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Objective The presence of autoantibodies to citrullinated proteins (ACPAs) often precedes the development of rheumatoid arthritis (RA). Citrullines are arginine residues that have been modified by peptidylarginine deiminases (PADs). PAD4 is the target of autoantibodies in RA. ACPAs could arise because PAD4 is recognized by T cells, which facilitate the production of autoantibodies to proteins bound by PAD4. We previously found evidence for this hapten–carrier model in mice. This study was undertaken to investigate whether there is evidence for this model in humans. Methods We analyzed antibody response to PAD4 and T cell proliferation in response to PAD4 in 41 RA patients and 36 controls. We tested binding of 65 PAD4 peptides to 5 HLA–DR alleles (DRB1*04:01, *04:02, *04:04, *01:01, and *07:01) and selected 11 PAD4 peptides for proliferation studies using samples from 22 RA patients and 27 controls. Peripheral blood lymphocytes from an additional 10 RA patients and 7 healthy controls were analyzed by flow cytometry for CD3, CD4, CD154, and tumor necrosis factor expression after PAD4 stimulation. Results Only patients with RA had both antibodies and T cell responses to PAD4. T cell response to peptide 8, a PAD4 peptide, was associated with RA (P = 0.02), anti‐PAD4 antibodies (P = 0.057), and the shared epitope (P = 0.05). Conclusion ACPA immunity is associated with antibodies to PAD4 and T cell responses to PAD4 and PAD4 peptides. These findings are consistent with a hapten–carrier model in which PAD4 is the carrier and citrullinated proteins are the haptens.

Introduction Currently, there is no biomarker available to diagnose psoriatic arthritis (PsoA). Genome wide association studies showed that the majority of PsoA loci are shared with PsoC.1 However, PsoA has a strong familial predisposition, more so than PsoC as was shown in an Icelandic population.2 In the GWAS performed in UK and Germany, the strongest genetic locus is located within the major histocompatibility complex (MHC).3,4 No studies have been performed in southern Europe Objectives The primary objective of our study was to focus on the HLA class I and II alleles found in a cohort of 600 French patients with PsoA clinically well characterised, compared to a control cohort. The secondary objective was to compare two clinical subsets of PsoA, one axial and one peripheral, to test which genotype determines these phenotypes. Methods 600 patients from the Rheumatology department, St. Marguerite’s Hospital, Marseilles, who fulfilled the CASPAR criteria for PsoA, underwent clinical, radiographic and laboratory investigations. HLA Class I and Class II alleles were genotyped. A cohort of 2346 healthy blood donors (HBD) was also tested. Results Comparison between the PsoA population and controls showed one set of alleles significantly associated with PsoA; HLA-B*27, B*21(B*50), C*06 and with a weak significance HLA-A*01, A*25, B*13. Within the PsoA population, two genetically different subsets determine two different clinical subtypes: Peripheral disease was significantly associated with -C*06 in disequilibrium linkage with -B*13 and -DR*07, independently associated with HLA-A*01, -B*21 and -B*17. Axial disease was significantly associated with HLA-B*27 in disequilibrium linkage with C*01 and -C*02. Conclusions This is the first and the largest study ever realised in southern Europe. It lead to conclude that PsoA is genetically heterogeneous. We found that PsoA is divided in two genetically and phenotypically relevant subgroups, one axial group with HLA-B*27 predominance very close to Ankylosis spondylitis and one peripheral group with HLA-C*06 predominance. Other HLA alleles within the MHC are also implied. The clinical utility of HLA typing in PsoA should be further addressed in larger studies. References . Stuart PE, Nair RP, Tsoi LC, et al. Genome-wide association analysis of psoriatic arthritis and cutaneous psoriasis reveals differences in their genetic architecture. Am J Hum Genet2015;97:816–36. doi:10.1016/j.ajhg.2015.10.019 . Chandran V, Schentag CT, Brockbank JE, et al. Familial aggregation of psoriatic arthritis. Ann Rheum Dis2009;68:664–7. doi:10.1136/ard.2008.089367 . Rahman P, Elder JT. Genetics of psoriasis and psoriatic arthritis: A report from the GRAPPA 2010 annual meeting. J Rheumatol2012;39:431–3. doi:10.3899/jrheum.111242 . Bowes J, Budu-Aggrey A, Huffmeier U, et al. Dense genotyping of immune-related susceptibility loci reveals new insights into the genetics of psoriatic arthritis. Nat Commun2015;6:6046. doi:10.1038/ncomms7046 Disclosure of interest None declared

International audience; BACKGROUND:Epstein-Barr Virus (EBV) is a widely disseminated lymphotropic herpes virus implicated in benign and malignant disorders. In transplant patients, immunosuppressive drugs (cyclosporine) diminish control of EBV replication, potentially leading to lymphoproliferative disorders (LPD). Rheumatoid arthritis (RA) patients have impaired control of EBV infection and have EBV load ten times higher than controls. As post transplant patients, patients with RA have increased risk of developing lymphomas. Immunosuppressive drugs used to treat RA (conventional disease modifying drugs cDMARDs or biologics bDMARDs) could enhance the risk of developing LPD in RA patients. We have previously shown that long term treatment with Methotrexate and/or TNF alpha antagonists does not increase EBV load in RA. Our objective was to monitor the Epstein-Barr Virus load in RA patients treated with Abatacept (CTLA4 Ig), a T cell coactivation inhibitor, and Tocilizumab, an anti IL6 receptor antibody.METHODS:EBV load in the peripheral blood mononuclear cells (PBMCs) of 55 patients under Abatacept (in 34% associated with Methotrexate) and 35 patients under Tocilizumab (in 37% associated with Methotrexate) was monitored for durations ranging from 6 months to 3 years by real time PCR. The influences of treatment duration and disease activity score 28 (DAS28) index on EBV load were analyzed.RESULTS:Abatacept did not significantly modify EBV load over time. Tocilizumab significantly diminished EBV load over time. No patient (of 90) developed EBV associated lymphoma.CONCLUSION:Long term treatment with Abatacept or Tocilizumab does not increase EBV load in the PBMNCs of patients with RA.