Early restoration of immune and vascular phenotypes in systemic lupus erythematosus and rheumatoid arthritis patients after B cell depletion.

This translational multi-centre study explored early changes in serologic variables following B lymphocyte depletion by rituximab (RTX) treatment in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients and investigated in vitro effects on the activity of other immune cells and the vascular endothelium. Eighty-five SLE patients, seventy-five RA patients and ninety healthy donors were enrolled. Two additional cohorts of selected SLE and RA patients were treated with RTX for 3 months. Changes in circulating levels of inflammatory mediators, oxidative stress markers and NETosis-derived bioproducts were evaluated. Serum miRNomes were identified by next-generation sequencing, and RTX-induced changes were delineated. Mechanistic in vitro studies were performed to assess activity profiles. Altered inflammatory, oxidative and NETosis-derived biomolecules were found in SLE and RA patients, closely interconnected and associated to specific miRNA profiles. RTX treatment reduced SLE and RA patients' disease activity, linked to a prominent alteration in those biomolecules and the reversal of altered regulating miRNAs. In vitro studies showed inhibition of NETosis and decline of pro-inflammatory profiles of leucocytes and human umbilical vein endothelial cells (HUVECs) after B cell depletion. This study provides evidence supporting an early RTX-induced re-setting of the pro-inflammatory status in SLE and RA, involving a re-establishment of the homeostatic equilibrium in immune system and the vascular wall.

Genetic variants within the TNFRSF1B gene and susceptibility to rheumatoid arthritis and response to anti-TNF drugs: a multicenter study.

BACKGROUND: Recent research suggests that genetic variants in the tumor necrosis factor receptor 2 (TNFRSF1B) gene may have an impact on susceptibility to rheumatoid arthritis (RA) and drug response. The present population-based case-control study was carried out to evaluate whether 5 tagging single-nucleotide polymorphisms (SNPs) within the TNFRSF1B gene are associated with the risk of RA and response to antitumor necrosis factor (TNF) drugs. METHODS: The study population included 1412 RA patients and 1225 healthy controls. A subset of 596 anti-TNF-naive RA patients was selected to assess the association of TNFRSF1B SNPs and drug response according to the EULAR response criteria. RESULTS: We found that carriers of the TNFRSF1Brs3397C allele had a significantly increased risk of developing RA (P=0.0006). Importantly, this association remained significant after correction for multiple testing. We also confirmed the lack of association of the TNFRSF1Brs1061622 SNP with the risk of RA in the single-SNP analysis (P=0.89), but also through well-powered meta-analyses (PDOM=0.67 and PREC=0.37, respectively). In addition, our study showed that carriers of the TNFRSF1Brs3397C/C, TNFRSF1Brs1061622G/G, and TNFRSF1Brs1061631A/A genotypes had an increased risk of having a worse response to anti-TNF drugs at the level of P less than 0.05 (P=0.014, 0.0085 and 0.028, respectively). We also observed that, according to a log-additive model, carriers of the TNFRSF1Brs3397C or TNFRSF1Brs1061622G alleles showed an increased risk of having worse response to anti-TNF medications (P=0.018 and 0.0059). However, the association of the TNFRSF1Brs1061622 SNP only reached marginal significance after correction for multiple testing according to a log-additive model (P=0.0059) and it was not confirmed through a meta-analysis (PDOM=0.12). CONCLUSION: Our results suggest that the TNFRSF1Brs3397 variant may play a role in modulating the risk of RA, but does not provide strong evidence of an impact of TNFRSF1B variants in determining response to anti-TNF drugs.

