Case Report: Shifting the paradigm in refractory in-stent restenosis: systemic immunomodulation with hydroxychloroquine and sirolimus

Background Recurrent in-stent restenosis (ISR) refractory to repeated percutaneous interventions remains a formidable clinical challenge. Despite the established efficacy of drug-coated balloons (DCBs) and drug-eluting stents, a subset of patients experience relentless restenosis, highlighting the need for novel systemic strategies targeting underlying pathophysiological drivers. Objectives To describe a case of extreme, refractory recurrent ISR that failed multiple DCB interventions but was associated with a marked response to systemic therapy with Hydroxychloroquine (HCQ) and Sirolimus, and to discuss the mechanistic rationale and potential clinical implications. Methods A 56-year-old female presented with rapidly recurring ISR in both the left anterior descending (LAD) and right coronary arteries (RCA). Over a 6-year period, she underwent 11 interventional procedures at our center and at outside institutions. Sequential trials of oral anti-inflammatory agents failed to halt the restenosis cycle. In May 2023, HCQ was initiated, and Sirolimus was added in October 2023. Serial angiographic and intravascular ultrasound (IVUS) follow-up were performed. Results Prior to systemic therapy, restenosis occurred every 6 months in both vessels. After initiating HCQ and Sirolimus, the RCA remained free of restenosis for over one year. The LAD, while requiring additional focal DCB treatments, showed a marked reduction in restenosis burden, with disease becoming highly localized. IVUS revealed neointimal hyperplasia with superimposed lipid-rich and fibrous plaques, without evidence of stent fracture or malapposition. Conclusions In a patient with recurrent ISR, targeted systemic immunomodulation with HCQ and Sirolimus was associated with sustained vessel patency and reduced restenosis burden. This case provides a hypothesis-generating observation that addressing systemic inflammatory and proliferative drivers may repersent a potential salvage strategy for refractory recurrent ISR, warranting further prospective investigation.