Current concepts in the pathogenesis of early rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a systemic inflammatory disease with a predilection for symmetrically distributed diarthroidal joints. It is clinically heterogeneous, with particular disease phenotypes defined according to a complex interplay of genes and the environment. In this chapter we first summarize current knowledge of RA genetic susceptibility, a field which has been transformed in recent years by powerful modern genotyping technologies. The importance of a recently described subclassification for the disease based upon the presence or absence of circulating autoantibodies to citrullinated peptides has further informed genetic studies, and we consider the implications for our understanding of RA pathogenesis. We then review the cellular and molecular processes that initiate and perpetuate joint destruction.

Fig. 1

Histograms of odds ratios for developing anti-CCP-positive (A) and anti-CCP-negative (B) rheumatoid arthritis (RA) for different combinations of absence or presence of R620 W PTPN22, single or double HLA-DRB1 shared epitope (SE) alleles, and smoking (see text). CCP, cyclic citrullinated peptide. Reproduced from Kallberg et al Am J Hum Genet 2007;80:867–75) with permission.

Fig. 2

Various pathogenetic pathways account for the heterogeneity of the early rheumatoid arthritis (RA) phenotype. During both the pre-articular phase (1) and the triggering of synovitis itself (2), genetic and environmental determinants together induce a combination of pathogenetic pathways whose common outcome is a syndrome of synovitis ultimately recognizable as RA (3). The relative contributions of the various pathways in turn define an individual's disease phenotype (4). It is hoped that the search for biomarkers will yield a means of stratifying early RA into prognostically and therapeutically relevant subsets. TLR, ‘Toll-like’ receptor; DMARD, disease-modifying anti-rheumatic drug; IP, inflammatory polyarthritis.