Search

Objective Genetic factors account for an estimated 4558% of the variance in joint destruction in rheumatoid arthritis (RA). The serine proteinase granzyme B induces target cell apoptosis, and several in vitro studies suggest that granzyme B is involved in apoptosis of chondrocytes. Serum levels of granzyme B are increased in RA and are also associated with radiographic erosions. The aim of this study was to investigate GZMB as a candidate gene accounting for the severity of joint destruction in RA. Methods A total of 1,418 patients with 4,885 radiograph sets of the hands and feet from 4 independent cohorts were studied. First, explorative analyses were performed in 600 RA patients in the Leiden Early Arthritis Clinic cohort. Fifteen single-nucleotide polymorphisms (SNPs) tagging GZMB were tested. Significantly associated SNPs were genotyped in data sets representing patients from the Groningen, Sheffield, and Lund cohorts. In each data set, the relative increase in the annual rate of progression in the presence of a genotype was assessed. Data were summarized in a meta-analysis. The association of GZMB with the RNA expression level of the GZMB genomic region was tested by mapping expression quantitative trait loci (QTLs) on 1,469 whole blood samples. Results SNP rs8192916 was significantly associated with the rate of joint destruction in the first cohort and in the meta-analysis of all data sets. Patients homozygous for the minor allele of rs8192916 had a higher rate of joint destruction per year compared with other patients (P = 7.8 x 104). Expression QTL of GZMB identified higher expression in the presence of the minor allele of rs8192916 (P = 2.27 x 105). Conclusion SNP rs8192916 located in GZMB is associated with the progression of joint destruction in RA as well as with RNA expression in whole blood.

Background Progression of joint destruction in rheumatoid arthritis (RA) is partly heritable; knowledge of genetic factors may increase our understanding of the mechanisms underlying joint destruction. The activity of the Wnt/beta-catenin pathway influences osteoblast differentiation. Dickkopf-1 (Dkk-1) and sclerostin (Sost) are negative regulators and lipoprotein receptor-related protein-5 (LRP-5) and Kremen-1 are transmembrane receptors involved in this pathway.Objective To study variants in the genes encoding these proteins in relation to progression of joint destruction.Methods 1418 patients with RA of four cohorts with 4885 sets of hands and feet x-rays were studied. Explorative analyses were performed on 600 patients with RA from Leiden on single nucleotide polymorphisms (SNPs) tagging Dkk-1, Sost, Kremen-1 and LRP-5. SNPs significantly associating with joint damage progression were subsequently genotyped in cohorts from Groningen (NL), Sheffield (UK) and Lund (Sweden). Data were summarised in meta-analyses. Serum levels of functional Dkk-1 and sclerostin were measured and studied in relation to genotypes.Results In the first cohort, six Dkk-1, three Sost, one Kremen-1 and 10 LRP-5 SNPs were significantly associated with radiological progression of joint destruction. Three Dkk-1 SNPs were associated significantly with progression of joint damage in the meta-analysis, also after correction for multiple testing (rs1896368, rs1896367 and rs1528873). Two Sost SNPs tended to significance (rs4792909 and rs6503475, p=0.07 after false discovery rate correction). Gene-gene interactions between SNPs on Dkk-1 and Sost were seen. Serum levels of Dkk-1 were significantly correlated with the genotypes in rs1896368 (p=0.02).Conclusions Patients with RA carrying risk alleles of genetic variants in Dkk-1 have higher serum levels of functional Dkk-1 and more progressive joint destruction over time.

Background. Evidence supports the use of educational and physical training programs for people with rheumatoid arthritis (RA). Objective. The purpose of this study was to evaluate the effects of a group-based exercise and educational program on the physical performance and disease self-management of people with RA. Design. This was a randomized controlled trial. Setting. The study was conducted at a rehabilitation center in the Netherlands. Participants. Thirty-four people diagnosed with RA participated in the study. Participants were randomly assigned to either an intervention group (n = 19) or a waiting list control group (n = 15). Intervention. The intervention in this study was an 8-week, multidisciplinary, group therapy program for people with RA, consisting of physical exercise designed to increase aerobic capacity and muscle strength (force-generating capacity) together with an educational program to improve health status and self-efficacy for disease-self-management. Measurements. The main outcome measures were maximum oxygen uptake ((V) over dotO(2)max), muscle strength of the elbow and knee flexors and extensors, health status, and perceived self-efficacy. All data were recorded before intervention in week 1, after intervention in week 9, and at follow-up in week 22. Results. The intervention group showed significant improvement (12.1%) in (V) over dotO(2)max at week 9 compared with the control group (-1.7%). Although significant within-group changes were found over time for muscle strength of the upper and lower extremities and health status that favored the intervention group, no between-group changes were found regarding these outcomes. Limitations. An important limitation was the small number of participants included in our study, which may have resulted in a lack of power. Conclusions. The present group-based exercise and educational program for people with RA had a beneficial effect on aerobic capacity but not on muscle strength, health status, or self-efficacy

