ARTHRITIS & RHEUMATISM Vol. 54, No. 11, November 2006, pp 3381–3389 DOI 10.1002/art.22206 © 2006, American College of Rheumatology REVIEW Citrullinated Proteins in Rheumatoid Arthritis Crucial . . . but Not Sufficient! Tineke Cantaert, 1 Leen De Rycke, 2 Tim Bongartz, 3 Eric L. Matteson, 3 Paul P. Tak, 1 Anthony P. Nicholas, 4 and Dominique Baeten 5 Introduction Anti–citrullinated protein antibodies (ACPAs) are highly specific for rheumatoid arthritis (RA) and have thus become part of the diagnostic armamentarium in inflammatory arthritis. Circumstantial clinical evi- dence also suggests that ACPAs may participate in important pathophysiologic processes in RA. This con- cept has recently been supported by the specific gene– environment interaction between smoking and HLA– DR4 in ACPA-positive but not ACPA-negative patients with RA and by the enhancement of tissue injury by ACPAs in experimental arthritis. In parallel, important progress has been made in the detection and identifica- tion of citrullinated proteins as potential targets for ACPAs in inflamed synovium as well as other tissue. However, it becomes increasingly clear that well-defined citrullinated epitopes, rather than the mere presence of citrullinated proteins as such, may be relevant for the induction of ACPAs and, eventually, for the pathogenic- ity of anticitrulline reactivity. Therefore, defining the clinically relevant citrullinated epitopes and experimen- tally assessing the requirements for optimal and coordi- nated immune activation by these epitopes are 2 major challenges in this field. From systemic antibodies to synovial targets In the vast majority of patients with RA, one of the major features is the presence of serum autoantibod- ies. Besides the well-known rheumatoid factor, the so- called anti–citrullinated protein antibodies have been the subject of increasing scientific and clinical interest. For more than 40 years, these antibodies have been known as antiperinuclear factor, antikeratin antibodies, and antifilaggrin antibodies (1–3). Their commonalities have been evidenced by the crucial finding that they all target epitopes in which arginine residues have been converted to citrulline by the posttranslational action of peptidyl arginine deiminase (PAD) enzymes (4,5). The high specificity for RA (6–8) and the development of citrullinated substrates that allow easy and reliable de- tection of these autoantibodies (4,5,9,10) have boosted clinical interest in ACPAs as a new diagnostic tool. Besides this diagnostic application, recent clinical observations have provided some circumstantial evi- dence that ACPAs may be related to important patho- physiologic processes in RA. First, ACPAs can be found early in the disease course of RA (11–14), even years before the onset of clinical symptoms (15,16). Second, the presence of ACPAs is associated with more severe joint destruction (13,17,18) and greater disease activity (13,18,19), with ACPA positivity at the time of diagnosis being an important predictor of a more aggressive disease course (13,15,17). Third, recent studies suggest that ACPAs define a separate etiologic entity within RA (20,21), and a striking gene–-environment interaction between the HLA–DR shared epitope and smoking has Supported by the European Community (FP6). This research reflects only the authors’ views. The European Community is not liable for any use that may be made of the information herein. 1 Tineke Cantaert, Paul P. Tak, MD, PhD: University of Amsterdam, Amsterdam, The Netherlands; 2 Leen De Rycke, MD: Ghent University Hospital, Ghent, Belgium; 3 Tim Bongartz, MD, Eric L. Matteson, MD: Mayo Clinic College of Medicine, Rochester, Minnesota; 4 Anthony P. Nicholas, MD, PhD: University of Alabama at Birmingham, and Birmingham Veterans Administration Medical Center, Birmingham, Alabama; 5 Dominique Baeten, MD, PhD: Uni- versity of Amsterdam, Amsterdam, The Netherlands, and Ghent University Hospital, Ghent, Belgium. Address correspondence and reprint requests to Dominique Baeten, MD, PhD, Division of Clinical Immunology and Rheumatol- ogy, Academic Medical Center, University of Amsterdam, F4-218, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail: D.L.Baeten@amc.uva.nl. Submitted for publication May 3, 2006; accepted in revised form August 9, 2006. 3381