Histologic and Transcriptional Evidence of Subclinical Synovial Inflammation in Patients With Rheumatoid Arthritis in Clinical Remission

Arthritis Rheumatol. 2019 Jul;71(7):1034-1041. doi: 10.1002/art.40878. Epub 2019 Jun 5.


Objective: Patients with rheumatoid arthritis (RA) in clinical remission may have subclinical synovial inflammation. This study was undertaken to determine the proportion of patients with RA in remission or with low disease activity at the time of arthroplasty who had histologic or transcriptional evidence of synovitis, and to identify clinical features that distinguished patients as having subclinical synovitis.

Methods: We compared Disease Activity Score in 28 joints (DAS28) to synovial histologic features in 135 patients with RA undergoing arthroplasty. We also compared DAS28 scores to RNA-Seq data in a subset of 35 patients.

Results: Fourteen percent of patients met DAS28 criteria for clinical remission (DAS28 <2.6), and another 15% met criteria for low disease activity (DAS28 <3.2). Histologic analysis of synovium revealed synovitis in 27% and 31% of samples from patients in remission and patients with low disease activity, respectively. Patients with low disease activity and synovitis also exhibited increased C-reactive protein (CRP) (P = 0.0006) and increased anti-cyclic citrullinated peptide (anti-CCP) antibody levels (P = 0.03) compared to patients without synovitis. Compared to patients with a "low inflammatory synovium" subtype, 183 genes were differentially expressed in the synovium of patients with subclinical synovitis. The majority of these genes (86%) were also differentially expressed in the synovium of patients with clinically active disease (DAS28 ≥3.2).

Conclusion: Thirty-one percent of patients with low clinical disease activity exhibited histologic evidence of subclinical synovitis, which was associated with increased CRP and anti-CCP levels. Our findings suggest that synovial gene expression signatures of clinical synovitis are present in patients with subclinical synovitis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Anti-Citrullinated Protein Antibodies / immunology
  • Arthritis, Rheumatoid / genetics
  • Arthritis, Rheumatoid / immunology
  • Arthritis, Rheumatoid / pathology*
  • Arthritis, Rheumatoid / surgery
  • Arthroplasty, Replacement, Hip
  • Arthroplasty, Replacement, Knee
  • Asymptomatic Diseases
  • Female
  • Gene Expression Profiling
  • Humans
  • Male
  • Middle Aged
  • Remission Induction
  • Sequence Analysis, RNA
  • Synovial Membrane / metabolism
  • Synovial Membrane / pathology*
  • Synovitis / genetics
  • Synovitis / pathology*


  • Anti-Citrullinated Protein Antibodies