Hydroxychloroquine as an Adjunct Therapy for Secondary Thrombosis Prevention in Primary Antiphospholipid Syndrome: A Systematic Review and Meta-analysis

INTRODUCTION: Patients with primary antiphospholipid syndrome (PAPS) remain at significant risk of recurrent thrombosis despite long-term anticoagulation. Hydroxychloroquine (HCQ) has demonstrated antithrombotic and immunomodulatory effects in systemic lupus erythematosus and experimental models of antiphospholipid syndrome, but its role in thrombotic PAPS remains incompletely defined. This study aimed to systematically review and quantitatively synthesize the available clinical evidence evaluating hydroxychloroquine as adjunctive therapy for secondary thrombosis prevention in non-pregnant patients with primary antiphospholipid syndrome. METHODS: A systematic search of PubMed/MEDLINE, EMBASE, Web of Science, and Scopus was conducted from inception through March 2026, following PRISMA 2020 guidelines. Eligible studies included adult patients with thrombotic PAPS comparing HCQ plus standard antithrombotic therapy versus standard therapy alone. Obstetric APS, systemic lupus erythematosus-associated APS, and primary prevention studies were excluded. The primary outcome was recurrent arterial or venous thrombosis. A qualitative synthesis was performed, followed by an exploratory random-effects meta-analysis using time-to-event or incidence-based effect estimates. RESULTS: Three studies met the inclusion criteria, comprising 164 patients with thrombotic PAPS (82 receiving HCQ and 82 controls), with a cumulative follow-up of approximately 380 patient-years. Across studies, adjunctive HCQ therapy was consistently associated with lower rates of recurrent thrombosis. Absolute risk reductions ranged from 30 to 100%, depending on study design and follow-up duration. The pooled analysis demonstrated a relative risk reduction of approximately 65-70%, corresponding to a summary effect estimate equivalent to a hazard ratio of ~ 0.33, favoring HCQ. No increase in major bleeding or serious adverse events was reported. CONCLUSIONS: In non-pregnant patients with thrombotic primary antiphospholipid syndrome, adjunctive hydroxychloroquine therapy was associated with a substantial reduction in recurrent thrombotic events when added to standard anticoagulation. Although based on limited evidence and small studies, the consistency and magnitude of the observed effect support further adequately powered randomized trials and suggest that HCQ may represent a rational adjunctive strategy in selected high-risk PAPS patients.