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Objective.We tested the discriminatory capacity of diffusion-weighted magnetic resonance imaging (DWI) and its potential as an objective measure of treatment response to tumor necrosis factor inhibition in ankylosing spondylitis (AS).Methods.Three cohorts were studied prospectively: (1) 18 AS patients with Bath Ankylosing Spondylitis Disease Activity Index > 4, and erythrocyte sedimentation rate > 25 and/or C-reactive protein > 10 meeting the modified New York criteria for AS; (2) 20 cases of nonradiographic axial spondyloarthritis (nr-axSpA) as defined by the Assessment of Spondyloarthritis international Society (ASAS) criteria; and (3) 20 non-AS patients with chronic low back pain, aged between 18 and 45 years, who did not meet the imaging arm of the ASAS criteria for axSpA. Group 1 patients were studied prior to and following adalimumab treatment. Patients were assessed by DWI and conventional magnetic resonance imaging (MRI), and standard nonimaging measures.Results.At baseline, in contrast to standard nonimaging measures, DWI apparent diffusion coefficient (ADC) values showed good discriminatory performance [area under the curve (AUC) > 80% for Group 1 or 2 compared with Group 3]. DWI ADC values were significantly lower posttreatment (0.45 ± 0.433 before, 0.154 ± 0.23 after, p = 0.0017), but had modest discriminating capacity comparing pre– and posttreatment measures (AUC = 68%). This performance was similar to the manual Spondyloarthritis Research Consortium of Canada (SPARCC) scoring system.Conclusion.DWI is informative for diagnosis of AS and nr-axSpA, and has moderate utility in assessment of disease activity or treatment response, with performance similar to that of the SPARCC MRI score.

Background Gout progresses through three stages: hyperuricemia, deposition of monosodium urate (MSU) crystals, and innate immune system response to MSU crystals. Genome wide association studies (GWAS) have provided insight into the molecular control of progression to hyperuricemia. However, less is known about the progression from hyperuricemia to gout. Objectives To conduct a GWAS for gout (where an immune response to MSU crystals has occurred) using 5,835 cases - the largest GWAS of gout to date. Methods The GWAS comprised 3 data sets: NZ/Eurogout (2,365 clinically-ascertained cases; 1,485 controls), the Health Professionals Follow-Up (HPFS) and Nurses9 Health Studies (NHS) (1,038 cases, self-ascertained using ACR criteria; 1,095 controls), and UK Biobank (2,432 cases, ascertained by self-report of gout, hospital records, and/or use of urate-lowering therapy; 102,989 controls). The NZ/Eurogout samples were genotyped using the Illumina CoreExome v24 bead chip array (547,644 markers), the HPFS/NHS samples using the Illumina OmniExpress v12 bead chip array (730,525 markers), and the UK Biobank samples using an Affymetrix Axiom array (820,967 markers). UK Biobank genotypes had been imputed to ∼73.3M SNPs. Neither the NZ/Eurogout nor NHS/HPFS genotype sets were imputed. Markers common to all three data sets (279,939) were associated with gout (adjusted for sex, age) within each data set separately using PLINK 1.9. An inverse-variance weighted meta-analysis was done with meta v4.4 in R. Results There were seven loci with genome-wide significant (P Conclusions All seven loci have been previously associated with serum urate levels in GWAS. Our data emphasise the relative importance of genetic control of serum urate, compared to the genetic control of MSU crystal formation or the innate immune response, in determining gout. Disclosure of Interest None declared

