Macrophage infiltration into the synovium may be a feature of rheumatoid arthritis that persists in both patients with clinically active disease and those who are in clinical remission, while higher expression of certain angiogenic factors and vascularity may explain why ultrasound power Doppler signal continues to occur in patients in remission, according to a study comparing synovial biopsy samples.
Because persistent synovitis on either ultrasound or MRI in RA patients classified as being in clinical remission has been associated with increased probability of disease reactivation or flare as well as joint damage or radiological progression during follow-up, first author Dr. Julio Ramirez of the department of rheumatology and the Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) at the Hospital Clinic of Barcelona (Spain) and his colleagues sought to characterize the immunopathologic differences between the two states and “determine whether immunopathologic changes predict the relapse from clinical remission” during 12 months of follow-up.
©Suze777/Thinkstock.com
They compared ultrasound-guided synovial biopsy samples from 20 patients with RA who had a power Doppler (PD) signal but were in clinical remission for at least 6 months based on a 28-joint Disease Activity Score of less than 2.6 (using erythrocyte sedimentation rate) and no swollen or tender joints; samples from 22 patients with clinically active RA based on swollen joints with confirmed inflammatory synovial fluid (inflammatory control patients); and samples from 10 non-inflammatory controls (Arthritis Res Ther. 2016;18:74. doi: 10.1186/s13075-016-0970-9).
All RA patients with clinically active disease had synovial hypertrophy grade of 2 or higher and a moderate-to-severe PD signal of 2 or greater. Of the 20 RA patients in clinical remission, 16 had synovial hypertrophy grade of 2 or higher, 17 had a mild PD signal equal to 1, and 3 had a PD signal of 2.
RA patients in clinical remission had high macrophage infiltration, comparable with patients with clinically active RA. This finding suggests, according to the investigators, that ultrasound “synovitis does not differ physiopathologically from clinically active synovitis. Despite the absence of clinical signs (i.e., non-tender and non-swollen joints), RA patients in remission, who have PD signal, would appear to have a pathologic status whereby macrophage depletion has not been achieved by therapy.”
RA patients in remission also showed increased vascularity in comparison with noninflammatory controls based on significantly elevated levels of the angiogenic factors bFGF and CXCL12, which were the same or even high among patients with clinically active disease. The investigators also found progressively higher density of CD31+ blood vessels from non-inflammatory controls to patients in remission to patients with clinically active disease, confirming “the link between PD and increased vascularity in these patients, as was previously suggested to be characteristic of joints in clinically active disease,” they wrote.
RA patients in remission showed significantly lower inflammatory cell infiltration in synovial tissue (CD3+ T lymphocytes, CD20+ B lymphocytes, and CD117+ mast cells) than did patients with clinically active disease, but the density of these cells was still significantly higher than that of non-inflammatory controls.
After 12 months, 8 patients (40%) came out of remission, all of whom met a more stringent criterion for ultrasound synovitis (PD signal plus synovial hypertrophy grade 2 or higher) on biopsy. These patients had a significantly higher density of CD20+ B cells, CD117+ mast cells, and a non-significant trend toward higher density of lining macrophages than did patients maintaining clinical remission.
The investigators said their study was limited by a relatively small sample size and the retrospective inclusion of samples from joints with clinically active disease from patients with clinically active RA. “The association between the immunopathologic findings and disease reactivation are only exploratory and require further confirmation,” they noted.
The study was supported by grants from the Instituto de Salud Carlos III, Ministerio de Economía y Competitividad. The authors said they had no competing interests.