Heritability of spinal curvature and its relationship to disc degeneration and bone mineral density in female adult twins.

PURPOSE: To determine the heritability of spine curve using plain radiographs and to identify risk factors for spine curvature including age, body mass index, smoking, bone mineral density (BMD), and lumbar disc degeneration (LDD). METHODS: A classical twin study of 110 MZ and 136 DZ adult female twins. Demographic and clinical information obtained from long spine radiographs, lumbar spine degeneration on spine MR scan, and BMD assessed by DEXA at hip and lumbar spine were included in multiple logistic regression models to determine risk factors for spine curvature. RESULTS: Heritability estimates ranged between 41 (19-59) % for pelvic incidence to 61 (46-72) % for thoracic kyphosis; with lumbar lordosis and cervical lordosis having 59 (42-71) % and 43 (23-59) % heritability, respectively. For each spine curve, the model showing the best fit contained additive genetic and shared environmental components with no contribution from the unique environment. Significant risk factors for increased thoracic kyphosis were lumbar spine BMD, age, and cervical lordosis; for pelvic incidence were lumbar spine BMD and lumbar lordosis; for lumbar lordosis were cervical lordosis, pelvic incidence and LDD; and age alone predicted cervical lordosis (p = 0.001). CONCLUSION: In this sample of middle-aged and elderly women, there were significant genetic influences on all spine curves but particularly thoracic kyphosis and lumbar lordosis. The strongest predictor for lumbar lordosis was LDD (p < 0.0001) which is itself genetically determined in part. For thoracic kyphosis, BMD was strongly associated and remained so (for lumbar BMD) with the inclusion of age, showing BMD to be an independent risk factor. This work highlights the genetic factors influencing normal spine curvature in women.

Association of variants at 1q32 and STAT3 with ankylosing spondylitis suggests genetic overlap with Crohn's disease.

Ankylosing spondylitis (AS) is a common inflammatory arthritic condition. Overt inflammatory bowel disease (IBD) occurs in about 10% of AS patients, and in addition 70% of AS cases may have subclinical terminal ileitis. Spondyloarthritis is also common in IBD patients. We therefore tested Crohn's disease susceptibility genes for association with AS, aiming to identify pleiotropic genetic associations with both diseases. Genotyping was carried out using Sequenom and Applied Biosystems TaqMan and OpenArray technologies on 53 markers selected from 30 Crohn's disease associated genomic regions. We tested genotypes in a population of unrelated individual cases (n = 2,773) and controls (n = 2,215) of white European ancestry for association with AS. Statistical analysis was carried out using a Cochran-Armitage test for trend in PLINK. Strong association was detected at chr1q32 near KIF21B (rs11584383, P = 1.6 × 10(-10), odds ratio (OR) = 0.74, 95% CI:0.68-0.82). Association with disease was also detected for 2 variants within STAT3 (rs6503695, P = 4.6 × 10(-4). OR = 0.86 (95% CI:0.79-0.93); rs744166, P = 2.6 × 10(-5), OR = 0.84 (95% CI:0.77-0.91)). Association was confirmed for IL23R (rs11465804, P = 1.2 × 10(-5), OR = 0.65 (95% CI:0.54-0.79)), and further associations were detected for IL12B (rs10045431, P = 5.2 × 10(-5), OR = 0.83 (95% CI:0.76-0.91)), CDKAL1 (rs6908425, P = 1.1 × 10(-4), OR = 0.82 (95% CI:0.74-0.91)), LRRK2/MUC19 (rs11175593, P = 9.9 × 10(-5), OR = 1.92 (95% CI: 1.38-2.67)), and chr13q14 (rs3764147, P = 5.9 × 10(-4), OR = 1.19 (95% CI: 1.08-1.31)). Excluding cases with clinical IBD did not significantly affect these findings. This study identifies chr1q32 and STAT3 as ankylosing spondylitis susceptibility loci. It also further confirms association for IL23R and detects suggestive association with another 4 loci. STAT3 is a key signaling molecule within the Th17 lymphocyte differentiation pathway and further enhances the case for a major role of this T-lymphocyte subset in ankylosing spondylitis. Finally these findings suggest common aetiopathogenic pathways for AS and Crohn's disease and further highlight the involvement of common risk variants across multiple diseases.