Free to read Objective To use high-density genotyping to investigate the genetic associations of acute anterior uveitis (AAU) in patients with and those without ankylosing spondylitis (AS). Methods We genotyped samples from 1,711 patients with AAU (either primary or combined with AS), 2,339 AS patients without AAU, and 10,000 control subjects on an Illumina Immunochip Infinium microarray. We also used data for AS patients from previous genome-wide association studies to investigate the AS risk locus ANTXR2 for its putative effect in AAU. ANTXR2 expression in mouse eyes was investigated by real-time quantitative reverse transcription–polymerase chain reaction. Results A comparison between all patients with AAU and healthy control subjects showed strong association over HLA–B, corresponding to the HLA–B27 tag single-nucleotide polymorphism rs116488202. The association of 3 non–major histocompatibility complex loci, IL23R, the intergenic region 2p15, and ERAP1, reached genome-wide significance (P < 5 × 10−8). Five loci harboring the immune-related genes IL10–IL19, IL18R1–IL1R1, IL6R, the chromosome 1q32 locus harboring KIF21B, as well as the eye-related gene EYS, were also associated, reaching a suggestive level of significance (P < 5 × 10−6). Several previously confirmed AS associations demonstrated significant differences in effect size between AS patients with AAU and AS patients without AAU. ANTXR2 expression varied across eye compartments. Conclusion These findings of both novel AAU-specific associations and associations shared with AS demonstrate overlapping but also distinct genetic susceptibility loci for AAU and AS. The associations in IL10 and IL18R1 are shared with inflammatory bowel disease, suggesting common etiologic pathways.

Free to read on journal website (may need to create free account first) There have been marked improvements in treatment options but none have yet been shown to induce remission The past decade has seen major advances in the diagnosis and management of ankylosing spondylitis (AS) and in research into its pathogenesis. It remains the case that no current treatments have been shown to lead to disease remissions or to halt the progression of the bony ankylosis that causes the major morbidity associated with this condition. Nonetheless, improved diagnostic methods and management have led to major benefits for patients, with marked improvements in quality of life with reduced treatment-associated side effects.

UNLABELLED: Bisphosphonates can increase bone mineral density (BMD) in children with osteogenesis imperfecta (OI). In this study of adults with OI type I, risedronate increased BMD at lumbar spine (but not total hip) and decreased bone turnover. However, the fracture rate in these patients remained high. INTRODUCTION: Intravenous bisphosphonates given to children with OI can increase BMD and reduce fracture incidence. Oral and/or intravenous bisphosphonates may have similar effects in adults with OI. We completed an observational study of the effect of risedronate in adults with OI type I. METHODS: Thirty-two adults (mean age, 39 years) with OI type I were treated with risedronate (total dose, 35 mg weekly) for 24 months. Primary outcome measures were BMD changes at lumbar spine (LS) and total hip (TH). Secondary outcome measures were fracture incidence, bone pain, and change in bone turnover markers (serum procollagen type I aminopropeptide (P1NP) and bone ALP). A meta-analysis of published studies of oral bisphosphonates in adults and children with OI was performed. RESULTS: Twenty-seven participants (ten males and seventeen females) completed the study. BMD increased at LS by 3.9% (0.815 vs. 0.846 g/cm(2), p = 0.007; mean Z-score, -1.93 vs. -1.58, p = 0.002), with no significant change at TH. P1NP fell by 37% (p = 0.00041), with no significant change in bone ALP (p = 0.15). Bone pain did not change significantly (p = 0.6). Fracture incidence remained high, with 25 clinical fractures and 10 major fractures in fourteen participants (0.18 major fractures per person per year), with historical data of 0.12 fractures per person per year. The meta-analysis did not demonstrate a significant difference in fracture incidence in patients with OI treated with oral bisphosphonates. CONCLUSIONS: Risedronate in adults with OI type I results in modest but significant increases in BMD at LS, and decreased bone turnover. However, this may be insufficient to make a clinically significant difference to fracture incidence.

Ankylosing spondylitis (AS) is a common chronic immune-mediated arthropathy affecting primarily the spine and pelvis. The condition is strongly associated with HLA-B*27 as well as other human leukocyte antigen variants and at least 47 individual non-MHC-associated variants. However, substantial additional heritability remains as yet unexplained. To identify further genetic variants associated with the disease, we undertook an association study of AS in 5,040 patients and 21,133 healthy controls using the Illumina Exomechip microarray. A novel association achieving genome-wide significance was noted at CDKAL1. Suggestive associations were demonstrated with common variants in FAM118A, C7orf72 and FAM114A1 and with a low-frequency variant in PNPLA1. Two of the variants have been previously associated with inflammatory bowel disease (IBD; CDKAL1 and C7orf72). These findings further increase the evidence for the marked similarity of genetic risk factors for IBD and AS, consistent with the two diseases having similar aetiopathogenesis.

