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New anti-cancer therapeutics have been developed in the recent years and dramatically change prognosis and patient management. Either used alone or in combination, immune checkpoint inhibitors (ICI), such as anti-CTLA-4 and anti-PD1/PD-(L)1, act by removing T-cell inhibition to enhance their antitumor response. This change in therapeutic targets leads to a break in immune-tolerance and a unique toxicity profile resulting in immune complications. These side effects, called Immune-Related Adverse Events (IrAEs), can affect all organs, with a wide range of clinical and biological presentations and severity. Various rheumatic and musculoskeletal manifestations have been reported in the literature, ranging from mild arthralgia, polymyalgia rheumatica, to genuine serodefined rheumatoid arthritis and myositis. Tolerance studies suggest some correlations between IrAEs occurrence and tumor response. Assessment of patient musculoskeletal status prior to the start of the ICI is warranted. Management of rheumatic IrAEs does not usually request ICI discontinuation, exception for myositis or very severe forms where it should be discussed. Treatment relies on non-steroidal anti-inflammatory drugs (NSAIDs) or low dose glucocortioids (

Vaccination is considered as a cornerstone of the management of COVID-19 pandemic. However, while vaccines provide a robust protection in immunocompetent individuals, the immunogenicity in patients with inflammatory rheumatic diseases (IRD) is not well established.A monocentric observational study evaluated the immunogenicity of a two-dose regimen vaccine in adult patients with IRD (n=123) treated with targeted or biological therapies. Serum IgG antibody levels against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike proteins were measured after the second vaccination. In addition, a search for observational studies performed in IRD under biologic or targeted therapies up to September 31, 2021 (PROSPERO registration number: CRD42021259410) was undertaken in publication databases, preprint servers, and grey literature sources. Studies that reported sample size, study date, location, and seroprevalence estimate were included. A meta-analysis was conducted to identify demographic differences in the prevalence of SARS-CoV-2 antibodies.Of 123 patients (median age 66 IQR 57-75), 69.9% have seroconverted after vaccination. Seroconverted patients were older than non-seroconverted ones in our cohort. Rituximab was associated with a significantly low antibody response. Besides, we identified 20 seroprevalence studies in addition to our cohort including 4423 participants in 11 countries. Meta-analysis confirmed a negative impact of rituximab on seroconversion rate and suggested a less substantial effect of abatacept, leflunomide and methotrexate.Rituximab impairs serological response to SARS-CoV-2 vaccines in patients with IRD. This work suggests also a negative impact of abatacept, methotrexate or leflunomide especially when associated to biological therapy.

International audience; Psoriatic arthritis (PsA) is a type of inflammatory arthritis associated with psoriasis. HLA association studies performed in northern Europe, comparing patients with control populations, have shown that the highest risk for PsA is carried by HLA-C*06, HLA-B*57 and HLA-B*27 alleles. This retrospective association study compared HLA-A, -B, -C, and -DR alleles of 500 patients from southern France, who fulfilled the CASPAR criteria for Psoriatic Arthritis (PsA), with 2346 controls from healthy blood donors, using the chi-square test. We classified PsA patients into three different subgroups according to disease: purely axial, purely peripheral and combined axial and peripheral. The 'axial' subgroup was associated with HLA-B*27 (OR = 16.3, p = 2.7 × 10-28) and its haplotypes: HLA- B*27-C*01 (OR = 12.4, p = 1.7 × 10-12) and HLA-B*27-C*02 (OR = 8.7, p = 10 × 10-9). The 'axial and peripheral' and the 'peripheral' subgroups were associated with HLA-C*06 (respectively OR = 1.5, p = 3.6 × 10-10 and OR = 2.4, p = 3.6 × 10-12) and its haplotypes HLA-C*06-B*13 (respectively OR = 2.4, p = 1.2 × 10-6 and OR = 2.8, p = 6.4 × 10-11). This association study on a southern French PsA cohort identifies HLA-C*06 as a marker for peripheral PsA and HLA-B*27 as a marker for purely axial PsA.

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

Background Epstein-Barr Virus (EBV) is a widely disseminated lymphotrophic herpes virus implicated in a lot of benign and malignant disorders. In transplant patients, EBV load is enhanced because of immunosuppressive drugs (cyclosporine) and in a few cases, it can lead to lymphoproliferative disorders (LPD). An EBV load higher than 500 copies per 500 ng of DNA is a predictive factor of post transplant lymphoma [1,2] Similarly, immunity against EBV is particular in RA patients: the level of antibodies against EBV is higher in RA than in healthy controls [3], RA patients have a defective EBV specific supressor T cell function [4].The risk to develop a lymphoma is higher in RA patients than in controls. We have previously shown that: 1/ EBV load is 10 fold higher in RA patients than in controls [5] and 2/ Methotrexate and TNF alpha antagonists (immunosuppressive drugs used in RA patients) do not increase EBV load in RA [6]. Objectives Here, we monitored EBV load over 3 years in patients with RA treated by 2 more recent biologics, Abatacept (CTLA4 Ig) a T cell activation inhibitor, or Tocilizumab, an anti IL6 receptor antibody. Methods EBV load in the peripheral blood mononuclear cells (PBMCs) from 55 patients under Abatacept (+/− Methotrexate) and 35 patients under Tocilizumab (+/− Methotrexate) was monitored from 6 months up 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 Neither Abatacept nor Tocilizumab significantly enhanced EBV load over time. None of our patients developed EBV associated lymphoma. Conclusions Long term usage of Methotrexate with Abatacept or Tocilizumab in patients with RA does not significantly influence EBV load in PBMCs. References Baldanti F et al. High levels of Epstein Barr virus DNA in blood of solid organ transplant recipients and their value in predicting postransplant lymphoproliferative disorders. Journal of Clinical Microbiology 38: 613–619, 2000 Morito M,et al. Quantitative analysis of Epstein Barr virus load by using a real time PCR assay. Journal of Clinical Microbiology 37: 132–136, 1999 Alspaugh M et al. Elevated levels of antibodies to Epstein Barr virus antigens in sera and synovial fluids of patients with rheumatoid arthritis. Journal of Clinical Investigation 67: 1134–1140, 1981 Tosato G et al. Defective EBV specific suppressor T cell function in rheumatoid arthritis. New England Journal of Medicine 305: 1238–1243, 1981 Balandraud N et al. Epstein-Barr Virus Load in the peripheral blood of patients with Rheumatoid arthritis. accurate quantification using re[2] Kimura H, al time Polymerase chain reaction. Arthritis and Rheumatism 2003;48:1223–1228. Balandraud N et al. Long-term treatment with methotrexate or tumor necrosis factor alpha inhibitors does not increase epstein-barr virus load in patients with rheumatoid arthritis. Arthritis and Rheumatism 57(5): 762–767, 2007 Acknowledgement This work was supported by AORC AP-HM, INSERM and Chugai. Disclosure of Interest E. Massy: None declared, O. Muis-Pistor: None declared, M. Martin: None declared, I. Auger: None declared, M.-C. Guzian: None declared, S. Guis: None declared, J. Roudier: None declared, T. Pham: None declared, N. Balandraud Grant/research support from: This work has been partially supported by Chugai group