Summary Osteoporosis is a well recognized complication of ankylosing spondylitis (AS). This study indicates that increased bone turnover, inflammation, and low vitamin D levels are important in the pathophysiology of AS-related osteoporosis, and that bone turnover markers (BTM) are valuable markers to detect bone loss in AS. Introduction The aim of this study was to elucidate the pathophysiology of AS-related osteoporosis by investigating the relation between bone mineral density (BMD), BTM, vitamin D, and clinical assessments of disease activity and physical function, as well as to identify parameters that are related to low BMD (osteopenia or osteoporosis) in AS patients with active disease. Methods One hundred twenty-eight consecutive Dutch AS outpatients were included in this cross-sectional study. Bath AS Disease Activity Index (BASDAI), erythrocyte sedimentation rate (ESR), C-reactive protein, ASAS-endorsed disease activity score (ASDAS), Bath AS Functional Index (BASFI), bone formation markers procollagen type 1 N-terminal peptide (PINP) and osteocalcin (OC), bone resorption marker serum C-telopeptides of type I collagen (sCTX), 25-hydroxyvitamin D (25OHvitD), lumbar spine and hip BMD, and vertebral fractures were assessed. Z-scores of BTM were calculated using matched 10-year cohorts of a Dutch reference group to correct for the normal influence that age and gender have on bone turnover. Results sCTX Z-score, OC Z-score, BASDAI, age, and gender were independently related to low BMD. In addition, PINP Z-score, ESR, 25OHvitD, age, and gender were independently related to sCTX and/or OC Z-score. Conclusions This study indicates that increased bone turnover, inflammation, and low vitamin D levels are important in the pathophysiology of AS-related osteoporosis. Furthermore, sCTX and OC Z-scores seem to be valuable markers to detect bone loss in AS patients in daily clinical practice where BMD of the lumbar spine, measured by DXA, may be overestimated due to osteoproliferation in patients with advanced AS.

INTRODUCTION: Ankylosing spondylitis (AS) is characterized by excessive bone formation and bone loss. Our aim was to investigate the association of bone turnover markers (BTM) with spinal radiographic damage and bone mineral density (BMD) in AS patients with active disease.METHODS: 201 consecutive AS outpatients of the Groningen Leeuwarden AS (GLAS) cohort were included. Serum markers of bone resorption (C-telopeptides of type-I collagen, sCTX) and bone formation (procollagen type-I N-terminal peptide, PINP; bone-specific alkaline phosphatase, BALP) were measured. Z-scores were used to correct for the normal influence that age and gender have on bone turnover. Radiographs were scored by two independent readers according to modified Stoke AS Spinal Score (mSASSS). The presence of complete bridging (ankylosis of at least two vertebrae) was considered as measure of more advanced radiographic damage. Low BMD was defined as lumbar spine and/or hip BMD Z-score ≤ -1.RESULTS: Of the 151 patients with complete data, 52 (34%) had ≥ 1 complete bridge, 49 (33%) had ≥ 1 syndesmophyte (non-bridging), and 50 (33%) had no syndesmophytes. 66 (44%) had low BMD. Patients with bridging had significantly higher sCTX and PINP Z-scores than patients without bridging (0.43 vs. -0.55 and 0.55 vs. 0.04, respectively). Patients with low BMD had significantly higher sCTX Z-score than patients with normal BMD (-0.08 vs. -0.61). After correcting for gender, symptom duration, and CRP, sCTX Z-score remained significantly related to the presence of low BMD alone (OR: 1.60), bridging alone (OR: 1.82), and bridging in combination with low BMD (OR: 2.26).CONCLUSIONS: This cross-sectional study in AS patients with active and relatively long-standing disease demonstrated that higher serum levels of sCTX, and to a lesser extent PINP, are associated with the presence of complete bridging. sCTX was also associated with low BMD. Longitudinal studies are needed to confirm that serum levels of sCTX can serve as objective marker for bone-related outcome in AS.