Objective Ankylosing spondylitis (AS) is a common inflammatory arthritis affecting primarily the axial skeleton. IL23R is genetically associated with AS. This study was undertaken to investigate and characterize the role of interleukin-23 (IL-23) signaling in AS pathogenesis. Methods The study population consisted of patients with active AS (n = 17), patients with psoriatic arthritis (n = 8), patients with rheumatoid arthritis, (n = 9), and healthy subjects (n = 20). IL-23 receptor (IL-23R) expression in T cells was determined in each subject group, and expression levels were compared. Results The proportion of IL-23R–expressing T cells in the periphery was 2-fold higher in AS patients than in healthy controls, specifically driven by a 3-fold increase in IL-23R–positive γ/δ T cells in AS patients. The proportions of CD4+ and CD8+ cells that were positive for IL-17 were unchanged. This increased IL-23R expression on γ/δ T cells was also associated with enhanced IL-17 secretion, with no observable IL-17 production from IL-23R–negative γ/δ T cells in AS patients. Furthermore, γ/δ T cells from AS patients were heavily skewed toward IL-17 production in response to stimulation with IL-23 and/or anti-CD3/CD28. Conclusion Recently, mouse models have shown IL-17–secreting γ/δ T cells to be pathogenic in infection and autoimmunity. Our data provide the first description of a potentially pathogenic role of these cells in a human autoimmune disease. Since IL-23 is a maturation and growth factor for IL-17–producing cells, increased IL-23R expression may regulate the function of this putative pathogenic γ/δ T cell population.

Summary Background Sacroiliitis is a recognized complication of Crohn’s disease and may occur distinct from progressive ankylosing spondylitis (AS). Aim To estimate prospectively the prevalence of sacroiliitis in patients with established Crohn’s disease, to characterize the clinical features and to correlate these with the presence of HLA-B27. Methods All Crohn's disease patients under active follow-up of between 5 and 12 years duration were invited to participate. Patients underwent a clinical evaluation including symptom questionnaire, rheumatological examination and underwent HLA genotyping. Patients then underwent magnetic resonance imaging (MRI) of the sacroiliac joints. The clinical and radiological factors were correlated with HLA-B27 status. Results 56 patients underwent initial assessment and 44 had MRI scans. Seventeen of 44 (39%) patients had MRI evidence of sacroiliitis, of whom 5 fulfilled the criteria for AS. Symptoms of low back pain were elicited in a majority of these patients – 11/17 (65%) compared to 3 of 27 (11%) patients with normal scans (P = 0.003). There were no differences in functional indices with the exception of patients with AS. HLA-B27 was present in seven patients, and all seven had MRI evidence of sacroiliitis, five had AS. Conclusions Sacroiliitis is common in patients with established Crohn’s disease and in the majority of cases, patients have symptoms of inflammatory low back pain if questioned carefully. HLA-B27 is not associated with isolated sacroiliitis, but is associated with AS. However, possession of HLA-B27 appears to convey a very high risk of developing axial inflammation in Crohn’s disease.

