The Jak/STAT pathway: A focus on pain in rheumatoid arthritis

Simon, Lee S.; Taylor, Peter; Choy, Ernest; Sebba, Anthony; Quebe, Amanda; Knopp, Kelly L.; Porreca, Frank

doi:10.1016/j.semarthrit.2020.10.008

Cited by 136 publications

(78 citation statements)

References 88 publications

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“…Rapid control of symptoms is intimately linked to the downregulation of pain in patients with RA. Inflammatory cytokines including TNFα, GMCSF, IL-6 and IL-17 stimulate peripheral nociceptive nerves and trigger pain in the context of inflammation [ 22 , 23 ]. Most cytokines associated with RA pathogenesis and pain are affected directly (via signaling through the Jak/STAT pathway) or indirectly (via enhancement by or a decrease in upstream or downstream signaling through the Jak/STAT pathway) [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

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Prediction of response to Certolizumab-Pegol in rheumatoid arthritis (PreCePRA) by functional MRI of the brain – Study protocol for a randomized double-blind controlled study

Schenker

Taşçılar

Konerth

et al. 2021

Contemporary Clinical Trials Communications

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Background Tumor necrosis factor inhibitors (TNFi) signify a major advance in the treatment of rheumatoid arthritis (RA). However, treatment success initially remains uncertain as approximately half of the patients do not respond adequately to TNFi. Thus, an unmet need exists to better predict therapeutic outcome of biologicals. Objectives We investigated whether brain activity associated with arthritis measured by functional magnetic resonance imaging (fMRI) of the brain can serve as a predictor of response to TNFi in RA patients. Methods PreCePRA is a multi-center, randomized, double-blind, placebo-controlled fMRI trial on patients with RA [1] [2]. Active RA patients failing csDMARDs therapy with a DAS28 > 3.2 and at least three tender and/or swollen joints underwent a brain BOLD (blood-oxygen-level dependent) fMRI scan upon joint compression at screening. Patients were then randomized into a 12-week double-blinded treatment phase with 200 mg Certolizumab Pegol (CZP) every two weeks (arm 1: fMRI BOLD signal activated volume > 2000 voxel, i.e. 2 cm 3 ; arm 2: fMRI BOLD signal activated volume <2000 voxel) or placebo (arm 3). DAS28 low disease activity at 12 weeks was assigned as primary endpoint. A 12-week follow-up phase in which patients were switched from the placebo to the treatment arm followed the blinded phase. fMRI was carried out at screening as well as after 12 and 24 weeks of receiving CZP or placebo. Conclusion We hypothesize that high-level central nervous representation of pain in patients with rheumatoid arthritis predicts response to the TNFi CZP which we further investigate in the PreCePRA trial.

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Section: Discussionmentioning

confidence: 99%

“…Taken together, these studies show that targeting peripheral inflammation by immunosuppressants will not necessarily affect persistent, chronic pain. Moreover, chronic pain mainfests itself in the CNS not only by functional but also anatomical changes [ 23 ]. However, modulating multiple pathways at the spinal level (e.g.…”

Section: Discussionmentioning

confidence: 99%

Prediction of response to Certolizumab-Pegol in rheumatoid arthritis (PreCePRA) by functional MRI of the brain – Study protocol for a randomized double-blind controlled study

Schenker

Taşçılar

Konerth

et al. 2021

Contemporary Clinical Trials Communications

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“…Indeed, GSK-3β inhibitors have potent anti-inflammatory activity and have been shown to be useful in treating neurodegenerative diseases, including Alzheimer’s disease (reviewed in [ 103 , 104 ]). Finally, recent findings from a Phase 3 clinical trial showed that patients with rheumatoid arthritis who were treated with a JAK1/2 inhibitor had significantly greater improvements in pain reduction [ 93 , 105 ]. Thus, oximes targeting JAK1/2 also have anti-inflammatory potential.…”

Section: Anti-inflammatory Activity Of Oximesmentioning

confidence: 99%

Oximes: Novel Therapeutics with Anticancer and Anti-Inflammatory Potential

et al. 2021

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Oximes have been studied for decades because of their significant roles as acetylcholinesterase reactivators. Over the last twenty years, a large number of oximes have been reported with useful pharmaceutical properties, including compounds with antibacterial, anticancer, anti-arthritis, and anti-stroke activities. Many oximes are kinase inhibitors and have been shown to inhibit over 40 different kinases, including AMP-activated protein kinase (AMPK), phosphatidylinositol 3-kinase (PI3K), cyclin-dependent kinase (CDK), serine/threonine kinases glycogen synthase kinase 3 α/β (GSK-3α/β), Aurora A, B-Raf, Chk1, death-associated protein-kinase-related 2 (DRAK2), phosphorylase kinase (PhK), serum and glucocorticoid-regulated kinase (SGK), Janus tyrosine kinase (JAK), and multiple receptor and non-receptor tyrosine kinases. Some oximes are inhibitors of lipoxygenase 5, human neutrophil elastase, and proteinase 3. The oxime group contains two H-bond acceptors (nitrogen and oxygen atoms) and one H-bond donor (OH group), versus only one H-bond acceptor present in carbonyl groups. This feature, together with the high polarity of oxime groups, may lead to a significantly different mode of interaction with receptor binding sites compared to corresponding carbonyl compounds, despite small changes in the total size and shape of the compound. In addition, oximes can generate nitric oxide. This review is focused on oximes as kinase inhibitors with anticancer and anti-inflammatory activities. Oximes with non-kinase targets or mechanisms of anti-inflammatory activity are also discussed.