Introduction: Progression of joint destruction in rheumatoid arthritis (RA) is partly heritably; 45 to 58% of the variance in joint destruction is estimated to be explained by genetic factors. The binding of RANKL (Receptor Activator for Nuclear Factor kappa B Ligand) to RANK results in the activation of TRAF6 (tumor necrosis factor (TNF) receptor associated factor-6), and osteoclast formation ultimately leading to enhanced bone resorption. This bone resorption is inhibited by osteoprotegerin (OPG) which prevents RANKL-RANK interactions. The OPG/RANK/RANKL/TRAF6 pathway plays an important role in bone remodeling. Therefore, we investigated whether genetic variants in OPG, RANK, RANKL and TRAF6 are associated with the rate of joint destruction in RA. Methods: 1,418 patients with 4,885 X-rays of hands and feet derived from four independent data-sets were studied. In each data-set the relative increase of the progression rate per year in the presence of a genotype was assessed. First, explorative analyses were performed on 600 RA-patients from Leiden. 109 SNPs, tagging OPG, RANK, RANKL and TRAF6, were tested. Single nucleotide polymorphisms (SNPs) significantly associated in phase-1 were genotyped in data-sets from Groningen (Netherlands), Sheffield (United Kingdom) and Lund (Switzerland). Data were summarized in an inverse weighted variance meta-analysis. Bonferonni correction for multiple testing was applied. Results: We found that 33 SNPs were significantly associated with the rate of joint destruction in phase-1. In phase-2, six SNPs in OPG and four SNPs in RANK were associated with progression of joint destruction with P-value

Introduction: The aim of this study was to investigate the effect of three years of tumor necrosis factor-alpha (TNF-alpha) blocking therapy on bone turnover as well as to analyze the predictive value of early changes in bone turnover markers (BTM) for treatment discontinuation in patients with ankylosing spondylitis (AS).Methods: This is a prospective cohort study of 111 consecutive AS outpatients who started TNF-alpha blocking therapy. Clinical assessments and BTM were assessed at baseline, three and six months, as well as at one, two, and three years. Z-scores of BTM were calculated to correct for age and gender. Bone mineral density (BMD) was assessed yearly.Results: After three years, 72 patients (65%) were still using their first TNF-alpha blocking agent. In these patients, TNF-alpha blocking therapy resulted in significantly increased bone-specific alkaline phosphatase, a marker of bone formation; decreased serum collagen-telopeptide (sCTX), a marker of bone resorption; and increased lumbar spine and hip BMD compared to baseline. Baseline to three months decrease in sCTX Z-score (HR: 0.394, 95% CI: 0.263 to 0.591), AS disease activity score (ASDAS; HR: 0.488, 95% CI: 0.317 to 0.752), and physician's global disease activity (HR: 0.739, 95% CI: 0.600 to 0.909) were independent inversely related predictors of time to treatment discontinuation because of inefficacy or intolerance. Early decrease in sCTX Z-score correlated significantly with good long-term response regarding disease activity, physical function and quality of life.Conclusions: Three years of TNF-alpha blocking therapy results in a bone turnover balance that favors bone formation, especially mineralization, in combination with continuous improvement of lumbar spine BMD. Early change in sCTX can serve as an objective measure in the evaluation of TNF-alpha blocking therapy in AS, in addition to the currently used more subjective measures.

Objective.To investigate whether level of serum matrix metalloproteinase-3 (MMP-3) can serve as a biomarker for monitoring and predicting response to etanercept treatment in patients with ankylosing spondylitis (AS) in daily clinical practice.Methods.Ninety-two consecutive AS outpatients with active disease who started etanercept treatment were included in this longitudinal observational study. Clinical data were collected prospectively at baseline and after 3 and 12 months of treatment. At the same timepoints, serum MMP-3 levels were measured retrospectively by ELISA.Results.Since baseline serum MMP-3 levels were significantly higher in male compared to female patients with AS, data analysis was split for gender. Changes in serum MMP-3 levels after etanercept treatment correlated positively with changes in clinical assessments of disease activity and physical function in both male and female patients. Receiver operating characteristic analysis in male patients showed that baseline serum MMP-3 levels had poor accuracy (AUC < 0.7) to discriminate between Assessments in Ankylosing Spondylitis 20 (ASAS20) or ASAS40 responders and nonresponders after 3 or 12 months of treatment. The accuracy of change in serum MMP-3 levels from baseline to 3 months in predicting response after 3 or 12 months of treatment was poor for ASAS40 (AUC < 0.7) or moderate for ASAS20 (AUC = 0.752 and 0.744, respectively), and was not superior to the accuracy of change in the currently used objective biomarkers, erythrocyte sedimentation rate and C-reactive protein.Conclusion.Although significant changes in serum MMP-3 levels were found after etanercept treatment, data analysis indicates that serum MMP-3 levels are not very useful for monitoring and predicting response to etanercept treatment in patients with AS in daily clinical practice.