The association of endoplasmic reticulum aminopeptidase 2 (ERAP2) with ankylosing spondylitis (AS) was recently described in the large International Genetics of AS Consortium Immunochip study. Variants in ERAP2 have also been associated with inflammatory bowel disease, psoriasis, acute anterior uveitis and birdshot chorioretinopathy. Subsequent investigation demonstrated an association of ERAP2 with AS which was present when one conditioned on one of the two independent haplotypes of ERAP1 associated with AS or when HLA-B27-negative patients were analysed separately. These two analyses provide analogous evidence for the association of ERAP2 with AS in HLA-B27-negative cases because of the genetic interaction between HLA-B27 and the AS-associated ERAP1 variants in AS cases. ERAP1 and ERAP2 are located on chromosome 5q15 in the opposite orientation. The locus is challenging to analyse because of the strong linkage disequilibrium (LD) across the locus and the epistasis between ERAP1 and HLA-B alleles associated with AS. We therefore sought to investigate the association of ERAP2 with AS in HLA-B27-positive patients. This is of clinical importance because functional studies have demonstrated that the strongly AS-protective variant rs2248374 causes a functional ERAP2 protein knockout, because its G allele causes a loss of ERAP2 protein expression. There is also a variant of ERAP2 which changes its enzyme catalytic activity and specificity (rs2549782, K392A). Because this is in almost complete LD with rs2248374 (1000 Genomes D′=1.00, r2=0.90), it is almost never translated in vivo. Further, the very strong LD between these markers means that analysis of rs2549782 for association would yield results almost identical to the results for rs2248374 presented below. Therefore, it is of relevance to determine whether the association of ERAP2 with HLA-B27-negative disease is also found in HLA-B27-positive cases, since ERAP inhibition may offer a novel therapeutic for AS...

Following an information-giving workshop to senior nurses within the hospital by the Research Nurse Group, a research-practice gap was identified. To ascertain the extent of this, a survey with an explanatory letter was distributed to all qualified nurses within the Trust. Although initially the response rate was thought to be low, it compared favourably to other studies. Results showed that 45% of respondents did not feel confident to undertake a research project but more than 80% felt that research was a part of their clinical role and was relevant to nursing. Three-quarters of respondents also acknowledged that they had read a paper resulting in a change in their clinical practice. When asked about skills and resources, 29% did not know how to conduct a literature search and 39% were unable to critically appraise a paper. Furthermore, 62% did not know what resources were available when considering a research project of their own. It was concluded therefore, that the research-practice gap does exist and nurses need encouragement and support in the implementation of the research process. In view of these conclusions, an action plan was developed.

Osteogenesis imperfecta (OI) is an inherited disease of bone fragility, usually due to mutation in type 1 collagen. High dose IV bisphosphonates are widely used in children with severe OI. OI type 1 (_mild_ OI) results from decreased synthesis of type 1 collagen; patients also have increased bone turnover. Patients with OI type 1 are often prescribed oral bisphosphonates although to date there is no data regarding the effects in this patient group or the required dose. Patients with OI type 1 were recruited from the metabolic bone and skeletal dysplasia clinics of the Nuffield Orthopaedic Centre, Oxford, UK; from local bone physicians; and from self referral. Entry criteria included age over 18 years, a clinical history of OI type 1, no other conditions contributing to low BMD (assessed by history and biochemical tests), and active contraception in fertile women. Patients were prescribed risedronate (either 5mg daily or 35 mg weekly) for 24 months.BMDwas assessed at lumbar spine (LS) and total hip using Hologic Discovery DXA scanning at time 0 and 24 months. Bone turnover markers (serum P1NP and bonespecific ALP) were assessed at time 0, 6, 12 and 24 months. BMD results were analysed using the paired t test; bone marker results by repeat measurements ANOVA. To date, 18 patients have completed the study (8 men, 10 women, mean age 39 years with range 18 to 76 at entry). At baseline, mean BMDat LS was 0.820 g/cm2 (t score =2.23, z score = 2.02). At 24 months, BMD significantly improved to 0.850 g/cm2, an increase of 3.7% (P = 0.008) (mean t score = 1.94 with mean z score = 1.93). At total hip, mean BMD at baseline was 0.873 g/cm2 (t score = 0.77, z score = 0.56) with no significant change seen at 24 months (P = 0.81). Bone turnover markers showed a significant drop in P1NP (P1NP= 33.6 ng/mL at baseline; P1NP = 18.0 ng/mL at 24 months; P = 0.008; a fall of 47% of baseline value) which was evident by 6 months (P1NP = 23.2 ng/mL; P = 0.002 compared with baseline). There was no significant change in BAP (P = 0.1). This study demonstrates that patients with OI type 1 can respond to oral bisphosphonates at standard doses for idiopathic osteoporosis with significant gain in BMD and decrease in bone turnover, surrogate measures for improved bone strength in these fragile bones. This study was supported by an unrestricted educational grant from Procter and Gamble Ltd.