Genetic variants within immune-modulating genes influence the risk of developing rheumatoid arthritis and anti-TNF drug response: a two-stage case-control study.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disease that arises as a result of the interaction between genetic and environmental factors. A growing body of research suggests that genetic variants within immune-related genes can influence the risk of developing the disease and affect drug response. MATERIALS AND METHODS: To test this hypothesis, we carried out a comprehensive two-stage case-control study in a White population of 1239 White RA patients and 1229 healthy controls to investigate whether 49 single nucleotide polymorphisms within or near 17 immune-related genes modulate the risk of developing RA and antitumor necrosis factor (anti-TNF) drug response. RESULTS: Logistic regression analyses showed that carriers of the IL4rs2070874T and IL4rs2243250T and IL8RBrs1126580A alleles or the IL8RBrs2230054C/C genotype had a significantly increased risk of developing RA [odds ratio (OR)=1.37, 95% confidence interval (CI) 1.13-1.67, P=0.0016; OR=1.24, 95% CI 1.03-1.49, P=0.020; OR=1.23, 95% CI 1.08-1.41, P=0.002 and OR=1.19, 95% CI 1.04-1.36, P=0.01, respectively]. The association of the IL4 variants was further supported by a meta-analysis including 7150 individuals (P =0.0010), whereas the involvement of the IL8RB locus in determining the susceptibility to RA was also supported by gene-gene interaction analyses that identified significant two-locus and three-locus interaction models including IL8RB variants that act synergistically to increase the risk of the disease (P=0.014 and 0.018). Interestingly, we also found that patients harbouring the IFNGrs2069705C allele showed a significantly better response to anti-TNF drugs than those patients carrying the wild-type allele (P=0.0075). CONCLUSIONS: Our data suggest that IL4 and IL8RB loci may have a small-effect genetic impact on the risk of developing RA, whereas IFNG might be involved in modulating the response to anti-TNF drugs.

Outcome of an education and home-based exercise programme for patients with ankylosing spondylitis: a nationwide randomized study.

OBJECTIVES: This study aims to assess the impact of a structured education and home exercise programme in daily practice patients with ankylosing spondylitis. METHODS: A total of 756 patients with ankylosing spondylitis (72% males, mean age 45 years) participated in a 6-month prospective multicentre controlled study, 381 of whom were randomised to an education intervention (a 2-hour informative session about the disease and the implementation of a non-supervised physical activity programme at home) and 375 to standard care (controls). Main outcome measures included Bath Ankylosing Spondylitis Disease Activity and Functional Index (BASDAI, BASFI). Secondary outcome measures were 0-10 cm visual analog scale (VAS) for total pain, nocturnal pain and global disease activity and quality of life (ASQoL), knowledge of disease (self-evaluation ordinal scale) and daily exercise (diary card). RESULTS: At 6 months, the adjusted mean difference between control and educational groups for BASDAI was 0.32, 95% confidence interval (CI) 0.10-0.54, p=0.005, and for BASFI 0.31, 95%CI 0.12-0.51, p=0.002. Significant differences were found also in VAS for total pain, patient´s global assessment and in ASQoL. Patients in the education group increased their knowledge about the disease and its treatments significantly (p<0.001) and practised more regular exercise than controls (p<0.001). CONCLUSIONS: A structured education and home exercise programme for patients with ankylosing spondylitis in daily practice was feasible and helped to increase knowledge and exercise. Although statistically significant, the magnitudes of the clinical benefits in terms of disease activity and physical function were poor.

Resources and strategies for the optimal care of patients with axial spondyloarthritis: The CREA project.

