To investigate genetic architecture and identify novel risk loci shared between juvenile idiopathic arthritis (JIA) and other human leukocyte antigen (HLA)-associated autoimmune diseases (AIDs) by leveraging genome-wide association studies (GWAS) data. We analyzed GWAS summary statistics from over two million participants (123,997 cases and 1,843,249 controls) of European ancestry across multiple AIDs including JIA, autoimmune thyroid disease (AITD), celiac disease, inflammatory bowel disease (IBD), multiple sclerosis (MS), psoriasis (Ps), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and type 1 diabetes (T1D). The conjunctional false discovery rate (conjFDR) method was employed to identify shared genetic loci, followed by functional annotation and pathway analysis. We identified 46 novel loci shared between JIA and various AIDs: 17 with AITD, 16 with RA, 13 with IBD, five each with MS and Ps, four with SLE, and seven with T1D. Notable shared risk genes included BACH2, UBASH3A, IRF4, IL12A-AS1, ETS1, PSMD14, FOXK1, NEK6, SP140, TNIP1, VAV3, CYP20A1, DNMT3A, LAX1, CASC15, ZC3H12C, KALRN, TBC1D1, PIK3CB, ANXA6 , and HIF1A . Functional annotation revealed 170 nonsynonymous exonic variants and 478 potentially deleterious variants (CADD score > 12.37). Gene Ontology analysis consistently highlighted enrichment of T cell-related processes and immune system regulation pathways. This study expands the understanding of genetic architecture in JIA by identifying novel risk loci shared with other AIDs. The extensive genetic overlap and shared biological pathways, particularly in T cell-mediated immunity, suggest common pathogenic mechanisms and potential therapeutic targets across multiple autoimmune conditions.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease characterized by post-exertional malaise, fatigue and pain. Yet, its underlying biological mechanisms remain poorly understood. Extracellular vesicles (EVs) are nanoparticles carrying biological cargo and are involved in cell-cell communication. Plasma EVs reflect several disease states and may serve as minimally invasive biomarkers. In this exploratory study, we characterized the plasma EV profiles of ME/CFS patients (N = 49) and healthy controls (N = 50), by enriching for EVs by size-exclusion chromatography coupled to high-resolution quantitative proteomics. The ME/CFS patients had significantly higher concentrations of EVs than healthy controls. Among the 424 detected proteins included for analyses, 11 had different levels in EVs from ME/CFS patients. The ME/CFS associated EV proteins appear to mainly originate from erythroid cells, hepatocytes and plasma B cells, based on their tissue expression. Albeit differences in EV protein levels did not withstand correction for multiple testing, our study is the largest to date, thereby encouraging future investigations on the role of EV and its cargo in ME/CFS.