Background Obesity is associated with an increased risk for many disorders, impaired functional capacity, and impaired quality of life (QoL). Objectives The aim of the present study was to evaluate the prevalence of obesity and the relation to clinical assessments of disease activity, physical function, and QoL in patients with axial spondyloarthritis (SpA). Methods 465 consecutive patients from the Groningen Leeuwarden Axial SpA (GLAS) cohort who visited the outpatient clinic between January 2011 and December 2012 were included in this cross-sectional analysis. All patients fulfilled the modified New York criteria for ankylosing spondylitis (AS; >90%) or the ASAS criteria for axial SpA. Body mass index (BMI) was calculated and patients were divided into groups according to the WHO criteria: low BMI (BMI 30 kg/m2). BMI was compared with the LifeLines cohort, a three generation population-based longitudinal cohort study in the North of the Netherlands. Disease activity was assessed by Bath AS Disease Activity Index (BASDAI), AS Disease Activity Score (ASDAS), and C-reactive protein (CRP), physical function by Bath AS Functional Index (BASFI), and quality of life by ASQoL questionnaire. Results Mean age of the 465 patients was 45 years (SD ±13), median symptom duration was 17 years (range 0-61), 65% were male, and median BMI was 26.0 kg/m2 (range 17.0-45.4). In total, 8 (2%) patients had low BMI, 183 (39%) had normal BMI, 174 (37%) were overweight, and 100 (22%) were obese. Of the 100 obese patients, 19 had BMI between 35-40 kg/m2 and 3 had BMI >40 kg/m2. In comparison, the LifeLines population (n=136577) had an estimated prevalence of 1% low BMI, 42% normal BMI, 43% overweight, and 15% obesity. Obese axial SpA patients were significantly older, had longer disease duration, and more comorbidity than patients with normal BMI. Disease activity of obese patients was significantly higher and physical function and QoL were significantly worse compared to patients with normal BMI ([Table 1][1]). These differences remained statistically significant after correcting for age, disease duration, and comorbidity. View this table: Table 1. Disease activity, physical function, and QoL of axial SpA patients with overweight and obesity compared to those with normal BMI Conclusions This cross-sectional analysis shows a high prevalence of obesity in a large cohort of axial SpA patients. The presence of obesity was associated with higher disease activity and worse physical function and QoL. Acknowledgements The GLAS cohort was supported by an unrestricted grant from Pfizer. Pfizer had no role in the design, conduct, interpretation, or publication of this study. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.4363 [1]: #T1

Background Non-steroidal anti-inflammatory drugs (NSAIDs) are regarded as the cornerstone of conventional therapy in ankylosing spondylitis (AS). TNF-α blocking therapy is available for AS patients who have insufficient response to conventional therapy. However, little is known about concomitant NSAID use during TNF-α blocking therapy. Objectives The aim of the present study was to evaluate NSAID use in AS patients with and without TNF-α blocking therapy during 2-year follow-up. Methods The present analysis is part of the GLAS cohort, an ongoing longitudinal observational cohort study in daily clinical practice. Since November 2004, consecutive AS outpatients who started TNF-α blocking therapy because of active disease at the UMCG and the MCL were included. In 2009, this inclusion was extended to all consecutive AS outpatients, irrespective of treatment regimen. All patients fulfilled the modified New York criteria for AS (>90%) or the ASAS criteria for axial spondyloarthritis. At every follow-up visit, disease activity was assessed using Bath AS disease activity score (BASDAI), AS disease activity score (ASDAS), and C-reactive protein (CRP). NSAID use (yes/no) and type of NSAID were recorded prospectively. In addition, dosage and frequency were assessed retrospectively from clinical records and the recently developed ASAS-NSAID index was calculated. NSAID use during the first 2 years of follow-up was compared between patients with and without TNF-α blocking therapy. Results Of the 407 included patients, 66% were male, 73% HLA-B27 positive, mean age was 43.5 years (SD ±12.6), and median symptom duration 15 years (range 1-59). These patient characteristics were comparable between patients with (n=270) and without (n=137) TNF-α blocking therapy. As expected, patients who started TNF-α blocking therapy had significantly higher disease activity at baseline (median BASDAI 6.0 vs. 3.6, ASDAS 3.7 vs. 2.3, CRP 12 vs. 4; p Of the 270 patients who started TNF-α blocking therapy, 79% used NSAIDs at baseline and this proportion decreased significantly during follow-up; 40% after 12 months (p Conclusions In this observational cohort study in daily clinical practice, there was no difference in NSAID use between AS patients with and without indication for starting TNF-α blocking therapy. During TNF-α blocking therapy, the proportion of patients who used concomitant NSAIDs decreased significantly over time. NSAID use remained stable in patients without TNF-α blocking therapy. Acknowledgements The GLAS cohort was supported by an unrestricted grant from Pfizer. Pfizer had no role in the design, conduct, interpretation, or publication of this study. Disclosure of Interest M. Carbo: None declared, S. Arends Grant/research support: Abbott, Pfizer, Wyeth, E. Brouwer Grant/research support: Abbott, Pfizer, Wyeth, R. Bos Grant/research support: Pfizer, Consultant for: Pfizer, M. Efde: None declared, M. Leijsma: None declared, H. Bootsma: None declared, E. van der Veer: None declared, A. Spoorenberg Grant/research support: Abbott, Pfizer, Wyeth, Consultant for: Abbvie, Pfizer, UCB DOI 10.1136/annrheumdis-2014-eular.4947