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“…Не исключено, что у не ответивших на терапию пациентов (3-я группа), у которых экспрессия этих генов имела тенденцию к снижению, метаболизм находится на пределе активности и дальнейшее его повышение невозможно. Кроме того, у всех обследованных нами больных РА наблюдалось уменьшение ЧПС и ЧБС, включая не ответивших на лечение, у которых воспалительная активность из-менялась очень незначительно, что объясняется ранее отмеченной ассоциацией между действием иJAK и снижeнием показателей боли, обусловленной как воспалением, так и рядом других причин [22].…”

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“…Современная ревматология. 2021;15(3):[20][21][22][23][24][25][26] factors, associated with RA. Identification of patients sensitive to JAKi before treatment could significantly improve therapy outcomes.…”

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confidence: 99%

Association between a low baseline level of gene expression of energy metabolism in the blood and the development of clinical remission in response to tofacitinib therapy in patients with rheumatoid arthritis

Четина¹,

Сатыбалдыев²,

Маркова³

et al. 2021

Sovremennaâ revmatologiâ

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Background. Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology, characterized by erosive arthritis (synovitis) and systemic inflammation. Janus kinase (JAK) inhibitors (JAKi) are small molecules that block major signal pathways of many cytokines a growth factors, associated with RA. Identification of patients sensitive to JAKi before treatment could significantly improve therapy outcomes. Currently it is not possible to predict JAKi efficacy in every patient, while some patients are non-responsive to the drug, other develop adverse effects. JAKi effect in RA patients has been recently associated with alterations in mitochondrial function and ATP production. Therefore, we hypothesized that baseline metabolic status of RA patients prior to drug administration can predict the therapeutic outcome.Objective: to investigate the predictive value of baseline expression of genes involved in energy generation in the blood of RA patients, for treatment response to JAKi.Patients and methods. We examined peripheral blood of 28 RA patients aged 52.2±15.6 years, average disease duration 3.5 years (range 0.6–19), treated with Tofacitinib (TOFA, 5–10 mg twice a day) during three months and 26 healthy age-matched control subjects. Clinical response was assessed by disease activity score (DAS28-ESR), immunological status by measurements of serum levels of anti-citrullinated protein antibodies (ACPA), rheumatoid factor (RF), and C-reactive protein (CRP). Gene expression was assessed in peripheral blood cells by realtime reverse-transcription polymerase chain reaction (RT-PCR). At baseline all patients had Steinbrocker radiographic stage II–III. Most patients (85.7%) were ACPA and RF positive. Thirteen patients had medium, others – high RA activity.Results and discussion. JAKi treatment significantly decreased the inflammatory disease activity according to DAS28. At the end of the study 17 patients demonstrated moderate disease activity (3.2<DAS28<5.1), 4 patients retained high disease activity while 7, attained remission (DAS28 <2.6). Disease remission, achieved on TOFA treatment, was accompanied by significant decrease in CRP and the number of swollen and tender joints. ESR values were not changed significantly. Gene expression analysis revealed that RA patients, which attained clinical remission after TOFA treatment, demonstrated significantly lower baseline expression of genes associated with glycolysis (pyruvate kinase, PKM2) and oxidative phosphorylation (succinate dehydrogenase, SDHB) compared to other examined RA patients, but higher expression of the abovementioned genes compared to control subjects. Moreover, RA patients who attained clinical remission demonstrated a trend to increase of these gene expressions within follow-up period, while in the rest of patients these gene expression was tending to downregulate.Conclusion. Clinical remission in RA patients treated with JAKi is associated with significantly lower baseline expression of genes associated with energy generation pathways (PKM2 and SDHB) compared to other examined subjects.

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The Jak/STAT pathway: A focus on pain in rheumatoid arthritis

Cited by 136 publications

References 88 publications

Prediction of response to Certolizumab-Pegol in rheumatoid arthritis (PreCePRA) by functional MRI of the brain – Study protocol for a randomized double-blind controlled study

Prediction of response to Certolizumab-Pegol in rheumatoid arthritis (PreCePRA) by functional MRI of the brain – Study protocol for a randomized double-blind controlled study

Oximes: Novel Therapeutics with Anticancer and Anti-Inflammatory Potential

Association between a low baseline level of gene expression of energy metabolism in the blood and the development of clinical remission in response to tofacitinib therapy in patients with rheumatoid arthritis

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