ARTHRITIS & RHEUMATISM Vol. 64, No. 1, January 2012, pp 62–66 DOI 10.1002/art.30655 © 2012, American College of Rheumatology BRIEF REPORT Macrophage Positron Emission Tomography Imaging as a Biomarker for Preclinical Rheumatoid Arthritis: Findings of a Prospective Pilot Study Yoony Y. J. Gent, 1 Alexandre E. Voskuyl, 1 Reina W. Kloet, 1 Dirkjan van Schaardenburg, 2 Otto S. Hoekstra, 1 Ben A. C. Dijkmans, 2 Adriaan A. Lammertsma, 1 and Conny J. van der Laken 1 Objective. To conduct a prospective pilot study to determine whether macrophage targeting by 11 C-(R)- PK11195 positron emission tomography (PET) can vi- sualize subclinical synovitis in arthralgia patients who have anti–citrullinated protein antibodies (ACPAs). Methods. Twenty-nine arthralgia patients who were positive for ACPAs but did not have clinical arthritis were studied. High (spatial)–resolution 11 C- (R)-PK11195 PET scans of the hands and wrists were performed. For all metacarpophalangeal, proximal in- terphalangeal, and wrist joints (i.e., 22 joints per pa- tient), tracer uptake was scored semiquantitatively (0–3 scale) by 2 observers who were blinded with regard to the clinical data. Patients were followed up prospec- tively for 24 months to investigate the development of clinical arthritis. Results. Overall agreement and kappa values for the readings of the 2 observers were, respectively, 97% and 0.91 (95% confidence interval [95% CI] 0.74–1) at the patient level and 99% and 0.81 (95% CI 0.65–0.96) at the joint level. In 4 patients, at least 1 and as many as 5 PET-positive joints (score >1) were found at baseline. Within 2 years of followup, 9 patients had developed clinical arthritis. This included all 4 patients with positive findings on the 11 C-(R)-PK11195 scan, who developed clinical arthritis in the hand/wrist region, as identified on PET scans. Of the 5 remaining arthritis patients with negative findings on PET scans, 2 devel- oped arthritis in the hand joints and 3 developed arthritis at locations outside the field of view of the PET scanner. Conclusion. Subclinical arthritis in ACPA- positive arthralgia patients could be visualized by 11 C- (R)-PK11195 PET scanning and was associated with development of arthritis within 2 years of followup. This indicates that 11 C-(R)-PK11195 PET may be useful in determining arthritis activity in the preclinical phase of RA. Timely recognition of rheumatoid arthritis (RA) is highly relevant, as early treatment may slow down disease progression and improve long-term clinical out- come (1). There is evidence that RA is preceded by a preclinical phase that is characterized by the develop- ment of autoantibodies, such as rheumatoid factor (RF) and anti–citrullinated protein antibodies (ACPAs) (2– 4). The presence of arthralgia may even further increase the risk of developing arthritis in ACPA-positive indi- viduals (4). However, it was shown that 73% of 95 ACPA-positive patients that were included in an arthral- gia study cohort (n = 147) did not develop clinical arthritis after a median followup of 28 months (inter- quartile range [IQR] 19–39) (4). Development of sensitive methods for detecting subclinical arthritis could offer a window of opportunity for early detection of disease and, hence, initiation of treatment at a very early stage. There are indications that subclinical arthritis can be detected by advanced imaging techniques (5–7). Advanced imaging may there- fore be useful for providing additional predictive infor- mation on the development of RA. Positron emission tomography (PET) is a novel imaging technique for the investigation of subclinical arthritis in preclinical RA. Previous studies have shown the value of 11 C-(R)-PK11195 (1-[2-chlorophenyl]-N- methyl-N-[1-methylpropyl]-3-isoquinoline carboxamide) and 18 F-2-fluoro-2-deoxy-D-glucose ( 18 F-FDG) in visu- alizing active arthritis in established RA (8,9). 11 C-(R)- 1 Yoony Y. J. Gent, MD, Alexandre E. Voskuyl, MD, PhD, Reina W. Kloet, MSc, Otto S. Hoekstra, MD, PhD, Adriaan A. Lammertsma, PhD, Conny J. van der Laken MD, PhD: VU University Medical Center, Amsterdam, The Netherlands; 2 Dirkjan van Schaardenburg, MD, PhD, Ben A. C. Dijkmans, MD, PhD: Jan van Breemen Research Institute/Reade, Amsterdam, The Netherlands. Address correspondence to Conny J. van der Laken, MD, PhD, Department of Rheumatology 3A64, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. E-mail: j.vanderlaken@vumc.nl. Submitted for publication December 15, 2010; accepted in revised form August 23, 2011. 62