Objective. The ank/ank mouse develops a phenotype similar to ankylosing spondylitis (AS) in humans. ANKH, the human homolog of the mutated gene in the ank/ank mouse, has been implicated in familial autosomal-dominant chondrocalcinosis and autosomal-dominant craniometaphyseal dysplasia. This study was undertaken to investigate the role of ANKH in susceptibility to and clinical manifestations of AS. Methods. Sequence variants were identified by genomic sequencing of the 12 ANKH exons and their flanking splice sites in 48 AS patients; variants were then screened in 233 patients and 478 controls. Linkage to the ANKH locus was assessed in 185 affected-sibling-pair families. Results. Five single-nucleotide polymorphisms were identified within the coding region and flanking splice sites. No association between either susceptibility to AS or its clinical manifestations and these novel polymorphisms, or between disease susceptibility and 3 known promoter variants, was seen. No linkage between the ANKH locus and AS was observed. Multipoint exclusion mapping rejected the hypothesis of a locus of a magnitude lambdagreater than or equal to1.4 (logarithm of odds score 10% to the AS sibling recurrence risk ratio) within this area contributing to AS. Conclusion. These findings indicate that ANKH is not significantly involved in susceptibility to or clinical manifestations of AS.

Gnathodiaphyseal dysplasia (GDD) is a rare autosomal dominant condition characterized by bone fragility, irregular bone mineral density (BMD) and fibro-osseous lesions in the skull and jaw. Mutations in Anoctamin-5 (ANO5) have been identified in some cases. We aimed to identify the causative mutation in a family with features of GDD but no mutation in ANO5, using whole exome capture and massive parallel sequencing (WES). WES of two affected individuals (a mother and son) and the mother's unaffected parents identified a mutation in the C-propeptide cleavage site of COL1A1. Similar mutations have been reported in individuals with osteogenesis imperfecta (OI) and paradoxically increased BMD. C-propeptide cleavage site mutations in COL1A1 may not only cause 'high bone mass OI', but also the clinical features of GDD, specifically irregular sclerotic BMD and fibro-osseous lesions in the skull and jaw. GDD patients negative for ANO5 mutations should be assessed for mutations in type I collagen C-propeptide cleavage sites.

Objective. To assess the role of genes and the environment in determining the severity of ankylosing spondylitis. Methods. One hundred seventy-three families with >1 case of ankylosing spondylitis were recruited (120 affected sibling pairs, 26 affected parent-child pairs, 20 families with both first- and second-degree relatives affected, and 7 families with only second-degree relatives affected), comprising a total of 384 affected individuals. Disease severity was assessed by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and functional impairment was determined using the Bath Ankylosing Spondylitis Functional Index (BASFI). Disease duration and age at onset were also studied. Variance-components modeling was used to determine the genetic and environmental components contributing to familiality of the traits examined, and complex segregation analysis was performed to assess different disease models. Results. Both the disease activity and functional capacity as assessed by the BASDAI and the BASFI, respectively, were found to be highly familial (BASDAI familiality 0.51 [p = 10(-4)], BASFI familiality 0.68 [P = 3 x 10(-7)]). No significant shared environmental component was demonstrated to be associated with either the BASDAI or the BASFI. Including age at disease onset and duration of disease as covariates made no difference in the heritability assessments. A strong correlation was noted between the BASDAI and the BASFI (genetic correlation 0.9), suggesting the presence of shared determinants of these 2 measures. However, there was significant residual heritability for each measure independent of the other (BASFI residual heritability 0.48, BASDAI 0.36), perhaps indicating that not all genes influencing disease activity influence chronicity. No significant heritability of age at disease onset was found (heritability 0.18; P = 0.2). Segregation studies suggested the presence of a single major gene influencing the BASDAI and the BASFI. Conclusion. This study demonstrates a major genetic contribution to disease severity in ankylosing spondylitis. As with susceptibility to ankylosing spondylitis, shared environmental factors play little role in determining the disease severity.

