MANCHESTER, U.K. – Analysis of synovial tissue taken by ultrasound-guided biopsy could help stratify patients with rheumatoid arthritis and decide if treatment with a tumor necrosis factor inhibitor is appropriate, according to research presented at the British Society for Rheumatology annual conference.
In a small yet intriguing study, Dr. Maria Di Cicco of Queen Mary University of London and her colleagues found that patients who had a lymphoid synovial pathotype were more likely to respond to treatment with the anti-TNF inhibitor certolizumab pegol than if they had other synovial pathotypes.
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“Rheumatoid arthritis is a clinically heterogeneous disease to the extent that we should think of it as a syndrome rather than a disease,” Dr. Di Cicco said. “This heterogeneity is expressed as a variable outcome and response to treatment,” she added.
Although biologic drugs have dramatically changed how patients are treated, 30%-40% of patients do not respond to treatment and the way biologic treatment is selected for RA is more down to trial and error than personalized medicine, Dr. Di Cicco observed. This is concerning, as the number of biologic medicines available is exponentially increasing and ways of matching the right drug to the right patient need to be found.
The aim of the current study was to see if different synovial subtypes could influence patients’ first response to treatment with anti-TNF therapy. Recent research looking at synovial tissue suggests that there are three clear synovial subtypes: myeloid, Pauci-immune, and lymphoid.
The myeloid and Pauci-immune pathotypes are characterized by diffuse cellular infiltration distributed evenly through the synovium. The lymphoid synovial pathotype, on the other hand, is characterized by the presence of large lymphocytic aggregates that are known as ectopic lymphoid structures (ELS). Dr. Di Cicco noted that ELS had been linked to B-cell proliferation within the synovium and to promoting in situ autoantibody production and class switching.
For the study, 28 patients with RA on stable doses of methotrexate who qualified for anti-TNF treatment according to U.K. National Institute for Health and Care Excellence guidance were recruited at a single center. All patients underwent ultrasound-guided biopsy of an active joint, which tended to be a small joint such as the wrist or metacarpophalangeal, before they were treated with certolizumab pegol. Twenty patients had a repeat synovial biopsy when the clinical efficacy of treatment was assessed at 12 weeks.
A minimum of six samples were taken from each biopsied joint, and this material underwent immunohistochemical analysis for the presence of T cells expressing CD3, B cells expressing CD20, macrophages expressing CD68, and plasma cells expressing CD138.
Samples were then classified as being the lymphoid pathotype if they contained mainly B and T cells and formed large lymphocytic aggregates or ELS. Myeloid subtype was defined as the presence of sublining macrophages and Pauci-immune if none of these features was present.
Thirteen (46.4%) patients were found to the have the Pauci-immune pathotype, with the lymphoid pathotype being the next most common (39.3% of patients), and four (14.3%) had the myeloid pathotype.
Apart from no prior oral steroid use in patients with the lymphoid pathotype versus 75% of patients with the myeloid pathotype and 38.5% of patients with the Pauci-immune pathotype, there were no significant differences among the groups in terms of demographics, clinical features, inflammatory markers, antibody or erosive status, or other treatments.
“After 12 weeks of therapy, the myeloid and the lymphoid groups showed a significantly higher fall in [Disease Activity Score] 28 compared to the Pauci-immune group,” Dr. Di Cicco reported.
“We also assessed achievement of EULAR response, and 71% of patients did respond. Half of them were good responders and half of them were moderate responders,” she added.
EULAR response by synovial pathotype was 100% for patients with the lymphoid pathotype, 75% for those with the myeloid pathotype, and 46% for those with the Pauci-immune pathotype.
Greater decreases in synovial thickening and power Doppler ultrasound also were seen in the myeloid and lymphoid pathotypes, compared with the Pauci-immune pathotype, which appeared more resistant to change in response to the anti-TNF therapy.
In the 20 patients who had a repeat biopsy, 9 had ELS at baseline. After treatment, three patients were ELS negative, four remained ELS positive, and two were ungraded.
“Our work shows that the presence of synovial ectopic lymphoid structures defining a lymphoid pathotype is a predictor of clinical response to anti-TNF-alpha,” Dr. Di Cicco said. Although further research and confirmation is needed, “we think that synovial tissue analysis could be considered as a promising tool to stratify RA patients and guide therapeutic decision,” she said.