Long-term outcomes of Qing-Dai-induced pulmonary arterial hypertension.

Background: Qing-Dai (indigo naturalis), which is used to treat inflammatory bowel disease in Japan, has been linked to pulmonary arterial hypertension (PAH) and is recognised in the 2022 European Society of Cardiology/European Respiratory Society guidelines as a drug associated with PAH. However, the long-term clinical course of Qing-Dai-induced PAH has not been studied. Methods: This retrospective multicentre study included 20 patients diagnosed with PAH after Qing-Dai use in Japan between 2011 and 2024. Haemodynamic data were collected when PAH was diagnosed, within 1 year after Qing-Dai discontinuation and at the final follow-up evaluation. To elucidate the underlying mechanisms, we analysed the composition of Qing-Dai and examined its effects on vascular endothelial cells. Results: The study cohort comprised 11 female and nine male patients (median age: 40 years; range: 19-70 years). The median duration of Qing-Dai exposure before PAH was diagnosed was 4.8 years (range: 0.5-15 years). Discontinuation of Qing-Dai and the use of PAH medications were associated with significant improvement in haemodynamic parameters. The mean pulmonary arterial pressure decreased from 52.5 to 25.0 mmHg, and the median pulmonary vascular resistance decreased from 10.8 to 2.6 Wood units. Six (30%) patients discontinued PAH medication and remained recurrence-free. One patient experienced PAH relapse after discontinuation of PAH medications. Seven (35%) patients exhibited persistent PAH despite treatment. A mass spectrometry analysis of Qing-Dai identified indirubin, which was found to induce endothelial apoptosis. Conclusion: Discontinuation of Qing-Dai is important to PAH management. Routine follow-up is necessary to monitor potential recurrence.