญ๐ฒ: If ME and long COVID are related to an exaggerated immune response, JAK-STAT inhibitors may help modulate this hyperactivity, decreasing autoaggression and improving the patient's quality of life.
๐๐ข๐ฌ๐ค๐ฌ: ๐๐๐ซ๐ฆ ๐ข๐ง ๐ญ๐ก๐ ๐๐จ๐ง๐ญ๐๐ฑ๐ญ ๐จ๐ ๐๐ก๐ซ๐จ๐ง๐ข๐ ๐๐ง๐๐๐๐ญ๐ข๐จ๐งHowever, in the case of long COVID and if ME has a chronic infectious basis, the use of JAK-STAT inhibitors could be detrimental. This risk is because the very pathway targeted for inhibition is crucial for defense against persistent infections:
๐๐จ๐ฆ๐ฉ๐ซ๐จ๐ฆ๐ข๐ฌ๐ข๐ง๐ ๐๐ฆ๐ฆ๐ฎ๐ง๐ ๐๐๐๐๐ง๐ฌ๐: The JAK-STAT pathway is essential not only for innate immunity but also for adaptive immunity, which is responsible for long-term clearance of infections. Inhibiting this pathway could weaken the body's ability to control and eradicate chronic infections, such as those caused by viruses, bacteria or even parasites. ๐๐ง๐๐ซ๐๐๐ฌ๐๐ ๐๐ข๐ฌ๐ค ๐จ๐ ๐๐๐ฐ ๐๐ง๐๐๐๐ญ๐ข๐จ๐ง๐ฌ: JAK-STAT inhibitor-induced immunosuppression may increase susceptibility to new infections. This is of particular concern in patients with ME and long COVID who may already have a compromised immune system. ๐๐๐๐๐ญ๐ข๐ฏ๐๐ญ๐ข๐จ๐ง ๐จ๐ ๐๐๐ญ๐๐ง๐ญ ๐๐ง๐๐๐๐ญ๐ข๐จ๐ง๐ฌ: The use of JAK-STAT inhibitors may trigger reactivation of latent infections, such as herpesviruses. This is because JAK-STAT inhibition may affect the immune system's ability to maintain these viruses in a latent state, which could aggravate symptoms and complicate treatment. In fact, it has been mentioned that โJAKinibs are able to simultaneously suppress the action of different cytokines, albeit transiently. This intrinsic feature of JAKinibs may explain the higher risk of zoster in comparisonโ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328488/ . In addition, JAK inhibitors may increase the risk of opportunistic and viral infections, such as varicella zoster virus (VZV) reactivation: โthe most frequently reported side effects of JAK inhibitors are infections, including respiratory and urinary tract infections, as well as opportunistic and viral infections with an increased risk of varicella zoster virus (VZV) reactivationโ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9908612/ .One exception that is being studied with caution is the case of ruxolitinib, a JAK-STAT inhibitor that has shown promising results in the treatment of chronic infections caused by Epstein-Barr virus (EBV). Some preliminary studies have suggested that ruxolitinib may be able to suppress EBV replication by blocking the JAK-STAT pathway, which the virus uses to replicate and avoid detection by the immune system. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8955311/
๐๐ข๐ฆ๐ข๐ญ๐๐ญ๐ข๐จ๐ง๐ฌ ๐ข๐ง ๐ญ๐ก๐ ๐๐จ๐ง๐ญ๐๐ฑ๐ญ ๐จ๐ ๐๐ฎ๐ญ๐จ๐ข๐ฆ๐ฆ๐ฎ๐ง๐ข๐ญ๐ฒ.In patients where immune hyperactivation has caused autoimmune damage, such as autoimmune hypophysitis, a disorder in which the immune system attacks the pituitary, the use of JAK-STAT inhibitors could help reduce inflammation. However, in those cases where autoimmune damage to the pituitary is permanent, this would not resolve the cortisol deficiency, it would only contribute to decreasing systemic inflammation. Therefore, while it may prevent further damage, it would not correct already established hormonal deficits.
๐๐จ๐ง๐๐ฅ๐ฎ๐ฌ๐ข๐จ๐ง
The use of JAK-STAT inhibitors in myalgic encephalomyelitis and long COVID may help control inflammation and immune hyperactivity, but it is not a cure, especially if the basis of the disease is chronic infection. Inhibition of this pathway may weaken the body's defenses against persistent or latent infections, increasing the risk of new infections or reactivations. Moreover, if treatment is discontinued, inflammatory symptoms may return, necessitating continued use, with the attendant long-term risks.
More information: https://x.com/manruipa/status/1835333569431920777?s=46&t=m4Zmq5Ji7bf6LgmUbeK4pA
