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Rheumatoid arthritis morning stiffness is associated with synovial fibrin and neutrophils


Orange DE1,2, Blachere NE2, DiCarlo EF3, Mirza S1, Pannellini T3, Jiang CS4, Frank MO2, Parveen S2, Figgie MP5, Gravallese EM6, Bykerk VP1, Orbai AM7, Mackie SL8,9, Goodman SM1. Arthritis Rheumatol. 2019 Oct 15. doi: 10.1002/art.41141. [Epub ahead of print]

Author Information

1 Rheumatology, Hospital for Special Surgery, New York, NY.

2 Laboratory of Molecular Neuro-Oncology &, Howard Hughes Medical Institute, The Rockefeller University, New York, NY.

3 Pathology, Hospital for Special Surgery, New York, NY.

4 Biostatistics, Rockefeller University Hospital, New York, NY.

5 Orthopedic Surgery, Hospital for Special Surgery, New York, NY.

6 Division of Rheumatology, University of Massachusetts Memorial Medical Center, Worcester, MA.

7 Rheumatology, Johns Hopkins Medicine, Baltimore, MD.

8 Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.

9 Leeds NIHR Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK.



Morning stiffness is a hallmark symptom of rheumatoid arthritis (RA), but its etiology is poorly understood. We sought to determine whether any histologic features of synovium associate with this symptom.


Patient reports of morning stiffness duration, stiffness severity and disease activity scores (DAS28) were collected from 176 patients with RA undergoing arthroplasty. Histopathology of synovium was scored for 10 features: synovial lining hyperplasia, lymphocytes, plasma cells, Russell bodies, binucleate plasma cells, fibrin, synovial giant cells detritus, neutrophils and mucin. Fibrinolysis of clots seeded with various cell types was measured in turbidimetric lysis assays.


Stiffness severity and morning stiffness duration were both significantly associated with DAS28 (p=0.0001 and p=0.001 respectively). None of the synovial features examined were associated with patient-reported stiffness severity. The presence of neutrophils and fibrin in RA synovial tissue were significantly (P<0.0001) associated with patient report of greater than one hour of morning stiffness, such that 73% of patients with both synovial fibrin and neutrophils report more than one hour of morning stiffness. Further, neutrophils and fibrin deposits colocalized along the synovial lining. In in vitro analyses, fibrin clots seeded with necrotic neutrophils were more resistant to fibrinolysis than those seeded with living neutrophils or no cells (p=0.008). DNase1 treatment of necrotic neutrophils abrogated the delay in fibrinolysis.


In RA, prolonged morning stiffness may be related to impaired fibrinolysis of neutrophil enmeshed fibrin deposits along the synovial membrane. Our findings also suggest that morning stiffness severity and duration may reflect distinct pathophysiological phenomena.