Investigating the genetic association between ERAP1 and ankylosing spondylitis.

A strong association between ERAP1 and ankylosing spondylitis (AS) was recently identified by the Wellcome Trust Case Control Consortium and the Australo-Anglo-American Spondylitis Consortium (WTCCC-TASC) study. ERAP1 is highly polymorphic with strong linkage disequilibrium evident across the gene. We therefore conducted a series of experiments to try to identify the primary genetic association(s) with ERAP1. We replicated the original associations in an independent set of 730 patients and 1021 controls, resequenced ERAP1 to define the full extent of coding polymorphisms and tested all variants in additional association studies. The genetic association with ERAP1 was independently confirmed; the strongest association was with rs30187 in the replication set (P = 3.4 x 10(-3)). When the data were combined with the original WTCCC-TASC study the strongest association was with rs27044 (P = 1.1 x 10(-9)). We identified 33 sequence polymorphisms in ERAP1, including three novel and eight known non-synonymous polymorphisms. We report several new associations between AS and polymorphisms distributed across ERAP1 from the extended case-control study, the most significant of which was with rs27434 (P = 4.7 x 10(-7)). Regression analysis failed to identify a primary association clearly; we therefore used data from HapMap to impute genotypes for an additional 205 non-coding SNPs located within and adjacent to ERAP1. A number of highly significant associations (P < 5 x 10(-9)) were identified in regulatory sequences which are good candidates for causing susceptibility to AS, possibly by regulating ERAP1 expression.

The chromosome 16q region associated with ankylosing spondylitis includes the candidate gene tumour necrosis factor receptor type 1-associated death domain (TRADD).

OBJECTIVE: To replicate and refine the reported association of ankylosing spondylitis (AS) with two non-synonymous single nucleotide polymorphisms (nsSNPs) on chromosome 16q22.1. METHODS: Firstly, 730 independent UK patients with AS were genotyped for rs9939768 and rs6979 and allele frequencies were compared with 2879 previously typed historic disease controls. Secondly, the two data sets were combined in meta-analyses. Finally, 5 tagging SNPs, located between rs9939768 and rs6979, were analysed in 1604 cases and 1020 controls. RESULTS: The association of rs6979 with AS was replicated, p=0.03, OR=1.14 (95% CI 1.01 to 1.28), and a trend for association with rs9939768 detected, p=0.06, OR=1.25 (95% CI 0.99 to 1.57). Meta-analyses revealed association of both SNPs with AS, p=0.0008, OR=1.31 (95% CI 1.12 to 1.54) and p=0.0009, OR=1.15 (95% CI 1.06 to 1.23) for rs9939768 and rs6979, respectively. New associations with rs9033 and rs868213 (p=0.00002, OR=1.23 (95% CI 1.12 to 1.36) and p=0.00002 OR=1.45 (95% CI 1.22 to 1.72), respectively, were identified. CONCLUSIONS: The region on chromosome 16 that has been replicated in the present work is interesting as the highly plausible candidate gene, tumour necrosis factor receptor type 1 (TNFR1)-associated death domain (TRADD), is located between rs9033 and rs868213. It will require additional work to identify the primary genetic association(s) with AS.

Association between the interleukin 23 receptor and ankylosing spondylitis is confirmed by a new UK case-control study and meta-analysis of published series.