Chronic low back pain (cLBP) lacks clear physiological explanations, and the treatment options are of limited effect. We aimed to elucidate the underlying biology of cLBP in a subgroup of patients with Modic changes type I (suggestive of inflammatory vertebral bone marrow lesions) by correlating gene expression in blood with patient-reported outcomes on disability and pain intensity and explore sex differences. Patients were included from the placebo group of a clinical study on patients with cLBP and Modic changes. Blood was collected at the time of inclusion, after three months, and after one year, and gene expression was measured at all time points by high-throughput RNA sequencing. The patients reported disability using the Roland–Morris Disability Questionnaire, and pain intensity was assessed as a mean of three scores on a 0–10 numeric rating scale: current LBP, worst LBP within the last two weeks, and mean LBP within the last two weeks. The gene expression profiles were then correlated to the reported outcomes. Changes in gene expression over time correlated significantly with changes in both disability and pain. The findings showed distinct patterns in men and women, with negligible overlap in correlated genes between the sexes. The genes involved were enriched in immunological pathways, particularly T cell receptor complex and immune responses related to neutrophils. Several of the genes harbour polymorphisms that previously have been found to be associated with chronic pain. Taken together, our results indicate gender differences in the underlying biology of disability and pain intensity in patients with low back pain.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease with unknown cause. Involvement of infection and immune dysregulation has been suggested, including changes in immune cell subsets and abnormal functions of natural killer (NK) cells. The regulatory NK cell receptors, killer cell immunoglobulin-like receptors (KIR) have previously been investigated in small cohorts of ME/CFS patients with conflicting results regarding gene content. Here, we studied KIR genes also at the allelic level using high-resolution sequencing, in 418 ME/CFS patients and 473 healthy controls. Human leukocyte antigen (HLA) class I genotype data were included for KIR ligand annotation. Our healthy control data represent KIR frequencies for a Norwegian population, which have not previously been reported. We found no association between ME/CFS and KIR gene content or copy number variations. However, our data suggested that specific KIR alleles at loci encoding inhibitory receptors were associated with ME/CFS, which was further supported by allelic haplotype analyses. Three alleles were more frequent in patients, i.e. KIR3DL3*002 (OR = 1.43, 95 % CI (1.09-1.86), p = 0.009), KIR3DL1*020 (OR = 2.20, 95 % CI (1.19-4.06), p = 0.01) and KIR3DL2*009 (OR = 1.56, 95 % CI (1.09-2.23), p = 0.01), while two alleles had a reduced patient frequency, i.e. KIR3DL3*013 (OR = 0.60, 95 % CI (0.42-0.86), p = 0.005) and KIR3DL2*010 (OR = 0.46, 95 % CI (0.30-0.71), p = 0.0005). Our data support an involvement of NK cells in ME/CFS.

Extracellular vesicles (EVs) are implicated in rheumatoid arthritis (RA) but have mainly been assessed in RA patients taking disease modifying anti-rheumatic drugs. EVs are nanoparticles important in cell-cell communication and their molecular cargo are biomarker candidates. We characterized the protein profiles of EVs from blood plasma from newly diagnosed, treatment naïve RA patients (N = 32) and compared them to healthy controls (N = 20), by size exclusion chromatography-based EV enrichment coupled with high-resolution quantitative proteomics. The RA patients had higher EV concentration and larger EVs than controls. A total of 682 EV proteins were reliably quantified, and the overall profiles were distinctly different between patients and controls. Specifically, 26 proteins were significantly upregulated and 31 downregulated in RA patients, with several proteins acting in inflammatory networks and with immunologically important upstream regulators. The RA associated EVs appear, based on the tissue expression of their cargo proteins, to originate mainly from hepatocytes or immune cells, like neutrophils. Interestingly, the strongest RA associated EV proteins were inflammatory molecules, like SAA1 and S100A9, already suggested as biomarkers in RA. Furthermore, the RA associated EV proteins were generally not correlated with total serum protein levels, stressing the importance of EV transport of inflammatory proteins in RA pathogenesis.

Immunogenicity to tumour necrosis factor inhibitors is a significant clinical problem leading to treatment failure and adverse events. The study aimed to assess human leukocyte antigen (HLA) associations with anti-drug antibody (ADAb) formation to infliximab. Immune-mediated inflammatory disease patients on infliximab therapy ( n  = 612) were included. Neutralising ADAb were assessed with a drug-sensitive assay. Next generation sequencing-based HLA typing was performed. Overall, 147 (24%) patients developed ADAb. Conditional analyses indicated HLA-DQB1 ( p  = 1.4 × 10 −6 ) as a primary risk locus. Highest risk of ADAb was seen when carrying at least one of the HLA-DQ2 haplotypes; DQB1*02:01–DQA1*05:01 or DQB1*02:02–DQA1*02:01 (OR 3.18, 95% CI 2.15–4.69 and p  = 5.9 × 10 −9 ). Results were consistent across diseases and when adjusting for concomitant immunomodulator. Computational predictions indicated that these HLA-DQ2 haplotypes bind to peptide motifs from infliximab light chain. A genome-wide significant association between two HLA-DQ2 haplotypes and the risk of ADAb formation to infliximab was identified, suggesting that HLA-DQ2 testing may facilitate personalised treatment decisions.

