Collectively, these findings suggest that sex- and organ-specific activation of the cyclooxygenase-2/cyclic AMP-responsive element-binding protein/estrogen receptor axis contributes to the inflammatory patterns in Rheumatoid arthritis-associated interstitial lung disease.<h4>Conclusion</h4>Our findings suggest that cyclooxygenase-2/cyclic AMP-responsive element-binding protein/estrogen receptor pathway activation in male lungs may explain their increased tendency toward fibrotic remodeling, whereas enhanced estrogen receptor signaling in female joints may contribute to more severe arthritis. Here, PTGS2 is linked to interstitial lung disease.