OBJECTIVES: It has been shown previously that IL-23R variants are associated with AS. We conducted an extended analysis in the UK population and a meta-analysis with the previously published studies, in order to refine these IL-23R associations with AS. METHODS: The UK case-control study included 730 new cases and 1331 healthy controls. In the extended study, the 730 cases were combined with 1088 published cases. Allelic associations were analysed using contingency tables. In the meta-analysis, 3482 cases and 3150 controls from four different published studies and the new UK cases were combined. DerSimonian-Laird test was used to calculate random effects pooled odds ratios (ORs). RESULTS: In the UK case-control study with new cases, four of the eight SNPs showed significant associations, whereas in the extended UK study, seven of the eight IL-23R SNPs showed significant associations (P < 0.05) with AS, maximal with rs11209032 (P < 10(-5), OR 1.3), when cases with IBD and/or psoriasis were excluded. The meta-analysis showed significant associations with all eight SNPs; the strongest associations were again seen not only with rs11209032 (P = 4.06 x 10(-9), OR approximately 1.2) but also with rs11209026 (P < 10(-10), OR approximately 0.6). CONCLUSIONS: IL-23R polymorphisms are clearly associated with AS, but the primary causal association(s) is(are) still not established. These polymorphisms could contribute either increased or decreased susceptibility to AS; functional studies will be required for their full evaluation. Additionally, observed stronger associations with SNPs rs11209026 and rs11465804 upon exclusion of IBD and/or psoriasis cases may represent an independent association with AS.

LRTae: improving statistical power for genetic association with case/control data when phenotype and/or genotype misclassification errors are present.

BACKGROUND: In the field of statistical genetics, phenotype and genotype misclassification errors can substantially reduce power to detect association with genetic case/control studies. Misclassification also can bias population frequency parameters such as genotype, haplotype, or multi-locus genotype frequencies. These problems are of particular concern in case/control designs because, short of repeated sampling, there is no way to detect misclassification errors. We developed a double-sampling procedure for case/control genetic association using a likelihood ratio test framework. Different approaches have been proposed to deal with misclassification errors. We have chosen the likelihood framework because of the ease with which misclassification probabilities may be incorporated into in the statistical framework and hypothesis testing. The statistic is called the Likelihood Ratio Test allowing for errors (LRTae) and is freely available via software download. RESULTS: We applied our procedure to 10,000 replicates of simulated case/control data in which we introduced phenotype misclassification errors. The phenotype considered is Ankylosing Spondylitis (AS). The LRTae method power was always greater than LRTstd power for the significance levels considered (5%, 1%, 0.1%, 0.01%). Power gains for the LRTae method over the LRTstd method increased as the significance level became more stringent. Multi-locus genotype frequency estimates using LRTae method were more accurate than estimates using LRTstd method. CONCLUSION: The LRTae method can be applied to single-locus genotypes, multi-locus genotypes, or multi-locus haplotypes in a case/control framework and can be more powerful to detect association in case/control studies when both genotype and/or phenotype errors are present. Furthermore, the LRTae method provides asymptotically unbiased estimates of case and control genotype frequencies, as well as estimates of phenotype and/or genotype misclassification rates.

Prevalence of inflammatory back pain in a cohort of patients with anterior uveitis.

PURPOSE: To determine the prevalence of inflammatory back pain in an anterior uveitis cohort. DESIGN: Retrospective cohort study. METHODS: Patients with anterior uveitis were recruited from the clinic of an ophthalmologist to complete a survey between March and December 2008. Patients were classified with inflammatory back pain if they had ≥2 positive responses to 4 validated inflammatory back pain questions: presence of morning stiffness >30 minutes in duration; improvement in back pain with exercise but not with rest; awakening from back pain during the second half of the night only; and presence of alternating buttock pain. Disease activity was assessed using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). The impact of disease on quality of life was measured using the EuroQOL (EQ-5D) questionnaire. Twenty-five patients underwent further rheumatologic examination. RESULTS: One hundred forty-one of 167 patients (84.4%) completed the survey. Sixty-six of 141 patients (46.8%) were classified to have inflammatory back pain. Mean BASDAI (4.2, SD 2.41) and EQ-5D scores (0.73, SD 0.21) were lower than patients with no inflammatory back pain (0.82, SD 0.16, P = .0048). In the subgroup that underwent rheumatologic assessment, a classification of inflammatory back pain was 92% sensitive and 67% specific for a diagnosis of inflammatory back pain. CONCLUSIONS: The prevalence of inflammatory back pain in a cohort of anterior uveitis patients was found to be 46.8%. Patients with inflammatory back pain had worse quality of life than those without. Ophthalmologists may use these questions on back pain to select patients classified to have inflammatory back pain to refer for early rheumatologic assessment.

Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility.

Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 × 10(-8) in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 × 10(-6) overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.

Visual assessment of the spine bruckel instrument, a novel status tool to reflect appearance of the spine in patients with ankylosing spondylitis.

OBJECTIVE: The Visual Assessment of the Spine Bruckel Instrument (VASBI) is a new status tool developed by the Spondylitis Association of America and the University of Toronto to reflect spinal appearance in patients with ankylosing spondylitis (AS). Our objective was to validate the VASBI according to the Outcome Measures in Rheumatoid Arthritis Clinical Trials filter (truth, discrimination, and feasibility). METHODS: Three hundred patients with AS were asked to rate their degree of perceived spinal deformity using the VASBI. To evaluate construct validity, VASBI scores were compared with functional outcome, spinal mobility, and radiographic spinal damage. Test-retest reliability was evaluated using kappa statistic (kappa). RESULTS: Patient VASBI demonstrated strong correlation with spinal mobility (r = 0.543) and moderate correlation with functional impairment (r = 0.490) and structural damage (r = 0.309). Reliability for VASBI was very good (kappa = 0.973, p < 0.001). CONCLUSION: The VASBI is a novel tool with practical applications in a busy clinical setting as it simplifies assessment of AS spinal deformity. Our study demonstrates that the VASBI has good feasibility, construct validity, and reliability.

Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci.

To identify susceptibility loci for ankylosing spondylitis, we undertook a genome-wide association study in 2,053 unrelated ankylosing spondylitis cases among people of European descent and 5,140 ethnically matched controls, with replication in an independent cohort of 898 ankylosing spondylitis cases and 1,518 controls. Cases were genotyped with Illumina HumHap370 genotyping chips. In addition to strong association with the major histocompatibility complex (MHC; P < 10(-800)), we found association with SNPs in two gene deserts at 2p15 (rs10865331; combined P = 1.9 x 10(-19)) and 21q22 (rs2242944; P = 8.3 x 10(-20)), as well as in the genes ANTXR2 (rs4333130; P = 9.3 x 10(-8)) and IL1R2 (rs2310173; P = 4.8 x 10(-7)). We also replicated previously reported associations at IL23R (rs11209026; P = 9.1 x 10(-14)) and ERAP1 (rs27434; P = 5.3 x 10(-12)). This study reports four genetic loci associated with ankylosing spondylitis risk and identifies a major role for the interleukin (IL)-23 and IL-1 cytokine pathways in disease susceptibility.

Significance of clinical evaluation of the metacarpophalangeal joint in relation to synovial/bone pathology in rheumatoid and psoriatic arthritis detected by magnetic resonance imaging.