To prevent autoimmunity, thymocytes expressing self-reactive T cell receptors (TCRs) are negatively selected, however, divergence into tolerogenic, agonist selected lineages represent an alternative fate. As thymocyte development, selection, and lineage choices are dependent on spatial context and cell-to-cell interactions, we have performed Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq) and spatial transcriptomics on paediatric human thymu​​s. Thymocytes expressing markers of strong TCR signalling diverged from the conventional developmental trajectory prior to CD4+ or CD8+ lineage commitment, while markers of different agonist selected T cell populations (CD8αα(I), CD8αα(II), T(agonist), Treg(diff), and Treg) exhibited variable timing of induction. Expression profiles of chemokines and co-stimulatory molecules, together with spatial localisation, supported that dendritic cells, B cells, and stromal cells contribute to agonist selection, with different subsets influencing thymocytes at specific developmental stages within distinct spatial niches. Understanding factors influencing agonist T cells is needed to benefit from their immunoregulatory effects in clinical use.

Supplementary materials and methods. Detailed bioinformatics analysis methods (softwares commands and parameters) used to analyse in silicon TCGA and OKG exam sequencing data.

Thymic T cell development comprises T cell receptor (TCR) recombination and assessment of TCR avidity towards self-peptide-MHC complexes presented by antigen-presenting cells. Self-reactivity may lead to negative selection, or to agonist selection and differentiation into unconventional lineages such as regulatory T cells and CD8[Formula: see text] T cells. To explore the effect of the adaptive immune receptor repertoire on thymocyte developmental decisions, we performed single cell adaptive immune receptor repertoire sequencing (scAIRR-seq) of thymocytes from human young paediatric thymi and blood. Thymic PDCD1+ cells, a putative CD8[Formula: see text] T cell precursor population, exhibited several TCR features previously associated with thymic and peripheral ZNF683+ CD8[Formula: see text] T cells, including enrichment of large and positively charged complementarity-determining region 3 (CDR3) amino acids. Thus, the TCR repertoire may partially explain the decision between conventional vs. agonist selected thymocyte differentiation, an aspect of importance for the development of therapies for patients with immune-mediated diseases.

Study Objectives Narcolepsy type 1 (NT1) is characterized by unstable sleep-wake and muscle tonus regulation during sleep. We characterized dream enactment and muscle activity during sleep in a cohort of post-H1N1 NT1 patients and their siblings, and analyzed whether clinical phenotypic characteristics and major risk factors are associated with increased muscle activity. Methods RBD symptoms and polysomnography m. tibialis anterior electromyographical signals [long (0.5-15 s); short (0.1-0.49 s)] were compared between 114 post-H1N1 NT1 patients and 89 non-narcoleptic siblings. Association sub-analyses with RBD symptoms, narcoleptic symptoms, CSF hypocretin-1 levels, and major risk factors [H1N1-(Pandemrix)-vaccination, HLA-DQB1*06:02-positivity] were performed. Results RBD symptoms, REM and NREM long muscle activity indices and REM short muscle activity index were significantly higher in NT1 patients than siblings (all p < 0.001). Patients with undetectable CSF hypocretin-1 levels (<40 pg/ml) had significantly more NREM periodic long muscle activity than patients with low but detectable levels (40-150 pg/ml) (p = 0.047). In siblings, REM and NREM sleep muscle activity indices were not associated with RBD symptoms, other narcolepsy symptoms, or HLA-DQB1*06:02-positivity. H1N1-(Pandemrix)-vaccination status did not predict muscle activity indices in patients or siblings. Conclusion Increased REM and NREM muscle activity and more RBD symptoms is characteristic of NT1, and muscle activity severity is predicted by hypocretin deficiency severity but not by H1N1-(Pandemrix)-vaccination status. In the patients' non-narcoleptic siblings, neither RBD symptoms, core narcoleptic symptoms, nor the major NT1 risk factors is associated with muscle activity during sleep, hence not indicative of a phenotypic continuum.