Background Ankylosing spondylitis is a common chronic immune-mediated arthropathy affecting primarily joints of the spine and pelvis. The condition is strongly associated with HLA-B27, and association with other HLA variants has been demonstrated. In addition to these effects, to date 30 non-MHC loci have been associated with the disease, and significant additional heritability remains. Objectives To identify further genetic variants associated with ankylosing spondylitis. Methods We undertook a study of ankylosing spondylitis using 5,040 patients and 21,133 healthy controls using the Illumina Exomechip microarray. This assays all coding variation in the genome along with genomewide association hits and major histocompatibility tag single nucleotide polymorphisms. Analysis was carried out with logistic regression using principal component analysis to correct for any population stratification. Results Novel associations achieving genomewide significance were found in USP8 ( P =3.5 x 10 -52 , OR =1.97) and CDKAL1 ( P =1.8 x10 -8 , OR =1.18). Suggestive associations with common variants in FAM118A ( P =5.9 x 10 -8 , OR =1.16), C7orf72 ( P =1.9 x 10 -7 , OR =1.14) and FAM114A1 ( P =1.4 x 10 -6 , OR =1.14) were also found. A low frequency association (MAF cases/controls: 0.0044/0.0017) was found in patatin-like phospholipase domain containing 1 ( PNPLA1) at a suggestive level of significance ( P =1.5 x 10 -6 , OR =2.6). Conclusions This study describes novel genetic associations with ankylosing spondylitis. Three of the variants have been previously associated with inflammatory bowel disease, and one variant with low hip bone mineral density. These findings further increase the evidence for the marked similarity of genetic risk factors for IBD and AS, consistent with the two diseases having very similar aetiopathogenesis. Disclosure of Interest None declared

OBJECTIVE: To identify genomic regions linked with determinants of age at symptom onset, disease activity, and functional impairment in ankylosing spondylitis (AS). METHODS: A whole genome linkage scan was performed in 188 affected sibling pair families with 454 affected individuals. Traits assessed were age at symptom onset, disease activity assessed by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and functional impairment assessed by the Bath Ankylosing Spondylitis Functional Index (BASFI). Parametric and nonparametric quantitative linkage analysis was performed using parameters defined in a previous segregation study. RESULTS: Heritabilities of the traits studied in this data set were as follows: BASDAI 0.49 (P = 0.0001, 95% confidence interval [95% CI] 0.23-0.75), BASFI 0.76 (P = 10(-7), 95% CI 0.49-1.0), and age at symptom onset 0.33 (P = 0.005, 95% CI 0.04-0.62). No linkage was observed between the major histocompatibility complex (MHC) and any of the traits studied (logarithm of odds [LOD] score

OBJECTIVE: To investigate the role of the gene NOD2 in susceptibility to, and clinical manifestations of, ankylosing spondylitis (AS). METHODS: A case-control study of NOD2 polymorphisms known to be associated with Crohn's disease (CD) (Pro(268)Ser, Arg(702)Trp, Gly(908)Arg, and Leu(1007)fsinsC) was performed in 229 cases of primary AS with no diagnosed inflammatory bowel disease (IBD), 197 cases of AS associated with IBD (referred to as colitic spondylarthritis; comprising 78 with CD and 119 with ulcerative colitis [UC]), and 229 ethnically matched, healthy controls. Associations between NOD2 polymorphisms and several clinical features of AS, including disease severity assessed by questionnaire and age at spondylarthritis onset, were also investigated. Exclusion linkage mapping of chromosome 16 was performed in a separate group of 185 multicase families with AS. RESULTS: An association was identified between Gly(908)Arg and UC spondylarthritis (P = 0.016, odds ratio [OR] 4.6, 95% confidence interval [95% CI] 1.3-16), and a nonsignificant trend with a similar magnitude was observed in association with CD spondylarthritis (P = 0.08, OR 3.9, 95% CI 0.8-18). The Pro(268)Ser variant was inversely associated with UC spondylarthritis (P = 0.003, OR 0.55, 95% CI 0.37-0.82), but not with CD spondylarthritis. No association was demonstrated between NOD2 variants and primary AS, or between other variants of NOD2 and either UC or CD spondylarthritis. Carriage of the Pro(268)Ser polymorphism was associated with greater disease activity as measured by the Bath Ankylosing Spondylitis Disease Activity Index (P = 0.002). Although patients with CD had a younger age at spondylarthritis onset than did those with UC (22.4 years versus 26.4 years; P = 0.01), no association was noted between the NOD2 variants linked with CD and age at spondylarthritis onset. In primary AS, the presence of a gene with a magnitude of association >2.0 was excluded (exclusion logarithm of odds score less than -2.0), and no association was observed with the microsatellite D16S3136. CONCLUSION: NOD2 variants do not significantly affect the risk of developing primary AS, but may influence susceptibility to, and clinical manifestations of, colitic spondylarthritis.

