A. Ruyssen-Witrand

New insights into the genetics of immune responses in rheumatoid arthritis

Rheumatoid arthritis (RA) is a common autoimmune disease with a strong genetic component. Numerous aberrant immune responses have been described during the evolution of the disease. In later years, the appearance of anti-citrullinated protein antibodies (ACPAs) has become a hallmark for the diagnosis and prognosis of RA. The post-translational transformation of arginine residues of proteins and peptides into citrulline (citrullination) is a natural process in the body, but for unknown reasons autoreactivity towards citrullinated residues may develop in disposed individuals. ACPAs are often found years before clinical manifestations. ACPAs are present in about 70% of RA patients and constitute an important disease marker, distinguishing patient groups with different prognoses and different responses to various treatments. Inside the human leukocyte antigen (HLA) region, some HLA-DRB1 alleles are strongly associated with their production. Genome-wide association studies in large patient cohorts have defined a great number of single nucleotide polymorphisms (SNPs) outside of the HLA region that are associated with ACPA positive (ACPA+) RA. The SNPs are generally located close to or within genes involved in the immune response or signal transduction in immune cells. Some environmental factors such as tobacco smoking are also positively correlated with ACPA production. In this review, we will describe the genes and loci associated with ACPA+ RA or ACPA- RA and attempt to clarify their potential role in the development of the disease.

Association of IL-2RA and IL-2RB genes with erosive status in early rheumatoid arthritis patients (ESPOIR and RMP cohorts).

OBJECTIVESnTo assess the impact of single nucleotide polymorphisms (SNPs) in IL-2RA (rs2104286) and IL-2RB (rs743777 and rs3218253) genes on the risk of erosions in rheumatoid arthritis (RA) patients.nnnMETHODSnThis work is derived from 2 prospective cohorts of early RA: ESPOIR (n = 439) and RMP (n = 180). The proportions of patients with erosions at baseline and 1 year according to the genotypes of IL2RA (rs2104286) or the haplotypes constructed with the 2 SNPs of IL2RB were compared in the whole population and in ACPA positive patients. A meta-analysis assessing the risk of erosion depending on the haplotypes of the 2 SNPs of IL-2RB was performed using the Mantel-Haenszel method. A multivariate model was used to assess the independent effect of the haplotypes of IL-2RB on the risk of erosions.nnnRESULTSnThe AC haplotype of IL-2RB carriage was significantly associated with the rate of erosions in ACPA positive patients in ESPOIR cohort (rate of erosions: AC/AC: 78% versus GC or GT/GC or GT: 44%, p = 0.001). A meta-analysis of ESPOIR and RMP cohorts confirmed that the carriage of AC haplotype was significantly associated with the rate of erosions at 1 year in the whole sample (OR[95%CI] = 1.92[1.14-3.22], p = 0.01) and in ACPA positive patients (OR[95%CI] = 3.34[1.68-6.67], p = 0.0006). A multivariate model in ESPOIR cohort demonstrated the independent effect of the carriage of the AC haplotype (6.03[1.94-18.69], p = 0.002) on the risk of erosions in ACPA+ patients.nnnCONCLUSIONnA haplotype constructed with 2 SNPs located on IL-2RB gene was associated with erosive status in early RA.

Effect of age at rheumatoid arthritis onset on clinical, radiographic, and functional outcomes: The ESPOIR cohort.

OBJECTIVESnTo investigate whether age at disease onset determines clinical, radiographic or functional outcomes in a cohort of early RA.nnnMETHODSnThe ESPOIR cohort is a multicenter cohort of patients with early arthritis. We selected patients fulfilling the 2010 ACR/EULAR criteria for RA during the first 3years of follow-up. Patients were pooled into 3xa0groups by age at RA onset: <45years (young-onset RA [YORA]), 45 to 60years (intermediate-onset RA [IORA]) and>60years (late-onset RA [LORA]). The following outcomes were compared at baseline and during the first 3years of follow-up: Simple Disease Activity Index (SDAI) remission rate, one additional erosion, Health Assessment Questionnaire Disability Index (HAQ-DI)<0.5 and first disease-modifying anti-rheumatic drug (DMARD) continuation rate.nnnRESULTSnWe included 698xa0patients (median [interquartile range] age 50.3 [39.8-57.2]years), 266 YORA, 314 IORA, and 118 LORA. At 1year, SDAI remission was greater for YORA than IORA and LORA (P<0.0001). Having at least one additional erosion was greater for LORA and IORA than YORA after 1year (P=0.009) and 3years (P=0.017). The proportion of patients with HAQ score<0.5 was greater for YORA than IORA and LORA at 1 (P=0.007), 2 and 3years. First DMARD continuation rate was lower for YORA than other groups during the 3years (P=0.005).nnnCONCLUSIONSnIn a cohort of early RA, young age at disease onset is associated with high rate of remission at 1year, no radiographic progression at 3years and low functional score during 3-year follow-up.