BACKGROUND AND OBJECTIVE: Axial spondyloarthritis (axSpA) are musculoskeletal diseases with different manifestations. In clinical practice, variability, and limitations in the collection of the outcomes required for follow-up have been observed. The objective of the CREA project was to agree on improvement strategies for the initial assessment and follow-up of patients with axSpA in Spain. MATERIALS AND METHODS: A survey with 33 questions was conducted by a representative sample of rheumatologists on clinical practice, resources, and present limitations in the follow-up of patients with axSpA. The results of the survey were discussed in 10 regional meetings, and 105 strategies were proposed and evaluated through a Delphi consensus in which 85 experts participated. RESULTS: The lack of time for clinical visits, the lack of nurses and/or support staff and the delay in performing the imaging tests were the most prominent limitations in the follow-up of patients with axSpA. One hundred and five strategies were proposed related to the evaluation of disease activity, physical function, quality of life and disease impact, to the evaluation of comorbidities and extra-articular manifestations, laboratory tests; imaging tests, physical examination and metrology. Of the total, 85 were considered highly advisable. No regional differences were found. CONCLUSIONS: The proposals agreed upon as highly advisable in the present study are applicable to the entire national territory, allow tighter and more homogeneous monitoring of the patients with axSpA, facilitate more comprehensive management of the disease, and respond to the unmet needs detected in the initial survey.

Strategies and resources to optimise the management of Psoriatic Arthritis patients: The CREA Project.

BACKGROUND AND AIM: Psoriatic arthritis (PsA) is a chronic immune-mediated inflammatory disease that affects the musculoskeletal system and skin, and manifests heterogeneously, with a variable course. In current clinical practice, variability and limitations in its follow-up have been observed. The aim of the CREA project was to agree on strategies to improve the initial assessment and follow-up of patients with PsA in Spain. MATERIALS AND METHODS: A survey was conducted among a representative sample of expert rheumatologists in Spain, containing 33 questions on current clinical practice, available resources, and current limitations in the follow-up of patients with PsA. The results were discussed in regional meetings and 105 strategies were proposed and finally evaluated by 85 experts in a Delphi consensus. RESULTS: The most important limitations in the follow-up of PsA were lack of consultation time, lack of nursing staff, and delays in performing imaging tests. A total of 108 strategies were proposed related to the assessment of quality of life and disease-impact indices; comorbidities and extra-articular manifestations; laboratory tests; imaging tests; physical examination and metrology; and activity and function indices. Of the total, 53 were considered highly advisable, with no regional differences in consensus values. DISCUSSION AND CONCLUSIONS: The proposals offered in the current study are applicable to the entire country, respond to the unmet needs detected in the initial survey, form a minimum action framework, and ensure optimal follow-up of patients with PsA.

A high density SNP genotyping approach within the 19q13 chromosome region identifies an association of a CNOT3 polymorphism with ankylosing spondylitis.

OBJECTIVE: To identify genomic variants in the 19q13 chromosome region associated with ankylosing spondylitis (AS) in human leucocyte antigen (HLA)-B27-positive populations. METHODS: High-throughput genotyping of 1536 haplotype-tag single nucleotide polymorphisms (SNPs) was performed in 249 patients with AS and 302 healthy controls. Some of the identified associations were validated by genotyping four SNPs in two additional cohorts consisting of 412 cases/301 controls and 144 cases/203 controls. All individuals selected (both cases and controls) were HLA-B27-positive. RESULTS: Two markers in two different genes (CNOT3 and LAIR2) showed significant association (p<10(-3)) with AS. In addition, sliding windows analysis showed association of groups of adjacent SNPs in regions located around CNOT3 (Chr19: 59347459-59356564, p=2.43 × 10(-4) to 6.54 × 10(-4)). The associations were validated by genotyping four SNPs from regions located near LAIR2 and CNOT3 genes (rs1055234, rs8111398, rs2287828 and rs4591276) in two additional cohorts. The CNOT3 polymorphism (rs1055234) remained associated with AS (combined p=9.73 × 10(-6)). One SNP, located downstream of KIR3DL1, was detected which, tested in combination with HLA-Bw4I80, was associated with AS. CONCLUSION: A novel significant association was detected between SNP rs1055234 and AS susceptibility.

Genetic polymorphisms inside and outside the MHC improve prediction of AS radiographic severity in addition to clinical variables.

