Biologic Markers of Antibiotic-Refractory Lyme Arthritis in Human: A Systematic Review

INTRODUCTION: Lyme disease—also known as Lyme borreliosis (LB)—is the most common vector-borne disease in North America and Europe. It may result in substantial morbidity, primarily from persistent Lyme arthritis (LA) that—although treatable—can develop into antibiotic-refractory LA (A-RLA). The aim of this study is to systematically review and evaluate a range of biomarkers for their potential predictive value in the development of A-RLA. METHODS: We conducted a systematic review of studies examining biomarkers among patients with A-RLA from MEDLINE via OVID, EMBASE and Web of Science databases and identified a total of 26 studies for qualitative analysis. RESULTS: All studies were of patient populations from the USA, with the exception of one from Europe. We identified an array of biomarkers that are commonly modulated in the A-RLA compared with subjects with antibiotic-responsive LA. These included a range of inflammatory markers (IL-6, IL-8, IL-10, IL-1β, IL-23, IL-17F, TNFα, IFNγ, CXCL9, CXCL10, CCL2, CCL3 and CCL4, CRP), factors along the innate and adaptive immune response pathways (e.g., CD4(+) T cells, GITR receptors, OX40 receptors, IL-4(+)CD4(+)Th2 cells, IL-17(+)CD4(+) T cells) and an array of miRNA species (e.g., miR-142, miR-17, miR-20a, let-7c and miR-30fam). CONCLUSION: The evidence base of biologic markers for A-RLA is limited. However, a range of promising biomarkers have been identified. Cytokines and chemokines related to Th17 pathway together with a number of miRNAs species (miR-146a, miR-155 and let-7a) may be promising candidates in the prediction of A-RLA. A panel of multiple biomarkers may yield clinically relevant prediction of the possible resistance at the time of LA first diagnosis. FUNDING: Public Health Agency of Canada. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40121-018-0223-0) contains supplementary material, which is available to authorized users.