Hydroxychloroquine in Systemic Lupus Erythematosus: From Molecular Mechanisms to Biomarkers and Systemic Outcomes

Abstract

Background: Systemic Lupus Erythematosus (SLE) is a chronic, relapsing, multi-system autoimmune disorder. It involves loss of tolerance to nuclear antigens, immune-complex formation, complement activation and the presence of a type I interferon signature. 

Importance of HCQ: One of the cornerstones of SLE therapy is Hydroxychloroquine (HCQ). It is currently recommended for most patients, except in cases where this is contraindicated.

Molecular and biochemical mechanisms: The HCQ is a weak diprotic base. It targets to acidic lysosomes and endosomes and increases their internal pH. This affects the signalling of endosomal Toll-like receptor 7 and 9 and reduces production of downstream MyD88, interferon regulatory factor 7, and type I interferon. HCQ may also directly interact with nucleic acids and prevent them from being recognized by these receptors.

Biomarker and systemic effects: The observational evidence links use of HCQ with a decrease in disease activity, less flares, less exposure to glucocorticoids and improved survival. At therapeutic concentrations, HCQ has been associated with a beneficial effect on glucose and lipid metabolism and with decreased thrombosis. Other benefits reported are renal and obstetric.

Evidence gaps: Many of the systemic benefits are based on observational cohorts. Causal inference is limited by confounding by indication and adherence bias.

Conclusion: The mechanisms of action of HCQ seem to involve all the immunological, inflammatory, metabolic, and vascular pathways, which are interconnected. The clinical biochemistry tools will enable these effects to be translated into biomarkers, monitoring, and ultimately personalised therapy.