OBJECTIVE: The aim of this study was to analyse if single nucleotide polymorphisms (SNPs) inside and outside the MHC region might improve the prediction of radiographic severity in AS. METHODS: A cross-sectional multi-centre study was performed including 473 Spanish AS patients previously diagnosed with AS following the Modified New York Criteria and with at least 10 years of follow-up from the first symptoms of AS. Clinical variables and 384 SNPs were analysed to predict radiographic severity [BASRI-total (BASRI-t) corrected for the duration of AS since first symptoms] using multivariate forward logistic regression. Predictive power was measured by the area under the receiver operating characteristic curve (AUC), specificity, sensitivity, positive predictive value (PPV) and negative predictive value (NPV). RESULTS: The model with the best fit measured radiographic severity as the BASRI-t 60th percentile and combined eight variables: male gender, older age at disease onset and six SNPs at ADRB1 (rs1801253), NELL1 (rs8176785) and MHC (rs1634747, rs9270986, rs7451962 and rs241453) genes. The model predictive power was defined by AUC = 0.76 (95% CI 0.71, 0.80), being significantly better than the model with only clinical variables, AUC = 0.68 (95% CI 0.63, 0.73), P = 0.0004. Internal split-sample analysis proved the validation of the model. Patient genotype for SNPs outside the MHC region, inside the MHC region and clinical variables account for 26, 38 and 36%, respectively, of the explained variability on radiographic severity prediction. CONCLUSION: Prediction of radiographic severity in AS based on clinical variables can be significantly improved by including SNPs both inside and outside the MHC region.

Fine mapping of a major histocompatibility complex in ankylosing spondylitis: association of the HLA-DPA1 and HLA-DPB1 regions.

OBJECTIVE: To investigate the potential association of major histocompatibility complex (MHC) markers other than HLA-B27 with ankylosing spondylitis (AS). METHODS: A total of 603 patients with AS and 542 healthy control subjects, all of whom were HLA-B27 positive, were selected for this study based on clinical criteria. First, high-density genotyping across the MHC region (2,360 single-nucleotide polymorphisms [SNPs]) was performed in a cohort of 191 patients and 241 control subjects. After a fine-mapping study, 5 SNPs from the HLA-DPA1/DPB1 region were validated in a second cohort of 412 patients with AS and 301 healthy control subjects. RESULTS: Seventeen SNPs located within or near the HLA-DPA1 and HLA-DPB1 loci showed association with AS (P = 1.38 × 10⁻5 to 0.05). In addition, multimarker tests, both linkage disequilibrium and sliding windows, showed association of some groups of adjacent SNPs within the HLA-DPA1/DPB1 region with AS (P = 1.0 × 10⁻4 to 3.96 × 10⁻7). We validated the association by genotyping 5 SNPs from the DPA1/DPB1 region in an additional cohort and obtained P values from 6.42 × 10⁻5 to 0.01 in the analysis of the combined cohorts. Subtyping analysis of HLA-DPA1 and HLA-DPB1 showed that HLA-DPA1*01:03, A1*02:01, and B1*13:01 were the subtypes most susceptible to AS. CONCLUSION: HLA markers and linkage disequilibrium blocks near HLA-DPA1 and HLA-DPB1 are statistically associated with AS. We identified a region located around the HLA-DPA1 and HLA-DPB1 loci associated with AS, another region within the MHC that is different from HLA-B27.

Characterising the axial phenotype of psoriatic arthritis: a study comparing axial psoriatic arthritis and ankylosing spondylitis with psoriasis from the REGISPONSER registry.