Background There are differences in clinical presentation of ankylosing spondylitis (AS). Women tend to have milder disease and may therefore be underdiagnosed. Male AS patients are more likely to develop spinal radiographic damage. Objectives The aim of the present study was to investigate whether there are differences in patient-reported assessments of disease activity, physical function, and quality of life between male and female patients with axial spondyloarthritis (SpA). Methods All consecutive patients from the Groningen Leeuwarden Axial SpA (GLAS) cohort who visited the outpatient clinic between January 2011 and December 2012 were included in this cross-sectional analysis. All patients fulfilled the modified New York criteria for AS (>90%) or the ASAS criteria for axial SpA. Disease activity was assessed using Bath AS disease activity index (BASDAI), AS disease activity score (ASDAS; calculated from BASDAI questions 2, 3 and 6, patient global assessment of disease activity (GDA), and C-reactive protein (CRP)), swollen joint index (range 0-44), and tender joint index (range 0-46). Physical function was assessed using Bath AS functional index (BASFI) and quality of life using AS quality of life (ASQoL) questionnaire. Results Of the 469 included patients, mean age was 45 years (SD ±13), mean duration of symptoms was 17 years (range 0-61), 66% were male, and 80% were HLA-B27+. Males were significantly older, had longer disease duration, and were more frequently HLA-B27+ compared to females. Extra-articular manifestations, comorbidity, and current use of NSAID, DMARD, and anti-TNF were comparable between both groups. Patient-reported measures of disease activity (BASDAI, patient GDA, and tender joints) and outcome (BASFI and ASQoL) were significantly higher in female compared to male patients. ASDAS, capturing both subjective and objective aspects of disease activity, was also significantly higher in females. This difference can be explained by patient-reported aspects of the ASDAS, since CRP levels were comparable between male and female patients (Table 1). Differences remained statistically significant after correcting for age, disease duration, and HLA-B27 status. Conclusions This cross-sectional study shows that patient-reported measures of disease activity and outcome as well as ASDAS were significantly worse in female axial SpA patients. We recommend to be aware of these differences when interpreting patient-reported measures in research and clinical practice. Acknowledgements The GLAS cohort was supported by an unrestricted grant from Pfizer. Pfizer had no role in the design, conduct, interpretation, or publication of this study. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4330

Background Physical activity questionnaires are considered to be the most applicable method to assess daily physical activity in population studies because of participant convenience, minimal cost, and scoring flexibility. The International Physical Activity Questionnaire (IPAQ) and the Short QUestionnaire to Asses Health-enhancing physical activity (SQUASH) are recall questionnaires that have acceptable construct validity and moderate to high test-retest reliability in healthy populations.(1,2) Until now, the validity and reliability of these physical activity questionnaires have not been studied in patients with ankylosing spondylitis (AS). Objectives To investigate the construct validity and test-retest reliability of the IPAQ and SQUASH in patients with AS. Methods The self-report questionnaires IPAQ (long form) and SQUASH were compared with daily physical activity assessed using the ActiGraph accelerometer during 7 consecutive days (gold standard) in 63 AS outpatients. The IPAQ and SQUASH were administered on two different occasions approximately one week apart in 52 AS outpatients. All patients fulfilled the modified New York criteria for AS or the ASAS criteria for axial spondyloarthritis. Validity was examined by calculating Spearman’s and Pearson’s correlation coefficients between accelerometer activity counts and IPAQ and SQUASH total scores, respectively. Test-retest reliability of the IPAQ and SQUASH was investigated by calculating intraclass correlation coefficients (ICC) between the first and the second assessments of the questionnaires. Additionally, Bland-Altman analysis was performed. Results Mean age of the in total 115 AS patients was 45 years (SD ± 12), median disease duration was 16 years (range 0-54), and 62% were male. IPAQ and SQUASH total scores correlated significantly with accelerometer outcome: ρ=0.38 and r=0.35, respectively. ICC’s between first and second assessments of the IPAQ and SQUASH were 0.83 and 0.89, respectively. Bland-Altman analyses showed no systemic bias, but in particular for the IPAQ the 95% limits of agreement were wide. Conclusions Both physical activity questionnaires showed moderate construct validity. The SQUASH showed good test-retest reliability, superior to the IPAQ. These results indicate that the SQUASH can be used to assess daily physical activity in AS population studies. References Craig CL, Marshall AL, Sjostrom M, et al. International physical activity questionnaire: 12-country reliability and validity. Med Sci Sports Exerc. 2003;35:1381-95. Wendel-Vos GC, Schuit AJ, Saris WH, et al. Reproducibility and relative validity of the short questionnaire to assess health-enhancing physical activity. J Clin Epidemiol. 2003;56:1163-9. Disclosure of Interest None Declared

