The persistence of Lyme arthritis after treatment with antibiotics comes with a shift from an immune response expected for bacterial infection to one characterized by chronic inflammation, synovial proliferation, and breakdown of wound repair processes, according to an analysis of microRNA expression in patients before, during, and after infection.
Based on the findings, investigators led by Robert B. Lochhead, PhD, of Massachusetts General Hospital, Boston, said that they “suspect that, in humans, genetic variables determine whether the response to B. burgdorferi infection elicits an appropriate wound repair response … or a maladaptive inflammatory cellular response and arrest of wound repair processes.”Arthritis Rheumatol. 2017 Jan 11. doi: 10.1002/art.40039). “The similarities in miRNA expression noted here between postinfectious LA and other forms of chronic inflammatory arthritis, including RA, support the practice of treating postinfectious LA patients with DMARDs [disease-modifying antirheumatic drugs] after appropriate antibiotic therapy.”
The investigators studied synovial fluid or tissue from 32 patients with LA who were representative of the spectrum of disease severity and treatment responses seen in this disease. In 18 patients for whom synovial fluid samples were available, 5 illustrated the differences in miRNA expression that occur from the time before any antibiotic treatment to the time after antibiotic treatment that successfully resolves arthritis symptoms, and 13 showed how an incomplete response to antibiotic treatment can affect miRNA expression. The expression profile of miRNA in synovial tissue samples from another 14 patients who underwent arthroscopic synovectomies 4-48 months after oral and intravenous antibiotics demonstrated the change in immune response seen in postinfectious LA.
The group of five patients with synovial fluid samples who were referred prior to antibiotic therapy when they had active B. burgdorferi infection (group 1) had a history of mild to severe knee swelling and pain for a median duration of 1 month prior to evaluation and the start of antibiotic treatment. A 1-month course of oral doxycycline resolved arthritis in three of the patients, and the other two continued to have marked knee swelling that later resolved after 1 month of IV ceftriaxone. Of six different miRNAs that the investigators measured, five were at low levels in these patients. The lone exception was a hematopoietic-specific miRNA, miR-223, which is abundantly expressed in polymorphonuclear lymphocytes (PMNs) and is associated with downregulation of acute inflammation and tissue remodeling.
In the group of 13 who still had joint swelling despite oral or IV antibiotics (group 2), only 2 had resolution of their swelling after IV antibiotics. Most of the remaining 11 had successful treatment with methotrexate. The synovial fluid samples for seven patients were collected after oral antibiotics but before IV antibiotics, and in the other six the samples were collected after both therapies. These 13 patients had significantly lower white blood cell counts in synovial fluid, fewer PMNs, and greater percentages of lymphocytes and monocytes than did group 1 patients. The five miRNAs that were found at low levels among the patients in group 1 were higher in these patients, which “suggested that the nature of the arthritis had changed after spirochetal killing.” The higher miR-223 levels seen in group 1 also occurred in group 2.
A separate analysis of synovial fluid samples from four patients with osteoarthritis and six patients with RA showed that levels of the six miRNAs from RA patients were similar to those of patients from group 2, and the low levels that were observed for most of the miRNAs in group 1 were similar to those seen in OA patients.
The investigators found that the five miRNAs with elevated levels in group 2 patients, but not miR-223, were positively correlated with arthritis duration after start of oral antibiotic therapy. B. burgdorferi IgG antibody titers negatively correlated with some of the elevated miRNAs in group 2.
The investigators analyzed a larger set of miRNAs in the synovial tissue samples obtained from 14 patients who underwent synovectomies for treatment of persistent synovitis a median of 15.5 months after they had undergone 2-3 months of antibiotic therapy (group 3). Some of the miRNAs overexpressed in these postinfectious LA samples, relative to samples from five OA patients, were associated with proliferative, tumor-associated responses and regulation of inflammatory processes. However, miRNAs overexpressed in tissues from OA patients relative to postinfectious LA patients were thought to affect genes that control tissue remodeling and cell proliferation, but not inflammation. The “distinct oncogenic miRNA profile” exhibited by postinfectious synovial tissue, according to the investigators, showed that “in these patients, the transition to the postinfectious phase was blocked by chronic inflammation, which stalled the wound repair process.”
The investigators concluded that “miRNAs hold promise as potential biomarkers to identify LA patients who are developing maladaptive immune responses during the period of infection. In such patients, it will be important to learn whether simultaneous treatment with antibiotics and DMARDs, rather than sequential treatment with these medications, will reduce the period of therapy and improve outcome, creating a new paradigm in treatment of this form of chronic inflammatory arthritis.”
The study was supported by grants from the National Institutes of Health, the Lucius N. Littauer Foundation, the Roland Foundation, the Lyme Disease and Arthritis Research Fund at Massachusetts General Hospital, the Rheumatology Research Foundation, and the English, Bonter, Mitchell Foundation.