AIMS: To explore the clinical and radiographical characteristics of axial psoriatic arthritis (PsA) and to compare it with ankylosing spondylitis (AS) with psoriasis. METHODS: Cross-sectional study from the national multicentre registry REGISPONSER where participants fulfilled the European Spondyloarthropathy Study Group spondyloarthritis criteria at entry. Clinical, laboratory and radiographical characteristics between patients classified as axial PsA and AS with psoriasis by their rheumatologist are compared according to HLA-B27 status. RESULTS: Of 2367 patients on REGISPONSER, n=405 had PsA, of whom 27% (n=109) had axial involvement as per the treating rheumatologist. 30% (n=26/86) of axial PsA were HLA-B27 positive. In the AS group, 9% (127/1422) had a history of psoriasis and were more frequently male, with longer diagnostic delay and more anterior uveitis than those with axial PsA who had more peripheral involvement and nail disease. Patients with HLA-B27-negative axial PsA reported less inflammatory pain and structural damage compared with AS with psoriasis. By contrast, HLA-B27-positive axial PsA shared clinical characteristics similar to AS and psoriasis although with a lower BASRI score. In the multivariable analysis, patients with AS and psoriasis were independently associated with HLA-B27 positivity (OR 3.34, 95% CI 1.42 to 7.85) and lumbar structural damage scored by BASRI (OR 2.14, 95% CI 1.4 to 3.19). CONCLUSION: The more prevalent axial PsA phenotype is predominantly HLA-B27 negative and presents different clinical and radiological manifestations when compared with AS with psoriasis. There is great heterogeneity in what rheumatologists consider axial PsA from a clinical and imaging perspective, highlighting the need for research into possible genetic drivers and a consensus definition.

Predicting the outcome of ankylosing spondylitis therapy.

OBJECTIVES: To create a model that provides a potential basis for candidate selection for anti-tumour necrosis factor (TNF) treatment by predicting future outcomes relative to the current disease profile of individual patients with ankylosing spondylitis (AS). METHODS: ASSERT and GO-RAISE trial data (n=635) were analysed to identify baseline predictors for various disease-state and disease-activity outcome instruments in AS. Univariate, multivariate, receiver operator characteristic and correlation analyses were performed to select final predictors. Their associations with outcomes were explored. Matrix and algorithm-based prediction models were created using logistic and linear regression, and their accuracies were compared. Numbers needed to treat were calculated to compare the effect size of anti-TNF therapy between the AS matrix subpopulations. Data from registry populations were applied to study how a daily practice AS population is distributed over the prediction model. RESULTS: Age, Bath ankylosing spondylitis functional index (BASFI) score, enthesitis, therapy, C-reactive protein (CRP) and HLA-B27 genotype were identified as predictors. Their associations with each outcome instrument varied. However, the combination of these factors enabled adequate prediction of each outcome studied. The matrix model predicted outcomes as well as algorithm-based models and enabled direct comparison of the effect size of anti-TNF treatment outcome in various subpopulations. The trial populations reflected the daily practice AS population. CONCLUSION: Age, BASFI, enthesitis, therapy, CRP and HLA-B27 were associated with outcomes in AS. Their combined use enables adequate prediction of outcome resulting from anti-TNF and conventional therapy in various AS subpopulations. This may help guide clinicians in making treatment decisions in daily practice.

A model for the development and implementation of a national plan for the optimal management of early spondyloarthritis: the Esperanza Program.

OBJECTIVES: To evaluate the performance of a healthcare programme in early spondyloarthritis (SpA). METHODS: Based on previous analyses and expectations of a nominal group, the following were set: (1) minimum standards to create early SpA units; (2) standard operating procedures; and (3) eight performance indicators that can be measured in real time using a web-based platform. RESULTS: At the end of the evaluation of the programme the expected level of performance was achieved in three of the indicators: 'referral reliability' (standard (S) >50%, real value (RV) 92%), 'accessibility' (S >90%, RV=91%) and 'duration of first visit' (S >50%, RV=53%). The performance in the remaining indicators was inferior: 'success of referral criteria' (S >50%, RV=28%), 'clinical reports issued' (S >90%, RV=25%), 'feedback guarantee' (S >85%, RV=2%), 'missing data' (S <10%, RV=24%) and 'frequency of review' (S >90%, RV=84%). Explanations for the low performance are provided. CONCLUSIONS: It is possible to implement a large-scale programme that is measurable.

