PURPOSE OF REVIEW: To update progress made between December 2008 and November 
2009 on the role of the rheumatoid arthritis (RA)-shared epitope in the cause 
and pathogenesis of RA.
RECENT FINDINGS: New evidence has been recently presented to suggest that 
noninherited human leukocyte antigens (HLAs) originating through pregnancy or 
exposure to maternal antigens in utero could contribute to RA development in 
shared epitope-negative women. An interaction between smoking and shared 
epitope-coding non-*04 HLA-DRB1 alleles (particularly HLA-DRB1*01 and 
HLA-DRB1*10) was formally established for the first time. Progress has been made 
in determining the relative contributions and the interaction of the shared 
epitope, PTPN22 and smoking in conferring the risk of anticitrullinated protein 
antibodies-positive and negative RA. The autoantigen that anticitrullinated 
protein antibodies recognize in a significant number of RA patients has been 
identified as citrullinated alpha-enolase and the importance of genetic factors 
in anticitrullinated protein antibodies-negative RA has been highlighted. 
Additionally, associations of RA risk with several new genetic markers have been 
reported. Among them: two new major histocompatibility complex, non-DRB1 loci, a 
polymorphism marker in major histocompatibility complex class I 
polypeptide-related sequence A, an allele of the Fcgamma receptor, a 
polymorphism marker in the beta2-adrenergic receptor and a low-inducible allele 
of the cytochrome P450 subtype 1A2.
SUMMARY: Although the mechanistic basis of shared epitope-RA association remains 
an enigma, observations made during the last year shed new light on the 
conditions in which the shared epitope - alone or in combination with other 
genes or environmental factors - affects the risk of RA and the phenotype of the 
disease.