Combination Therapy with Hydroxychloroquine and 5-ASA Induces Remission in Treatment-Refractory Ulcerative Colitis

Background and Aims

Ulcerative colitis (UC) is a complex autoimmune disorder characterized by chronic, recurring inflammation of the large intestine, necessitating lifelong medical treatment. First-line therapy includes 5-aminosalicylic acid (5-ASA), which is effective for mild to moderate UC; however, up to 37% of patients relapse within 6–12 months, often requiring escalation to advanced therapies.¹ The lifetime pharmaceutical cost burden for patients with treatment-refractory UC in the United States is estimated to exceed $100,000, based on a Markov model analysis of a recent large insurance database study.² This highlights the need for cost- effective second-line treatment options.

Hydroxychloroquine (HCQ), widely used and successful in treating autoimmune diseases such as lupus, modulates immune responses by altering phagolysosomal pH, preventing CTLA-4 degradation, and enhancing regulatory T-cell function.³ Despite its high safety profile, affordability, and accessibility, HCQ’s potential in UC remains underexplored. A small randomized trial in 1996 found that chloroquine (CQ) was as effective as sulfasalazine in achieving remission in mild to moderate UC.⁴

Our clinical trial aims to build on this earlier study by evaluating HCQ’s efficacy, in combination with 5-ASA—derived from sulfasalazine—as a potential second-line therapy for 5-ASA-refractory UC. Additionally, we aim to investigate its immunological role in CTLA-4 regulation. These findings could support HCQ as an alternative treatment for patients who do not respond to 5-ASA alone.

Methods

Our clinical trial enrolled patients with 5-ASA -refractory UC who received hydroxychloroquine (HCQ) 400 mg daily for four months alongside their existing 5-ASA regimen. Colonoscopy findings (Mayo score), colonic and rectal biopsies for histological analysis, and peripheral blood mononuclear cell (PBMC) samples were collected before and after treatment to evaluate molecular and cellular responses, including CTLA-4 expression.

Results

Three case reports describe successful HCQ use alongside 5-ASA in the treatment of refractory moderate to severe UC. After four months, all patients achieved endoscopic and histopathological remission, with flow cytometry analysis revealing significant CTLA-4 upregulation, suggesting immunological benefits.

Conclusion

Hydroxychloroquine shows promise as an adjunct therapy for UC, especially in patients refractory to 5-ASA. Its association with endoscopic and histopathological remission, along with significant CTLA-4 upregulation in patient-derived PBMCs, suggests it may enhance regulatory T-cell function and modulate excessive immune activation. These findings support the need for further investigation into HCQ’s immunomodulatory mechanisms and its potential as a cost-effective second-line therapy for UC management in larger clinical trials.