JAK Inhibitor Withdrawal Causes a Transient Proinflammatory Cascade: A Potential Mechanism for Major Adverse Cardiac...

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.