Background Gout results from innate immune response to monosodium urate (MSU) crystals that form when serum urate is elevated. Identification of genetic risk factors for hyperuricemia and the MSU immune response is therefore important for insight into the etiology of gout. Whilst genome-wide association studies have provided significant insights into the causes of hyperuricemia there are no confirmed loci for non-serum urate pathways in gout. Recently association of the rs2149356 variant in the TLR4 locus with gout was reported in a Chinese sample set (odds ratio TT genotype =1.88, P =8x10–5)1. TLR4 triggers innate immune response to endogenous ligands, including MSU crystals2. Objectives To test rs2149356 for association in European and New Zealand (NZ) Polynesian gout case-control sample sets. Methods All gout cases were clinically ascertained according to the American Rheumatism Association criteria. European cases (n=1606) were recruited from New Zealand (n=599), by the Eurogout consortium within the European Crystal Network (n=784) and by the Arthritis Genomics Recruitment Initiative in Australasia (AGRIA; n=223). European non-gouty controls (n=8066) were recruited from NZ (n=875) and sourced from the Atherosclerosis Risk in Communities (n=4144) and Framingham Heart (n=3047) studies. There were 872 New Zealand Maori and Pacific Island (Polynesian) cases and 1088 controls. Genotyping was done by Taqman and statistical analysis by STATA. Results Using unstratified controls the T allele, but not the TT genotype, was associated with gout in Europeans (ORTallele=1.09, P =0.05; ORTTgenotype=1.15, P =0.13). There was no evidence for association in Polynesians (ORTallele=0.90, P =0.12; ORTTgenotype=0.88, P =0.31). However, comparison of cases to hyperuricemic controls strengthened evidence for association with gout in Europeans (ORTallele=1.18, P =0.004; ORTTgenotype=1.38, P =0.017), but made no difference in Polynesians (ORTallele=, P =0.30; ORTTgenotype=0.87, P =0.47). ![Figure][1] Conclusions The previous report of association of TLR4 with gout in Chinese was replicated in Europeans but not Polynesians. Strengthening of association using hyperuricemic controls is consistent with a role for this locus in gouty inflammation in the presence of hyperuricemia. Subject to further replication, TLR4 represents the first non-serum urate genetic risk locus identified in gout, and provides support for a role of TLR4 in etiology. References 1. Qing et al. PLoS One 2013;5:e64845. 2. Liu-Bryan et al. Arthritis Rheum 2005;52:2936 Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.4781 [1]: pending:yes

Objective To investigate the association of CD14 and Toll-like receptor (TLR4) with ankylosing spondylitis (AS). Methods A promoter variant in CD14 and 2 coding polymorphisms in TLR4 were investigated in UK and Finnish families with AS and in a UK case-control study. A metaanalysis of published TLR4 and CD14 studies was performed. Results In the Finnish study the CD14-260bp T variant showed an association (p = 0.006), and the common 2-marker TLR4 haplotype showed a weak association (global p = 0.03), with AS. No associations were seen in the UK based studies or in the metaanalyses. Conclusion CD14 and TLR4 showed an association with AS in the Finns only.