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MicroRNA collected in patients’ synovial fluid after treatment with antibiotics resembles that seen in chronic inflammatory states.
MicroRNA collected from the synovial fluid of patients with active Borrelia burgdorferi (Lyme) infections was indicative of acute inflammation related to the killing of bacteria by antibiotics.
However, microRNA collected in patients’ synovial fluid after treatment with antibiotics for B. burgdorferi where arthritis persists more closely resembles that seen in chronic inflammatory states and is characterized by synovial proliferation and a breakdown of the wound repair process.
The robust immune response that bodies produce when confronted by a bacterial infection are necessary defenses, but if they persist, they can also lead to tissue damage.
Joint pain or arthritis associated with B. burgdorferi (Lyme disease) infection most often resolves with antibiotic treatment. The pathogenic processes associated with antibiotic-refractory Lyme arthritis have not previously been described.
Robert Lochhead and colleagues in New England pointed out that microRNAs have a vital role in gene expression and “provide robustness” to gene regulation by inhibiting or facilitating transcription.
A previous study found that rheumatoid arthritis had the most robust enrichment of microRNA-target gene risk factor of any disease ever studied. This evidence points to a crucial role for microRNA defects in the pathogenesis of inflammatory disease.
The authors presented the results of their investigation into the differences between synovial microRNA expression in the joints of patients with active Lyme arthritis and with antibiotic-refractory Lyme arthritis in a recent Arthritis & Rheumatology article.
Ultimately, 32 patients who had Lyme arthritis and synovial fluid or synovial tissue available were included. Patients were divided into 3 groups; group 1 patients were referred prior to antibiotic therapy, group 2 consisted of patients whose arthritis persisted after antibiotic treatment, and group 3 was composed of patients who required synovectomies after 2 or 3 months of antibiotic therapy.
• In groups 1 and 2, synovial fluid levels of microRNA-146a, microRNA-155, microRNA-142, microRNA-17, and microRNA-20a correlated positively with longer arthritis duration after oral antibiotic treatment.
• There was a negative correlation between B. burgdorferi immune globulin G antibody titers and microRNA-155 (r=-0.490, P=0.04), microRNA-146a (r=-0.49, P=0.04), and microRNA-142 (r=-0.54, P=0.02).
• There was a negative correlation in groups 1 and 2 between the duration of arthritis and the white blood cell count in the synovial fluid (P=0.022) and the percentage of polymorphonuclear cells (P=0.002) and a positive correlation between duration of arthritis and the percentages of lymphocytes (P=0.044) and mononuclear cells (P=0.011).
• Expression of microRNA-146a and microRNA-155 did not correlate with longer duration of arthritis after antibiotic treatment.
• Expression of microRNA-223 and onco-microRNA-17-92 did positively correlate with arthritis duration after antibiotic treatment; the let-7 family microRNA tumor suppressors correlated negatively with post-treatment Lyme arthritis duration.
• As in all forms of chronic inflammatory arthritis, the synovial lesions in the subjects with post-infectious Lyme arthritis showed massive, tumor-like proliferation of inflamed synovial tissue capable of invading cartilage and bone.
Implications for physicians
• The presence of specific microRNA signatures suggests there is immune dysregulation in the synovial tissue of patients with post-infectious Lyme arthritis.
• MicroRNA may have a role in the pathogenesis of post-infectious Lyme arthritis.
• The correlations between synovial cell counts and arthritis duration suggest that the pathologic characteristics of the arthritis changed between the active infectious period and the post-infectious Lyme arthritis period.
• The joint damage seen in post-infectious Lyme arthritis most closely resembles that seen in chronic inflammatory arthritis.
• There appears to be a malfunction in the down-regulation of antibacterial responses mitigated by micro-RNA that prevents an appropriate transition to wound repair in patients with post-infectious Lyme arthritis.
• Methotrexate and other disease-modifying antirheumatic drugs may play an important role in treating patients with post-Lyme arthritis.
The NIH; the Littauer Foundation; the Roland Foundation; the English, Bonter, Mitchell Foundation, and Massachusetts General Hospital supplied funding for this study.
Robert B. Lochhead, Klemen Strle, Nancy D. Kim, et al. “MicroRNA Expression Shows Inflammatory Dysregulation and Tumor-Like Proliferative Responses in Joints of Patients With Postinfectious Lyme Arthritis.” Arthritis Rheumatol. 2017;69:1100-1110. doi: 10.1002/art.40039.