Citrullinated proteins in rheumatoid arthritis: Crucial … but not sufficient!

Anti–citrullinated protein antibodies (ACPAs)are highly specific for rheumatoid arthritis (RA) andhave thus become part of the diagnostic armamentariumin inflammatory arthritis. Circumstantial clinical evi-dence also suggests that ACPAs may participate inimportant 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 patientswith RA and by the enhancement of tissue injury byACPAs in experimental arthritis. In parallel, importantprogress has been made in the detection and identifica-tion of citrullinated proteins as potential targets forACPAs in inflamed synovium as well as other tissue.However, it becomes increasingly clear that well-definedcitrullinated epitopes, rather than the mere presence ofcitrullinated proteins as such, may be relevant for theinduction of ACPAs and, eventually, for the pathogenic-ity of anticitrulline reactivity. Therefore, defining theclinically relevant citrullinated epitopes and experimen-tally assessing the requirements for optimal and coordi-nated immune activation by these epitopes are 2 majorchallenges in this field.