Extracellular vesicles (EVs) are implicated in the pathogenesis of rheumatoid arthritis (RA) but little is known about the composition of specific small EV (sEV) subpopulations. This study aimed to characterize the CD63, CD81 and CD9 tetraspanin profile in the membrane of single EVs in plasma from treatment naïve RA patients and assess potential discrepancies between methotrexate (MTX) responder groups. EVs isolated from plasma were characterized using transmission electron microscopy, and detection of surface markers (CD63, CD81 and CD9) on single EVs was performed on the ExoView platform. All RA patients ( N = 8) were newly diagnosed, treatment naïve, females, ACPA positive and former smokers. The controls ( N = 5) were matched for age and gender. After three months of MTX treatment, responders ( N = 4) were defined as those with ΔDAS28 > 1.2 and DAS28 ≤ 3.2 post-treatment. The isolated EVs were 50–200 nm in size. The RA patients had a higher proportion of both CD9 and CD81 single positive sEVs compared to healthy controls, while there was a decrease in CD81/CD9 double positive sEVs in patients. Stratification of RA patients into MTX responders and non-responders revealed a distinctly higher proportion of CD81 single positive sEVs in the responder group. The proportion of CD81/CD9 double positive sEVs (anti-CD9 captured) was lower in the non-responders, but increased upon 3 months of MTX treatment. Our exploratory study revealed distinct tetraspanin profiles in RA patients suggesting their implication in RA pathophysiology and MTX treatment response.

Long-term antibiotics are prescribed for a variety of medical conditions, recently including low back pain with Modic changes. The molecular impact of such treatment is unknown. We conducted longitudinal transcriptome and epigenome analyses in patients (n = 100) receiving amoxicillin treatment or placebo for 100 days in the Antibiotics in Modic Changes (AIM) study. Gene expression and DNA methylation were investigated at a genome-wide level at screening, after 100 days of treatment, and at one-year follow-up. We identified intra-individual longitudinal changes in gene expression and DNA methylation in patients receiving amoxicillin, while few changes were observed in patients receiving placebo. After 100 days of amoxicillin treatment, 28 genes were significantly differentially expressed, including the downregulation of 19 immunoglobulin genes. At one-year follow-up, the expression levels were still not completely restored. The significant changes in DNA methylation (n = 4548 CpGs) were mainly increased methylation levels between 100 days and one-year follow-up. Hence, the effects on gene expression occurred predominantly during treatment, while the effects on DNA methylation occurred after treatment. In conclusion, unrecognized side effects of long-term amoxicillin treatment were revealed, as alterations were observed in both gene expression and DNA methylation that lasted long after the end of treatment.

Disability and distress caused by chronic low back pain (LBP) lacking clear pathoanatomical explanations cause huge problems both for patients and society. A subgroup of patients has Modic changes (MC), identifiable by MRI as vertebral bone marrow lesions. The cause of such changes and their relationship to pain are not yet understood. We explored the pathobiology of these lesions using profiling of gene expression in blood, coupled with an edema-sensitive MRI technique known as short tau inversion recovery (STIR) imaging. STIR images and total RNA from blood were collected from 96 patients with chronic LBP and MC type I, the most inflammatory MC state. We found the expression of 37 genes significantly associated with STIR signal volume, ten genes with edema abundancy (a constructed combination of STIR signal volume, height, and intensity), and one gene with expression levels significantly associated with maximum STIR signal intensity. Gene sets related to interferon signaling, mitochondrial metabolism and defense response to virus were identified as significantly enriched among the upregulated genes in all three analyses. Our results point to inflammation and immunological defense as important players in MC biology in patients with chronic LBP.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease of unknown etiology and pathogenesis, which manifests in a variety of symptoms like post-exertional malaise, brain fog, fatigue and pain. Hereditability is suggested by an increased disease risk in relatives, however, genome-wide association studies in ME/CFS have been limited by small sample sizes and broad diagnostic criteria, therefore no established risk loci exist to date. In this study, we have analyzed three ME/CFS cohorts: a Norwegian discovery cohort (N = 427), a Danish replication cohort (N = 460) and a replication dataset from the UK biobank (N = 2105). To the best of our knowledge, this is the first ME/CFS genome-wide association study of this magnitude incorporating 2532 patients for the genome-wide analyses and 460 patients for a targeted analysis. Even so, we did not find any ME/ CFS risk loci displaying genome-wide significance. In the Norwegian discovery cohort, the TPPP gene region showed the most significant association (rs115523291, P = 8.5 x 10(-7)), but we could not replicate the top SNP. However, several other SNPs in the TPPP gene identified in the Norwegian discovery cohort showed modest association signals in the self-reported UK biobank CFS cohort, which was also present in the combined analysis of the Norwegian and UK biobank cohorts, TPPP (rs139264145; P = 0.00004). Interestingly, TPPP is expressed in brain tissues, hence it will be interesting to see whether this association, with time, will be verified in even larger cohorts. Taken together our study, despite being the largest to date, could not establish any ME/CFS risk loci, but comprises data for future studies to accumulate the power needed to reach genome-wide significance.