Background Ankylosing spondylitis (AS) is characterized by the combination of inflammation, bone formation, and bone loss. New bone formation can lead to the formation of syndesmophytes, ankylosis of the spine and sacroiliac joints, and bone formations on enthesal sites, whereas bone loss can result in osteoporosis and vertebral fractures. Objectives To investigate the relation between bone turnover markers (BTM) and the presence of (bridging) syndesmophytes and/or low bone mineral density (BMD) in AS patients with active disease. Methods 149 consecutive outpatients with AS based on the modified New York criteria and active disease (Bath AS disease activity index (BASDAI) ≥4 and/or based on expert opinion) were included. Patients with recent fractures ore use of bisphosphonates were excluded. The lateral view of radiographs of the cervical and lumbar spine were scored for the presence of (bridging) syndesmophytes at the anterior corners of the vertebrae by two independent observers. In case of discrepancy between the observers, consensus was reached afterwards. BMD of the lumbar spine (anterior-posterior projection at L1-L4) and hip (total proximal femur) were measured using DXA. Low BMD was defined as a lumbar spine and/or hip BMD Z-score ≤1. Markers of bone formation procollagen type 1 N-terminal peptide (PINP) and bone-specific alkaline phosphatase (BALP), and marker of bone resorption serum collagen-telopeptide (sCTX) were measured. Z-scores of BTM were calculated using matched 10-years-cohorts of a Dutch reference group (200 men or 350 women) to correct for the normal influence that age and gender have on bone turnover. Results Mean age was 42 years (SD±11), median symptom duration 15 years (range: 1-53), mean BASDAI 6.2 (SD±1.6), and 70% were male. Syndesmophytes, bridging syndesmophytes, and low BMD were present in 68%, 33%, and 42% of the patients, respectively. No significant differences in BTM were found between patients with and without syndesmophytes. Patients with bridging syndesmophytes had significantly higher PINP Z-scores (median: 0.55 vs. -0.01, p=0.002) and sCTX Z-scores (median: 0.44 vs. -0.52, p=0.000) than patients without bridging syndesmophytes. Patients with low BMD had significantly higher sCTX Z-scores (median: -0.03 vs. -0.61, p=0.010) than patients with normal BMD. The differences in sCTX Z-score remained statistically significantly after correcting for gender, age, disease duration, and disease activity. Conclusions This cross-sectional analysis in AS patients with active and relatively long-standing disease indicates that higher serum levels of sCTX are significantly associated with the presence of bridging syndesmophytes and/or low BMD. Longitudinal studies are needed to investigate whether BTM can serve as potential biomarkers or predictors for radiographic progression and/or osteoporosis in AS. Disclosure of Interest None Declared