ERAP1 polymorphisms and haplotypes are associated with ankylosing spondylitis susceptibility and functional severity in a Spanish population.

OBJECTIVES: The aim of this study was to assess the involvement of the endoplasmic reticulum aminopeptidase 1 (ERAP1) gene in AS susceptibility and functional severity in a Spanish population. METHODS: Eight single nucleotide polymorphisms (SNPs) spanning the ERAP1 gene were genotyped by allele-specific fluorescent PCR in 300 AS Spanish patients and 300 spondylarthritis-free controls. The influence of the ERAP1 SNPs on the functional severity of AS was analysed with the BASFI corrected for disease duration. Association analyses with AS susceptibility and functional severity were performed. RESULTS: Significant ERAP1 single marker association with AS susceptibility was found for five SNPs, namely rs30187 (allele T: P = 0.035), rs17482078 (allele C: P = 0.030), rs2287987 (allele T: P = 0.028), rs26653 (allele C: P = 0.041) and rs10050860 (allele C: P = 0.018). Three of the associated SNPs (rs17482078, rs2287987 and rs10050860) were in strong linkage disequilibrium. After imputing genotypes with the HapMap CEU data as reference, the strongest association was with rs41135 (P = 0.0046) in the 5'-upstream region of ERAP1. In addition, the SNP rs17481856 was found to be a risk factor for functional severity in AS and a borderline trend was observed for rs27044. CONCLUSIONS: These results suggest that the ERAP1 gene is associated with genetic predisposition to AS and influences the functional severity of the disease in a Spanish population.

High-dose etanercept in ankylosing spondylitis: results of a 12-week randomized, double blind, controlled multicentre study (LOADET study).

OBJECTIVES: Etanercept 50 mg a week is approved in the treatment of AS. Increasing the etanercept dose to 100 mg/week improves efficacy in cutaneous psoriasis, a clinical manifestation related to the spondylarthritis family, while maintaining its safety profile. The purpose of this study was to evaluate the efficacy and safety of etanercept 100 vs 50 mg/week in patients with AS. METHODS: Adult patients with AS were randomized to receive etanercept 50 mg twice a week (biw), or etanercept 50 mg once a week (qw) for 12 weeks. The primary efficacy endpoint was Ankylosing Spondylitis Assessment Study (ASAS20) response at Week 12; secondary endpoints included ASAS40, ASAS50, ASAS70 and ASAS5/6 responses, partial remission and quality of life. Safety was assessed until 15 days after the last visit. RESULTS: A total of 108 patients were randomly selected and treated, 54 in each arm. At 12 weeks, ASAS20 response was achieved by 34 (71%) out of 48 patients of the etanercept 50 mg biw group and by 37 (76%) out of 49 patients of the etanercept 50 mg qw group (not statistically significant differences). Other efficacy variables improved significantly over time, but not between treatment groups. Fifty-six patients experienced at least one adverse event (generally, infections and infestations, gastrointestinal disorders and injection site reactions), most of them mild or moderate. CONCLUSIONS: High-dose (100 mg/week) etanercept in the treatment of AS for 12 weeks is as safe as the standard dose (50 mg/week). However, it does not significantly increase its efficacy. Trial Registration. Clinicaltrials.gov, http://clinicaltrials.gov/, NCT00873730.

Phenotypic differences between familial versus sporadic ankylosing spondylitis: a cross-sectional Spanish registry of spondyloarthropathies (REGISPONSER).