OBJECTIVE:Juvenile idiopathic arthritis (JIA) is the most common chronic immune-mediated joint disease among children and encompasses a heterogeneous group of immune-mediated joint disorders classified into 7 subtypes according to clinical presentation. However, phenotype overlap and biologic evidence suggest a shared mechanistic basis between subtypes. This study was undertaken to systematically investigate shared genetic underpinnings of JIA subtypes. METHODS:We performed a heterogeneity-sensitive genome-wide association study encompassing a total of 1,245 JIA cases (classified into 7 subtypes) and 9,250 controls, followed by fine-mapping of candidate causal variants at each genome-wide significant locus, functional annotation, and pathway and network analysis. We further identified candidate drug targets and drug repurposing opportunities by in silico analyses. RESULTS:In addition to the major histocompatibility complex locus, we identified 15 genome-wide significant loci shared between at least 2 JIA subtypes, including 10 novel loci. Functional annotation indicated that candidate genes at these loci were expressed in diverse immune cell types. CONCLUSION:This study identified novel genetic loci shared by JIA subtypes. Our findings identified candidate mechanisms underlying JIA subtypes and candidate targets with drug repurposing opportunities for JIA treatment.

Abstract Background Immunogenicity is a leading cause of treatment failure to TNF inhibitors. Genetic variations in HLA class II genes have been suggested to predispose to anti-drug antibody formation, but studies using high-resolution HLA typing as well as characterisation of biologically relevant haplotypes are currently lacking. The aim of this study was to assess associations between HLA loci and immunogenicity to infliximab. Methods Patients with immune-mediated inflammatory diseases (IMID) treated with infliximab (N=612) (120 rheumatoid arthritis, 181 spondyloarthritis, 72 psoriatic arthritis, 114 ulcerative colitis, 80 Crohn disease, and 45 psoriasis) were included in the randomised, Norwegian Drug Monitoring (NOR-DRUM) trial. Neutralising anti-drug antibodies were detected with an automated fluorescence assay. Next generation HLA sequencing at G group resolution were performed and trimmed to 2nd field. Haplotype analyses including the most significant HLA loci were performed, and epitope predictions for the infliximab light- and heavy-chain were assessed. Results Anti-drug antibodies to infliximab were detected in 147 (24 %) of patients. The most significant associations with immunogenicity were with the genes HLA-DQB1 (P=1.4x10-6), -DRB1 (P= 2.7x10-5), -DQA1 (P=0.00017) and -B (P=0.0009). Conditional analyses indicated that HLA-DQB1 represents the primary association(Table 1). Haplotype analyses showed that there was significantly increased risk of immnogenicity in patients carrying the HLA-DQ2 haplotypes DQB1*02:01~DQA1*05:01 (P=1.1x10-6) and DQB1*02:02~DQA1*02:01 (P=0.008), while one protective haplotype DQB1*05:01~DQA1*01:01 (P=0.0005) was identified (Figure 1a-c). Presence of HLA-DQ2 more than doubled the risk of anti-drug antibody formation (HR 2.54, 95%CI 1.82–3.56) (Figure 1d), in a model including the covariates age, sex, diagnosis, and concomitant immunosuppressive therapy. Association tests of each level of HLA analyses showed that HLA-DQ2 represents the strongest association(Figure 2). Epitope predictions revealed that the HLA-DQ2 haplotypes DQB1*02:01-DQA1*05:01 and DQB1*02:02-DQA1*02:01 share nine strong binder peptides, originating from the infliximab light chain, encompassing the amino acid core-peptide sequences INTVESEDI and VYACEVTHQ. Conclusion Using high-resolution HLA sequencing, we here demonstrate a genetic association between HLA-DQ2 and infliximab immunogenicity in IMID patients. The presence of either HLA-DQ2 risk haplotypes more than doubled the risk of anti-drug antibody formation across all diagnoses. Testing for HLA-DQ2 could be of clinical value in identifying patients at risk for immunogenicity and facilitate treatment decisions. Whether these findings apply to other TNF inhibitors should be further explored.

