793 1 Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Florence, Italy; 2 Rheumatology Unit, Department of Medicine, University of Perugia, Italy; 3 Rheumatology Unit, Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Italy; 4 Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Italy. Eleonora Bellucci, MD* Riccardo Terenzi, MD* Giuliana M.C. La Paglia, MD Stefano Gentileschi MD Alessandra Tripoli, MD Chiara Tani, MD, PhD Alessia Alunno, MD *These authors contributed equally to this paper. Please address correspondence to: Riccardo Terenzi, MD, Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Florence, Viale Pieraccini 18, 50139 Firenze, Italy. E-mail: terenzi.ricca@gmail.com Received on July 25, 2016; accepted in revised form on September 1, 2016. Clin Exp Rheumatol 2016; 34: 793-801. © Copyright CliniCal and ExpErimEntal rhEumatology 2016. Key words: rheumatoid arthritis, genetics, T lymphocytes, B lymphocytes, cardiovascular risk Competing interests: none declared. ABSTRACT Rheumatoid arthritis (RA) is an autoim- mune disease characterised by chronic synovial inlammation leading to joint destruction and bone erosions. Although the pathogenic mechanisms underlying the disease are not fully elucidated, it is known that genetic susceptibility and environmental factors trigger an abnor- mal autoimmune response. Potentially, any organ and tissue could be affected by RA and the increased cardiovascular (CV) risk represents the major compli- cation responsible for a worse progno- sis. In this setting, the shared pathogenic mechanisms between RA pathogenesis and accelerated atherosclerosis further strengthen the rationale for a treat-to- target strategy with synthetic and bio- logic disease modifying anti-rheumatic drugs. The aim of this review is to pro- vide the novel insights, regarding the pathogenesis of RA, published over the last year. Introduction Following the previous papers of the ”one year in review” collection on rheu- matoid arthritis (RA) (1-3), the aim of this review is to provide an overview of the new data emerged on the patho- genesis of RA. We performed a Medli- ne search of English language articles published from the 1st January to 31st December 2015 using MESH terms and free text words for the following search keys: rheumatoid arthritis, genetics, hi- stocompatibility antigens class I, single nucleotide polymorphism, innate immu- nity, interferon type I, t-lymphocytes, b-lymphocytes, environment, smoking, microbiota, lung, skin, cardiovascular diseases. The most relevant articles were selected for inclusion in this review. Genetic factors HLA molecules In the last few years, knowledge about the role of genetics in the pathogenesis of rheumatoid arthritis (RA) has in- creased with the discovery of a grow- ing number of genetic loci and single polymorphisms associated with RA susceptibility (4). Recently, Iwaszko et al. demonstrat- ed for the irst time that the HLA-E 01:01/01:01 genotype may be associat- ed with reduced risk of RA and may in- crease the probability of good response to anti-TNF agents. Conversely, the HLA-E 01:03 variant may contribute to a lower probability of achieving dis- ease remission (5). Val and Leu at posi- tion 11 in the HLA-DRB1 locus were recently identiied as additional sus- ceptibility factors for ACPA-positive RA. Van Steenbergen et al. observed that these amino acids are also associ- ated with a more severe disease course and radiographic progression (6). An- other study revealed that HLA-DRB1 molecule variants deined by the pres- ence of certain amino acids at positions 11 and 13 displayed the strongest asso- ciation with the risk of ACPA-positive RA. This inding may be explained at least in part by the fact that the pres- entation of smoking-induced citrulli- nated autoantigen may be speciically dependent on the presence of certain amino acid residues at position 13 of the HLA-DRB1 chain (7). Another ex- ample of interaction involving HLA- DRB1 was the one detected by Shche- tynsky et al. concerning the MAP2K4 gene and in particular its single nucleo- tide polymorphism (SNP) rs10468473. The study suggests that MAP2K4 is an important candidate gene for RA for at least two reasons. First, it increases the risk for ACPA-positive disease in combination with HLA-DRB1 shared epitope (SE) alleles. Secondly, het- erozygous individuals for rs10468473 demonstrated higher expression of to- tal MAP2K4 mRNA in the peripheral Review One year in review 2016: pathogenesis of rheumatoid arthritis E. Bellucci 1 , R. Terenzi 1 , G.M.C. La Paglia 2 , S. Gentileschi 3 , A. Tripoli 4 , C. Tani 4 , A. Alunno 2