Antibody (Anti-CCP)-positive versus Anti-CCP-negative Early Rheumatoid Synovitis and Has a Different Temporal Course in Cyclic Citrullinated Peptide Cartilage Oligomeric Matrix Protein Associates Differentially with Erosions and JUNKER

Objective. Cyclic citrullinated peptide antibody (anti-CCP)-positive and anti-CCP-negative rheumatoid arthritis (RA) have been suggested as 2 distinctive disease subsets with respect to disease activity and prognosis. Previously, we proposed that anti-CCP antibodies might have a chondrocyte-suppressive effect. We aimed to compare circulating cartilage oligomeric matrix protein (COMP), a marker of cartilage turnover, in untreated anti-CCP-positive and anti-CCP-negative RA, and to study the temporal pattern of COMP through 4 years of treatment, including the relationship to imaging and clinical findings. Methods. A total of 160 patients with newly diagnosed RA who were naive to disease-modifying antirheumatic drugs were included in the CIMESTRA trial. Ninety healthy blood donors served as controls. Demographic and disease measures including Disease Activity Score in 28 joints, IgM rheumatoid factor, anti-CCP, Health Assessment Questionnaire, visual analog scale scores for pain and global and physician assessment, and magnetic resonance imaging (MRI) of the nondominant hand were recorded at baseline. COMP in serum was measured by ELISA at inclusion and serially through 4 years. Results. Median baseline COMP was higher in patients with RA [9.8 U/l (interquartile range 8.96, 10.5)] compared with controls [8.3 U/l (IQR 7.84, 8.9); p < 0.001] and remained elevated at 4 years [10.8 U/l (IQR 10.2, 11.7); p < 0.001]. At baseline, anti-CCP-positive patients had lower COMP than anti-CCP-negative patients (p = 0.048). In anti-CCP-positive patients, COMP exhibited a parabolic course over 4 years, while COMP in anti-CCP-negative patients had an almost linear course. In anti-CCP-positive patients, COMP was associated with MRI edema and erosion score, while COMP was correlated with synovitis score in anti-CCP-negative individuals. Conclusion. Our study provides additional evidence for the existence of different disease pathways in anti-CCP-positive and anti-CCP-negative subsets of RA, and evidence that anti-CCP antibodies may be implicated in the disease process by modifying cartilage metabolism. (First Release May 15 2011; J Rheumatol 2011;38:1563–8; doi:10.3899/jrheum.101241) Key Indexing Terms: RHEUMATOID ARTHRITIS CARTILAGE CYCLIC CITRULLINATED PEPTIDE ANTIBODY AUTOANTIBODIES SYNOVITIS CARTILAGE OLIGOMERIC MATRIX PROTEIN From the Department of Rheumatology, Odense University Hospital, Odense; Department of Rheumatology, Copenhagen University Hospital, Herlev, Gentofte, Glostrup, Rigshospitalet; Aarhus University Hospital, Aarhus; Research Unit, King Christian X Hospital for Rheumatic Diseases, Graasten; and Institute of Clinical Research, University of Southern Denmark, Odense, Denmark. Supported by The Danish Rheumatism Association. A.F. Christensen, PhD; P. Junker, DmSc, Professor; H.M. Lindegaard, PhD; A.J. Svendsen, PhD, Department of Rheumatology, Odense University Hospital and Institute of Clinical Research, University of Southern Denmark; T. Lottenburger, PhD; L.S. Andersen, PhD; J.K. Pedersen, PhD; K. Hørslev-Petersen, DmSc, King Christian X Hospital for Rheumatic Diseases; M.L. Hetland, PhD; H. Skjødt, PhD; B. Ejbjerg, PhD; U.B. Lauridsen, MD; M. Østergaard, PhD, DmSc, Professor, Department of Rheumatology, Copenhagen University Hospital; K. Stengaard-Pedersen, DmSc, Professor; T. Ellingsen, PhD; I. Hansen, PhD; U. Tarp, DmSc, Department of Rheumatology, Aarhus University Hospital; S. Jacobsen, DmSc, Department of Rheumatology, Copenhagen University Hospital, Rigshospitalet; J. Pødenphant, DmSc, Department of Rheumatology, Copenhagen University Hospital. Full Release Article. For details see Reprints/Permissions at jrheum.org Address correspondence to Dr. A.F. Christensen, Department of Rheumatology C, Odense University Hospital, Sdr. Boulevard 29, DK-5000 Odense C, Denmark. E-mail: [email protected] Accepted for publication March 2, 2011. Rheumatology The Journal of on June 19, 2017 Published by www.jrheum.org Downloaded from Cartilage oligomeric matrix protein (COMP), a member of the thrombospondin glycoprotein family, is an extracellular matrix protein mainly expressed in cartilaginous tissue1,2,3. Excess release of COMP leading to elevated levels in serum has been reported in various joint diseases, osteoarthritis and rheumatoid arthritis (RA) in particular4. While some studies have suggested that increased COMP in the circulation is a predictor of joint destruction of large5 and small joints6,7 in RA, discrepant results have been reported by others8,9,10. These disparities may be attributable to differences in the study populations, e.g., with respect to cyclic citrullinated peptide antibody (anti-CCP) seropositivity. Thus, Turesson, et al recently reported increased COMP levels in individuals who developed RA within 1–2 years, and elevated COMP was more likely in anti-CCP-negative subjects than in anti-CCP-posi tive individuals11. We recently reported that the N-propeptide of collagen IIA (PIIANP), a marker of cartilage collagen anabolism, is significantly lower in anti-CCP-positive compared to anti-CCP-negative patients with RA12. As well, we found a negative correlation between PIIANP and anti-CCP titer in serum12. These observations indicate that autoimmunity reflected by anti-CCP is implicated in the pathogenesis of RA by suppressing collagen II formation. Since COMP in serum is widely considered to be a reliable molecular marker of cartilage turnover, we undertook this investigation in order to compare circulating COMP in newly diagnosed, untreated anti-CCP-positive versus anti-CCP-negative RA; to elucidate the temporal COMP pattern in these 2 subsets; and to study the relationship between COMP and baseline magnetic resonance imaging (MRI) findings and disease activity measures. MATERIALS AND METHODS Patients and controls. A total of 160 patients with newly diagnosed untreated RA were included in the CIMESTRA trial13. Briefly, patients fulfilled the American College of Rheumatology (ACR) 1987 revised criteria for RA14. Further inclusion criteria were disease duration < 6 months, ≥ 2 swollen joints at baseline, and age 18–75 years. Health Assessment Questionnaire (HAQ score, 0–3)15, visual analog scale (VAS; 1–10) for pain and global and physician assessment, and Disease Activity Score in 28 joints (DAS28)16 were calculated and ACR response was recorded17. Ninety healthy blood donors (45 women, 45 men; median age 42.5 yrs, range 23–64 yrs) served as controls. In this healthy cohort, no other biochemical or clinical data were available and COMP was measured only once. The RA treatment strategy aimed at achieving maximal synovitis control using methotrexate (MTX) plus cyclosporine compared to MTX and placebo13. In addition, patients in both groups received intraarticular betamethasone injections into swollen joints (7 mg/l, maximum 4 joints or 4 ml per visit). After one year, hydroxychloroquine was added and cyclosporine/placebo was tapered to zero, while MTX and synovitis suppression by intraarticular steroid injections into swollen joints were continued13. During an open extension through study years 3–4 the strategy of maximal synovitis suppression was pursued18. Oral glucocorticoids were allowed during the open exten-