BackgroundImmunogenicity is a leading cause of treatment failure to TNF inhibitors, and also affects drug safety. Variations in HLA class II genes have been suggested to predispose to anti-drug antibody formation (ADA), but characterisation of biologically relevant HLA haplotypes, based on high-resolution genotyping, is lacking.ObjectivesTo assess associations between HLA loci and formation of ADA to infliximab across different immune mediated inflammatory diseases.MethodsPatients with immune mediated inflammatory diseases on infliximab therapy (N=612; 181 spondyloarthritis, 120 rheumatoid arthritis, 72 psoriatic arthritis, 114 ulcerative colitis, 80 Crohn’s disease and 45 psoriasis) participating in the Norwegian Drug Monitoring (NOR-DRUM) trials (1, 2) were included in the present analyses. Neutralising ADA were assessed with an automated fluorescence assay at each infusion. Next generation sequencing-based HLA typing was performed. Associations with ADA formation were assessed at locus, allele, haplotype and amino acid level. Peptide binding predictions for infliximab were performed.ResultsADA were detected in 147 patients (24%). Significant associations were shown between ADA and several HLA loci, whereas conditional analyses indicated HLA-DQB1 (p=1.4x10-6) as the primary risk locus. Highest risk of ADA formation was seen for patients carrying at least one of the HLA-DQ2 haplotypes; DQB1*02:01~DQA1*05:01 and DQB1*02:02~DQA1*02:01 (OR 3.18, 95% CI 2.15 to 4.69, p=5.9x10-9) (Figure 1). These findings were consistent across diagnoses (Table 1), and remained significant when adjusting for other possible predictors of ADA. Computational predictions indicated that both these HLA-DQ2 haplotypes could strongly bind two peptide motifs (INTVESEDI and VYACEVTHQ) in the infliximab heavy and light chain.Table 1.HLA-DQ2 carrier frequencies according to the different disease phenotypes and for all diagnosis combinedDiagnosisHLA-DQ2 carrier-frequency among patients with ADA formationHLA-DQ2 carrier-frequency among patients without ADA formationP-valueRA (N=120)0.3160.1340.02PsA (N=72)0.550.2310.01SpA (N=181)0.3640.1820.02UC (N=114)0.5560.2640.006CD (N=80)0.4290.3030.33Ps (N=45)0.8670.2670.0004All disease phenotypes0.4690.2175.9x10-9ConclusionThe risk of ADA to infliximab was three-fold higher in patients carrying the HLA-DQ2 risk haplotypes across diseases. A biological role for the HLA-DQ2 molecules encoded by the two different HLA-DQ2 risk haplotypes in the formation of ADA was further supported by peptide binding predictions. These novel findings provide promise for future incorporation of HLA-DQ2 testing to facilitate personalised treatment decisions.References[1]Syversen SW et al. Jama. 2021;326(23):2375-84.[2]Syversen SW et al. Jama. 2021;325(17):1744-54.Disclosure of InterestsMarthe Kirkesæther Brun: None declared, Kristin Hammersbøen Bjørlykke: None declared, Marte K. Viken: None declared, Bitte Stenvik Employee of: is a former employee of UCB Pharma, Rolf A. Klaasen: None declared, Johanna Gehin: None declared, David J Warren: None declared, Joe Sexton: None declared, Øystein Sandanger: None declared, Cato Mørk Speakers bureau: Novartis Norway, LEO Pharma, ACO Hud Norge, Cellgene, Abbvie, and Galderma Nordic AB., Consultant of: Novartis Norway, LEO Pharma, ACO Hud Norge, Cellgene, Abbvie, and Galderma Nordic AB., Tore K. Kvien Speakers bureau: Amgen, Celltrion, Evapharma, Gilead, Hikma, Mylan, Oktal, Pfizer, Sandoz, Sanofi, UCB, Consultant of: Amgen, Celltrion, Evapharma, Gilead, Hikma, Mylan, Oktal, Pfizer, Sandoz, Sanofi, UCB, Grant/research support from: AbbVie, Amgen, BMS, Novartis, Pfizer, UCB, Espen A Haavardsholm Speakers bureau: Pfizer, AbbVie, Celgene, Novartis, Janssen, Gilead, Eli-Lilly, and UCB, Consultant of: Pfizer, AbbVie, Celgene, Novartis, Janssen, Gilead, Eli-Lilly, and UCB, Jørgen Jahnsen Speakers bureau: AbbVie, Boerhinger Ingelheim, BMS, Celltrion, Giliad, Hikma, Janssen Cilag, Novartis, Orion Pharma, Pfizer, Roche, Takeda, and Sandoz, Consultant of: AbbVie, Boerhinger Ingelheim, BMS, Celltrion, Giliad, Hikma, Janssen Cilag, Novartis, Orion Pharma, Pfizer, Roche, Takeda, and Sandoz, Guro Løvik Goll Speakers bureau: Pfizer, AbbVie, Boehringer Ingelheim, Roche, Orion pharma, Sandoz, Novartis, and UCB, Consultant of: Pfizer, AbbVie, Boehringer Ingelheim, Roche, Orion pharma, Sandoz, Novartis, and UCB, Benedicte A. Lie: None declared, Kristin Kaasen Jørgensen Speakers bureau: Roche, BMS, Celltrion, and Norgine., Consultant of: Roche, BMS, Celltrion, and Norgine., Nils Bolstad Speakers bureau: Roche Pharmaceuticals and Novartis, Consultant of: Janssen, Silje Watterdal Syversen: None declared