Background Inflammation in Rheumatoid Arthritis leads to impaired bone formation. The activity of the Wnt pathway influences osteoblast differentiation. Dickkopf-1 (Dkk1) and Sclerostin (Sost) are important negative regulators of bone formation, they bind and inactivate signaling of the LRP-5 receptor. This inhibition is amplified in case Dkk-1 also binds to the transmembrane receptor Kremen-1. Data are emerging that Wnt signaling is important to maintain the integrity of joints and that TNF-α induced changes in Dkk-1 affect the balance between bone formation and resorption. Objectives Since the severity of joint destruction in Rheumatoid Arthritis is in part influenced by genetic factors, we aimed to study the influence of genetic variants in Dkk-1 , Sost , LRP-5 and Kremen-1 on the radiographic progression rate. Methods 1,418 RA-patients with 4,885 X-ray sets of both hands and feet of four independent cohorts were studied. First, explorative analyses were performed on 600 RA-patients enrolled in the Leiden-Early-Arthritis-Clinic on the SNPs tagging Dkk-1 (8), Sost (9), Kremen-1 (16) and LRP5 (44). Significantly associating SNPs were genotyped in cohorts from Groningen (NL), Sheffield (UK) and Lund (Sweden). In each dataset the relative increase of the progression rate per year in the presence of a genotype was assessed. Subsequently, data were summarized in a meta-analysis. In groups of 80, on their genotype selected, RA-patients from Leiden, serum levels of functional Dkk-1 and Sclerostin (Biomedica, Austria) were measured with ELISA and studied in relation to genotypes. Results In the first cohort, 7 SNPs on Dkk-1 , 3 SNPs on Sost , 1 SNP on Kremen-1 and 10 LRP-5 SNPs were significant. The SNPs on Kremen-1 and LRP-5 were not replicated in the second phase. 3 Dkk-1 SNPs associated significantly with progression of joint damage in the meta-analysis, also after FDR-correction for multiple testing (rs1896368, rs1896367 and rs1528873). Additionally, 2 Sost SNPs tended to significance (rs4792909 and rs6503475, p=0.01 and 0.03 in the meta-analysis and p=0.07 after FDR-correction). Epistasis between SNPs on Dkk-1 and Sost was observed. Sclerostin levels were not correlated to the SNPs in Sost . However, serum levels of Dkk-1 were significantly correlated with the genotypes in rs1896368 and rs1896367 (p=0.002). Patients carrying risk alleles (associated with more radiographic progression) had higher levels of Dkk-1. Conclusions The present data of four cohort studies show that RA-patients carrying the risk alleles of several genetic variants in Dkk-1 have higher serum levels of functional Dkk-1 and more progressive joint destruction over time. These data illustrate the relevance of Dkk-1 to progression of joint destruction in RA. Disclosure of Interest None Declared

Background In ankylosing spondylitis (AS), objective measurements evaluating the effect of tumor necrosis factor-alpha (TNF-α) blocking therapy are lacking. Objectives To investigate the predictive value of bone turnover markers (BTM) in relation to discontinuation of TNF-α blocking therapy in patients with AS. Methods 111 consecutive AS outpatients from the Medical Center Leeuwarden and the University Medical Center Groningen who started TNF-α blocking therapy (infliximab n=22; etanercept n=71; adalimumab n=18) were included between November 2004 and December 2007. All patients fulfilled the modified New York criteria for AS (n=109) or the ASAS criteria for axial spondyloarthritis (n=2). Patients with recent fractures and/or use of bisphosphonates were excluded. Continuation of TNF-α blocking therapy was based on decrease in Bath AS Disease Activity Index (BASDAI) of at least 50% or 2 units compared with baseline, and/or expert opinion in favor of treatment continuation. Clinical assessments, marker of bone formation bone-specific alkaline phosphatase (BALP), and marker of bone resorption serum collagen-telopeptide (sCTX) were assessed at baseline, 3 and 6 months, and 1, 2, and 3 years. Z-scores of BTM were calculated using matched 10-years-cohorts of a Dutch reference group (200 men or 350 women) to correct for the normal influence that age and gender have on bone turnover. Results Mean age of the 111 AS patients was 42.2 years (SD ± 10.3), median disease duration was 16 years (range 1-49), and 70% were male. Mean BASDAI was 6.1 (SD ± 1.7) and mean AS disease activity index (ASDAS) was 3.8 (SD ± 0.8) at baseline. After 3 years, 72 patients (65%) were still using their first TNF-α blocking agent. In these patients, TNF-α blocking therapy resulted in significantly increased BALP Z-score and significantly decreased sCTX Z-score compared to baseline. Baseline to 3 months decrease in sCTX Z-score (HR: 0.513, 95% CI: 0.367-0.717) was inversely associated with time to discontinuation of TNF-α blocking therapy in univariate Cox regression. Multivariate analysis showed that baseline to 3 months decrease in sCTX Z-score (HR: 0.394, 95% CI: 0.263-0.591), ASDAS (HR: 0.488, 95% CI: 0.317-0.752), and physician’s global disease activity (GDA) (HR: 0.739, 95% CI: 0.600-0.909) were independent inversely related predictors of time to treatment discontinuation. Conclusions In addition to the ASDAS and physician’s GDA, early change in bone resorption marker sCTX after starting treatment can serve as an objective measure in the prediction of long-term continuation of TNF-α blocking therapy in AS. Disclosure of Interest None Declared