OBJECTIVES: To analyse potential differences in disease phenotype between patients with familial ankylosing spondylitis (AS) and sporadic AS. METHODS: A cross-sectional study was conducted on all patients with definite AS registered at the internet database REGISPONSER. Sociodemographic data, clinical features, spinal mobility measurements, the Bath AS disease activity index (BASDAI), functional index (BASFI) and radiology index (BASRI), laboratory data (ESR, CRP, HLA-B27), overall patient assessment of the disease (VAS), and treatments used were obtained. Familial AS was considered when the patient was confirmed to have first-degree relatives with spondyloarthropathy. The Chi-square test and Mann-Whitney U-test were used for the statistical analysis. RESULTS: A total of 1316 AS patients (990 males, 326 females; mean age 48.2 ± 12.6 years), with mean age at symptom onset 26.1 ± 8.5 years, were evaluated. The prevalence of familial AS was 20% (n=263). Familial and sporadic AS groups presented differences (p<0.05) in the following parameters: female (34.6% vs. 22%), mean age at symptom onset (25.0±9.2 years vs. 27.3 ± 10.0 years), disease duration (23 ± 13 years vs. 21 ± 12 years), uveitis (27.5% vs. 19.3%), presence of HLA-B27+ (93% vs. 83%), VAS for overall patient assessment (5.0 cm vs. 4.4 cm), BASDAI (4.4 cm vs. 4.0 cm) and response to NSAID (82% vs. 74%). CONCLUSIONS: Patients with familial AS were younger at symptom onset and had poorer VAS for overall patient assessment and BASDAI than the other group. There was a higher prevalence of females, uveitis, positive HLA-B27, hip prostheses and a better response to NSAID in the familial AS group.

Association of the KIR3DS1*013 and KIR3DL1*004 alleles with susceptibility to ankylosing spondylitis.

OBJECTIVE: The killer cell immunoglobulin-like receptors (KIRs) form a group of regulatory molecules that specifically recognize HLA class I molecules. The aim of this study was to analyze the possible contribution of the KIR3DL1 and KIR3DS1 alleles, in addition to HLA-B27, in the susceptibility to ankylosing spondylitis (AS) in a population of individuals from Spain. METHODS: We genotyped the KIR3DS1 and KIR3DL1 alleles in 2 cohorts of patients with AS and healthy control subjects. In total, 270 patients with AS and 435 healthy, HLA-B27-positive matched control subjects from Spain were enrolled. The KIR3DS1 and KIR3DL1 alleles were genotyped by sequence-specific oligonucleotide probe-polymerase chain reaction, and their association with AS was analyzed. All individuals were typed for HLA-B. RESULTS: The KIR3DS1*013 allele was solely responsible for the increased frequency of the activator receptor KIR3DS1 in patients with AS compared with healthy HLA-B27-positive control subjects (35.7% versus 22.6% [P = 10(-6)], odds ratio 1.90, 95% confidence interval 1.50-2.40). The increased frequency of the KIR3DS1*013 allele in patients with AS was independent of the presence or absence of the HLA-Bw4I80 epitope. Moreover, the null allele KIR3DL1*004 was a unique inhibitory KIR3DL1 allele that showed a negative association with AS in the presence of HLA-Bw4I80. CONCLUSION: The increased frequency of the KIR3DS1*013 allele in patients with AS is clearly independent of the presence of the HLA-Bw4I80 epitope, whereas the presence of inhibitory allotypes such as KIR3DL1*004 demonstrated a negative association in patients with AS in the presence of HLA-Bw4I80. As a consequence, the influence of KIR genotypes on AS susceptibility would be mediated by a general imbalance between protective/inhibitory and risk/activating allotypes.

Validation of GWAS-Identified Variants for Anti-TNF Drug Response in Rheumatoid Arthritis: A Meta-Analysis of Two Large Cohorts.

