T cell subsets: an immunological biomarker to predict progression to clinical arthritis in ACPA-positive individuals.
OBJECTIVE
Anticitrullinated protein antibody (ACPA)+ individuals with non-specific musculoskeletal symptoms are at risk of inflammatory arthritis (IA). This study aims to demonstrate the predictive value of T cell subset quantification for progression towards IA and compare it with previously identified clinical predictors of progression.


METHODS
103 ACPA+ individuals without clinical synovitis were observed 3-monthly for 12 months and then as clinically indicated. The end point was the development of IA. Naïve, regulatory T cells (Treg) and inflammation related cells (IRCs) were quantified by flow cytometry. Areas under the ROC curve (AUC) were calculated. Adjusted logistic regressions and Cox proportional hazards models for time to progression to IA were constructed.


RESULTS
Compared with healthy controls (age adjusted where appropriate), ACPA+ individuals demonstrated reduced naïve (22.1% of subjects) and Treg (35.8%) frequencies and elevated IRC (29.5%). Of the 103 subjects, 48(46.6%) progressed. Individually, T cell subsets were weakly predictive (AUC between 0.63 and 0.66), although the presence of 2 T cell abnormalities had high specificity. Three models were compared: model-1 used T cell subsets only, model-2 used previously published clinical parameters, model-3 combined clinical data and T cell data. Model-3 performed the best (AUC 0.79 (95% CI 0.70 to 0.89)) compared with model-1 (0.75 (0.65 to 0.86)) and particularly with model-2 (0.62 (0.54 to 0.76)) demonstrating the added value of T cell subsets. Time to progression differed significantly between high-risk, moderate-risk and low-risk groups from model-3 (p=0.001, median 15.4 months, 25.8 months and 63.4 months, respectively).


CONCLUSIONS
T cell subset dysregulation in ACPA+ individuals predates the onset of IA, predicts the risk and faster progression to IA, with added value over previously published clinical predictors of progression.
Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Chapel Allerton Hospital, Leeds, UK.
L
L
Hunt
Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Chapel Allerton Hospital, Leeds, UK NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
E M
EM
Hensor
Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Chapel Allerton Hospital, Leeds, UK.
J
J
Nam
Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Chapel Allerton Hospital, Leeds, UK.
A N
AN
Burska
Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Chapel Allerton Hospital, Leeds, UK.
R
R
Parmar
Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Chapel Allerton Hospital, Leeds, UK NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
P
P
Emery
Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Chapel Allerton Hospital, Leeds, UK NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
F
F
Ponchel
D000328:Adult; D000368:Aged; D000906:Antibodies / Q000097:blood* / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000209:etiology* / Q000276:immunology; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000097:blood* / Q000276:immunology; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D012680:Sensitivity and Specificity; D013585:Synovitis / Q000097:blood* / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism
D000906:Antibodies; D015415:Biomarkers; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide
Arthritis; Synovitis; T Cells