Background Over five million joint replacements are performed across the world each year. Cobalt chrome (CoCr) components are used in most of these procedures. Some patients develop delayed-type hypersensitivity (DTH) responses to CoCr implants, resulting in tissue damage and revision surgery. DTH is unpredictable and genetic links have yet to be definitively established. Methods At a single site, we carried out an initial investigation to identify HLA alleles associated with development of DTH following metal-on-metal hip arthroplasty. We then recruited patients from other centres to train and validate an algorithm incorporating patient age, gender, HLA genotype, and blood metal concentrations to predict the development of DTH. Accuracy of the modelling was assessed using performance metrics including time-dependent receiver operator curves. Results Using next-generation sequencing, here we determine the HLA genotypes of 606 patients. 176 of these patients had experienced failure of their prostheses; the remaining 430 remain asymptomatic at a mean follow up of twelve years. We demonstrate that the development of DTH is associated with patient age, gender, the magnitude of metal exposure, and the presence of certain HLA class II alleles. We show that the predictive algorithm developed from this investigation performs to an accuracy suitable for clinical use, with weighted mean survival probability errors of 1.8% and 3.1% for pre-operative and post-operative models respectively. Conclusions The development of DTH following joint replacement appears to be determined by the interaction between implant wear and a patient’s genotype. The algorithm described in this paper may improve implant selection and help direct patient surveillance following surgery. Further consideration should be given towards understanding patient-specific responses to different biomaterials.