Background In ankylosing spondylitis (AS), objective measurements evaluating the effect of tumor necrosis factor-alpha (TNF-α) blocking therapy are lacking. Objectives To investigate the predictive value of bone turnover markers (BTM) in relation to discontinuation of TNF-α blocking therapy in patients with AS. Methods 111 consecutive AS outpatients from the Medical Center Leeuwarden and the University Medical Center Groningen who started TNF-α blocking therapy (infliximab n=22; etanercept n=71; adalimumab n=18) were included between November 2004 and December 2007. All patients fulfilled the modified New York criteria for AS (n=109) or the ASAS criteria for axial spondyloarthritis (n=2). Patients with recent fractures and/or use of bisphosphonates were excluded. Continuation of TNF-α blocking therapy was based on decrease in Bath AS Disease Activity Index (BASDAI) of at least 50% or 2 units compared with baseline, and/or expert opinion in favor of treatment continuation. Clinical assessments, marker of bone formation bone-specific alkaline phosphatase (BALP), and marker of bone resorption serum collagen-telopeptide (sCTX) were assessed at baseline, 3 and 6 months, and 1, 2, and 3 years. Z-scores of BTM were calculated using matched 10-years-cohorts of a Dutch reference group (200 men or 350 women) to correct for the normal influence that age and gender have on bone turnover. Results Mean age of the 111 AS patients was 42.2 years (SD ± 10.3), median disease duration was 16 years (range 1-49), and 70% were male. Mean BASDAI was 6.1 (SD ± 1.7) and mean AS disease activity index (ASDAS) was 3.8 (SD ± 0.8) at baseline. After 3 years, 72 patients (65%) were still using their first TNF-α blocking agent. In these patients, TNF-α blocking therapy resulted in significantly increased BALP Z-score and significantly decreased sCTX Z-score compared to baseline. Baseline to 3 months decrease in sCTX Z-score (HR: 0.513, 95% CI: 0.367-0.717) was inversely associated with time to discontinuation of TNF-α blocking therapy in univariate Cox regression. Multivariate analysis showed that baseline to 3 months decrease in sCTX Z-score (HR: 0.394, 95% CI: 0.263-0.591), ASDAS (HR: 0.488, 95% CI: 0.317-0.752), and physician’s global disease activity (GDA) (HR: 0.739, 95% CI: 0.600-0.909) were independent inversely related predictors of time to treatment discontinuation. Conclusions In addition to the ASDAS and physician’s GDA, early change in bone resorption marker sCTX after starting treatment can serve as an objective measure in the prediction of long-term continuation of TNF-α blocking therapy in AS. Disclosure of Interest None Declared

Contains fulltext : 96669.pdf (Publisher’s version ) (Open Access) INTRODUCTION: Identifying ankylosing spondylitis (AS) patients who are likely to benefit from tumor necrosis factor-alpha (TNF-alpha) blocking therapy is important, especially in view of the costs and potential side effects of these agents. Recently, the AS Disease Activity Score (ASDAS) has been developed to assess both subjective and objective aspects of AS disease activity. However, data about the predictive value of the ASDAS with respect to clinical response to TNF-alpha blocking therapy are lacking. The aim of the present study was to identify baseline predictors of response and discontinuation of TNF-alpha blocking therapy in AS patients in daily clinical practice. METHODS: AS outpatients who started TNF-alpha blocking therapy were included in the Groningen Leeuwarden Ankylosing Spondylitis (GLAS) study, an ongoing prospective longitudinal observational cohort study with follow-up visits according to a fixed protocol. For the present analysis, patients were excluded if they had previously received anti-TNF-alpha treatment. Predictor analyses of response and treatment discontinuation were performed using logistic and Cox regression models, respectively. RESULTS: Between November 2004 and April 2010, 220 patients started treatment with infliximab (n = 32), etanercept (n = 137), or adalimumab (n = 51). At three and six months, 68% and 63% of patients were Assessments in Ankylosing Spondylitis (ASAS)20 responders, 49% and 46% ASAS40 responders, and 49% and 50% Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)50 responders, respectively. Baseline predictors of response were younger age, male gender, higher ASDAS score, higher erythrocyte sedimentation rate (ESR) level, higher C-reactive protein (CRP) level, presence of peripheral arthritis, higher patient's global assessment of disease activity, and lower modified Schober test. In August 2010, 64% of patients were still using their TNF-alpha blocking agent with a median follow-up of 33.1 months (range 2.4 to 68.2). Baseline predictors of discontinuation of TNF-alpha blocking therapy were female gender, absence of peripheral arthritis, higher BASDAI, lower ESR level, and lower CRP level. CONCLUSIONS: Besides younger age and male gender, objective variables such as higher inflammatory markers or ASDAS score were identified as independent baseline predictors of response and/or continuation of TNF-alpha blocking therapy. In contrast, higher baseline BASDAI score was independently associated with treatment discontinuation. Based on these results, it seems clinically relevant to include more objective variables in the evaluation of anti-TNF-alpha treatment.