Favorable responses to upadacitinib, a JAK1 inhibitor, in [LC] with predominant neuropsychiatric symptoms: case reports [...], 2025, Jyonouchi et al

[forestglip]

Favorable responses to upadacitinib, a JAK1 inhibitor, in long COVID patients with predominant neuropsychiatric symptoms: case reports in 2 autistic patients and one typically developing patient

Harumi Jyonouchi, Jeffery Kornitzer, Lee Geng

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Abstract
The long-term impact of coronavirus disease 2019 (COVID-19) has become evident over the past 3–4 years, with the recognition of post-COVID long-term sequelae, often referred to as long COVID. Neuropsychiatric symptoms are one of the hallmarks of long COVID. In severe cases, it can even present features of encephalopathy.

Since some of the neuropsychiatric symptoms associated with long COVID overlap symptoms found in neuropsychiatric disorders, it has been difficult to sort out the effects of long COVID in such subjects. This is especially true in patients diagnosed with autism spectrum disorders (ASD), given their difficult behavioral symptoms and other co-morbid conditions.

COVID-19 is thought to affect the onset or progress of encephalopathy symptoms by activation of the immune system through the type 1 interferon (IFN) signaling pathway. In that case, treatment would require an immunomodulating agent that targets such pathways. However, such measures may not be applied to ASD subjects, in whom long COVID may not even be considered as the cause of their symptoms.

In this study, we present the beneficial effects of upadacitinib, a JAK (janus kinase) 1 inhibitor, that blocks downstream signaling of type 1 IFNs, on 3 patients, 2 with ASD and one without ASD. In these patients, long COVID was thought to have triggered or aggravated encephalopathy-like symptoms.

The beneficial effects of upadacitinib were not only noted by an improvement of their behavioral symptoms but also shown by an improvement of monocyte cytokine profiles (less activated state); peripheral blood monocytes were used as surrogates of microglial cells.

These three cases presented highlight a possible use of JAK inhibitors for treating long COVID-associated neuropsychiatric symptoms in both ASD and non-ASD subjects. The presented cases highlight the inherent difficulty of diagnosing long COVID in ASD cases.

Web | PDF | BMC Neurology | Open Access

 

[BrokenBeaktheBrave]

I don't have ASD and I have only one of the five "neuropsychiatric" symptoms they measured - namely "lethargy" - but I'm desperate enough to try upadacitinib if offered.

Does anyone know much about JAK2 with regard to the pathways mentioned in this article as my sister has a known JAK2 mutation. I wonder if it's relevant for me.

 

[hotblack]

Interesting given previous speculation about JAK/STAT inhibitors (the use of rituximab is also mentioned in one of the case descriptions). Here are the sections on measurements of cytokine responses, first the method

To assess changes in innate immune responses caused by COVID-19, we measured monocyte cytokine profiles in the 2 subjects enrolled in the study. Peripheral blood monocytes (PB Mo) were purified from the peripheral blood mononuclear cells with the use of immunoaffinity column (Miltenyi Biotec North America, Gaithersburg, MD). Then monocytes (5 × 105 cells/ml) were cultured overnight without a stimulus or with stimuli of innate immunity as described previously [21]. In this study, we used lipopolysaccharide (LPS), zymosan, CL097, and candida heat extract (as a source of ß-glucan) as stimuli [21]. Concentrations of monocyte cytokines (IL-1ß, IL-6, IL-10, IL-12p40, IL-23, TNF-α, sTNFRII, TGF-ß, CCL2, and IFN-α) in the culture supernatants were measured by ELISA (enzyme linked immunosorbent assay).

And the results

Changes in monocyte cytokine profiles before and after upadacitinib treatment are available for cases 1 and 3; they were enrolled in the current study protocol for checking changes in innate immune responses in long COVID subjects. The results obtained in both Cases 1 and 3 revealed a decrease in spontaneous production of inflammatory cytokines (TNF-α and IL-1ß) and the counter regulatory cytokine (IL-10) (Fig. 4 Panels A, B, C). Increase in IL-10 was not surprising, since patients suffering from autoinflammatory syndromes tend to reveal persistently high spontaneous IL-10 production, but such IL-10 production is often suppressed with stimuli of innate immunity as shown in our presented cases (Fig. 4 panel D). Production of TNF-α and IL-1ß by PB Mo was less after starting upadacitinib when compared to the levels prior to the start of this medication in both Cases 1 and 3. When the type 1 IFN-α pathway is activated, generated cytokines by innate immune cells are known to activate indoleamine 2,3-dioxygenase (IDO), shifting tryptophan metabolism from serotonin to kynurenine. We also observed declining serum levels of kynurenine in both Cases 1 and 3 after starting upadacitinib (Fig. 5).

With details from Fig 4

Changes in production of TNF-α, IL-1ß, and IL-10 (pg/ml) by peripheral blood monocytes under cultures witout stimuli (medium only) and under the CL097 stimulated cultures before and after the upadacitinib treatment in Case 1 and Case 3