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JAK Inhibitor Withdrawal Causes a Transient Proinflammatory Cascade: A Potential Mechanism for Major Adverse Cardiac
Ilya Gurevic1, Loic Meudec2, Xavier Mariette3,4
1Department of Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA.
Objective:
Our objective was to define the effect of JAK1/2 inhibitor (JAKinib) withdrawal on JAK/STAT biochemical response in the context of systemic rheumatic diseases.
Methods:
We tested Type I (bind kinase active conformation) and Type II (bind kinase inactive conformation) JAKinibs in vitro using mesenchymal stromal cells and endothelial cells. We translated our findings in vivo studying NK cells from rheumatoid arthritis (RA) patients treated with Type I JAKinibs or methotrexate.
Results:
Type I JAKinibs (ruxolitinib and baricitinib) increased phosphoJAK1 (pJAK1) and pJAK2 of IFNγ-stimulated MSCs and HUVECs in a time- and dose- dependent manner, with effect peaking after 24 hours. As expected, pSTAT1 was completely suppressed by JAKinibs. We found a marked and rapid increase of pSTATs upon discontinuation of Type I JAKinibs, that occurred to a lesser extent after Type II JAKinib withdrawal. Type I JAKinib withdrawal increased interferon and urokinase expression when compared to Type II JAKinib withdrawal. We found NK cells from RA patients taking Type I JAKinibs had a pro-inflammatory profile after JAKinib withdrawal compared to patients on methotrexate.
Conclusions:
Type I JAKinibs paradoxically accumulate functionally defective pJAK. Upon withdrawal, the primed pJAKs are de-repressed and initiate a pSTAT signaling cascade, resulting in high interferon and urokinase. Type II JAKinibs do not cause pJAK accumulation, pSTAT cascade, and subsequent pro-inflammatory transcripts. The resultant cytokines and proteins produced from this cascade might be associated with adverse cardiac outcomes. Thus, JAKinib withdrawal is a possible mechanism contributing to the major adverse cardiac events described with JAKinib therapy.
Insights
Withdrawal of Type I JAK inhibitors leads to a rapid increase in pSTATs and pro-inflammatory cytokines. This JAK inhibitor withdrawal mechanism may contribute to adverse cardiac events in patients with rheumatic diseases.
Area of Science:
- Immunology
- Pharmacology
- Rheumatology
Background:
- Janus kinase (JAK) inhibitors are used to treat systemic rheumatic diseases.
- Understanding the biochemical response to JAK inhibitor withdrawal is crucial for patient safety.
Purpose of the Study:
- To define the effect of JAK1/2 inhibitor (JAKinib) withdrawal on JAK/STAT signaling.
- To investigate the consequences of JAKinib withdrawal in systemic rheumatic diseases.
Main Methods:
- In vitro testing of Type I and Type II JAKinibs using mesenchymal stromal cells and endothelial cells.
- In vivo studies of NK cells from rheumatoid arthritis patients treated with Type I JAKinibs or methotrexate.
Main Results:
- Type I JAKinibs increased phospho-JAK1 (pJAK1) and pJAK2, suppressing pSTAT1.
- Withdrawal of Type I JAKinibs caused a rapid increase in pSTATs, interferon, and urokinase.
- NK cells from RA patients on Type I JAKinibs showed a pro-inflammatory profile post-withdrawal.
Conclusions:
- Type I JAKinibs paradoxically accumulate functionally defective pJAK, leading to a pro-inflammatory cascade upon withdrawal.
- Type II JAKinibs do not induce this pJAK accumulation or subsequent pro-inflammatory response.
- JAKinib withdrawal may contribute to adverse cardiac events observed in patients.
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