We aimed to validate the association of 28 GWAS-identified genetic variants for response to TNF inhibitors (TNFi) in a discovery cohort of 1361 rheumatoid arthritis (RA) patients monitored in routine care and ascertained through the REPAIR consortium and DANBIO registry. We genotyped selected markers and evaluated their association with response to TNFi after 6 months of treatment according to the change in disease activity score 28 (ΔDAS28). Next, we confirmed the most interesting results through meta-analysis of our data with those from the DREAM cohort that included 706 RA patients treated with TNFi. The meta-analysis of the discovery cohort and DREAM registry including 2067 RA patients revealed an overall association of the LINC02549rs7767069 SNP with a lower improvement in DAS28 that remained significant after correction for multiple testing (per-allele ORMeta=0.83, PMeta=0.000077; PHet=0.61). In addition, we found that each copy of the LRRC55rs717117G allele was significantly associated with lower improvement in DAS28 in rheumatoid factor (RF)-positive patients (per-allele ORMeta=0.67, P=0.00058; PHet=0.06) whereas an opposite but not significant effect was detected in RF-negative subjects (per-allele ORMeta=1.38, P=0.10; PHet=0.45; PInteraction=0.00028). Interestingly, although the identified associations did not survive multiple testing correction, the meta-analysis also showed overall and RF-specific associations for the MAFBrs6071980 and CNTN5rs1813443 SNPs with decreased changes in DAS28 (per-allele ORMeta_rs6071980 = 0.85, P=0.0059; PHet=0.63 and ORMeta_rs1813443_RF+=0.81, P=0.0059; PHet=0.69 and ORMeta_rs1813443_RF-=1.00, P=0.99; PHet=0.12; PInteraction=0.032). Mechanistically, we found that subjects carrying the LINC02549rs7767069T allele had significantly increased numbers of CD45RO+CD45RA+ T cells (P=0.000025) whereas carriers of the LINC02549rs7767069T/T genotype showed significantly increased levels of soluble scavengers CD5 and CD6 in serum (P=0.00037 and P=0.00041). In addition, carriers of the LRRC55rs717117G allele showed decreased production of IL6 after stimulation of PBMCs with B burgdorferi and E coli bacteria (P=0.00046 and P=0.00044), which suggested a reduced IL6-mediated anti-inflammatory effect of this marker to worsen the response to TNFi. In conclusion, this study confirmed the influence of the LINC02549 and LRRC55 loci to determine the response to TNFi in RA patients and suggested a weak effect of the MAFB and CNTN5 loci that need to be further investigated.

Hip involvement in ankylosing spondylitis: epidemiology and risk factors associated with hip replacement surgery.

OBJECTIVES: Although clinicians recognize hip involvement, which frequently leads to hip replacement surgery, as an important feature of AS, data on the epidemiology, nature of the disease and therapeutic strategies are scarce. We aimed to describe the epidemiology of clinical and radiological hip involvement and define the risk factors for the hip replacement surgery in AS patients. METHODS: Data from 3 datasets were merged, including 847 Belgian (ASPECT database), 1405 Spanish (REGISPONSER database) and 466 Ibero-American (RESPONDIA database) AS patients. The ASPECT and REGISPONSER database (Dataset A) are used for exploratory analysis; the RESPONDIA database (Dataset B) is used for confirmative analysis. Factors associated with hip involvement and the hip replacement surgery were analysed. RESULTS: Twenty four (REGISPONSER) to 36% (RESPONDIA) of AS patients under rheumatologist's care presented clinical hip involvement, including the 5% (Dataset A) of AS patients who needed hip replacement surgery. Patients with hip involvement had significantly worse overall Bath Ankylosing Spondylitis Functional Index (BASFI) scores compared with patients without hip involvement (mean difference = 1.6, P < 0.001) (Dataset A, confirmed in B). Corrected for disease duration, patients with early disease onset, enthesial and axial disease needed most frequently hip replacement surgery (Dataset A, confirmed in B). CONCLUSION: Hip involvement is commonly recognized by rheumatologists in AS patients, and involves about one out of the three to four patients with AS and is associated with impaired functioning reflected by higher overall BASFI scores. Early onset of disease, axial and enthesial disease are associated with the hip replacement surgery in AS.

Correction to: Influence of HLA-B27 on the Ankylosing Spondylitis phenotype: results from the REGISPONSER database.

An amendment to this paper has been published and can be accessed via the original article.