OBJECTIVE: Rheumatologists base many clinical decisions regarding the management of inflammatory joint diseases on joint counts performed at clinic. We investigated the reliability and accuracy of physically examining the metacarpophalangeal (MCP) joints to detect inflammatory synovitis using magnetic resonance imaging (MRI) as the gold standard. METHODS: MCP joints 2 to 5 in both hands of 5 patients with rheumatoid arthritis (RA) and 5 with psoriatic arthritis (PsA) were assessed by 5 independent examiners for joint-line swelling (visually and by palpation); joint-line tenderness by palpation (tender joint count, TJC) and stress pain; and by MRI (1.5 Tesla superconducting magnet). Interrater reliability was assessed using kappa statistics, and agreement between examination and corresponding MRI assessment was assessed by Fisher's exact tests (p < 0.05 considered statistically significant). RESULTS: Interrater agreement was highest for visual assessment of swelling (kappa = 0.55-0.63), slight-fair for assessment of swelling by palpation (kappa = 0.19-0.41), and moderate (kappa = 0.41-0.58) for assessment of joint tenderness. In patients with RA, TJC, stress pain, and visual swelling assessment were strongly associated with MRI evaluation of synovitis. Visual swelling assessment demonstrated high specificity (> 0.8) and positive predictive value (= 0.8). For PsA, significant associations exist between TJC and MRI synovitis scores (p < 0.01) and stress pain and MRI edema scores (p < 0.04). Assessment of swelling by palpation was not significantly associated with synovitis or edema as determined by MRI in RA or PsA (p = 0.54-1.0). CONCLUSION: In inflammatory arthritis, disease activity in MCP joints can be reliably assessed at the bedside by examining for joint-line tenderness (TJC) and visual inspection for swelling. Clinical assessment may have to be complemented by other methods for evaluating disease activity in the joint, such as MRI, particularly in patients with PsA.

The assessment of ankylosing spondylitis in clinical practice.

Ankylosing Spondylitis (AS) is a chronic inflammatory arthritis that predominantly affects the axial skeleton in adolescent patients causing spinal pain and stiffness. There is a marked delay, on average 8 years, between onset of disease symptoms and clinical diagnosis. The distinction between the symptoms of mechanical and inflammatory back pain remains one of the main contributing factors for the delay in diagnosis. Several classification criteria exist to aid the diagnosis of AS, but their accuracy is poor. The Ankylosing Spondylitis Assessment Study group (ASAS) has defined a core set of domains for clinical outcome measurement in AS in order to assess the disease process in individual patients and to identify those with rapidly progressive disease. New therapies, such as the tumor necrosis factor (TNF) inhibitors, have transformed the treatment paradigm in AS, especially for those patients with aggressive disease. Thus, the definition of both patient selection criteria for these agents and the development of clinical methods to assess response to therapy have become a priority. This Review focuses on measuring the degree of disease activity, function and damage in patients with AS in an ambulatory care setting, and the assessment of suitability of various outcome measures for monitoring response to treatment with TNF inhibitors.

International spondyloarthritis interobserver reliability exercise--the INSPIRE study: I. Assessment of spinal measures.

OBJECTIVE: To determine whether the axial measures used in primary ankylosing spondylitis (AS) were reproducible for both AS and psoriatic arthritis (PsA) with axial disease. METHODS: A group of 20 rheumatologists from 11 countries with expertise in spondyloarthritis (SpA) met for a combined physical examination exercise to assess 10 patients with PsA with axial involvement (9 men, 1 woman, mean age 52 yrs, mean disease duration 17 yrs) and 9 AS patients (7 men, 2 women, mean age 38 yrs, mean disease duration 16 yrs). A modified Latin-square design was used. Measures included were occiput to wall, tragus to wall, cervical rotation, chest expansion, lateral spinal bending, modified Schober, and hip mobility. Data were analyzed using intraclass correlation coefficients (ICC) adjusted for order of measurements. RESULTS: The majority of the variance was contributed by the patients. There was no order effect. Observer effect was noted especially for chest expansion for both AS and PsA patients, and for the modified Schober in PsA. The ICC demonstrated very good to excellent agreement for most measures for both AS and PsA. Chest expansion provided only moderate agreement for AS and PsA. CONCLUSION: Overall, measures of spinal mobility used in primary AS perform well with respect to interobserver reliability, and are equally reproducible when applied to PsA patients with axial involvement. Thus, these measures should now be evaluated in therapeutic trials of patients with PsA to determine sensitivity to change and concordance with other measures of structural damage.

International spondyloarthritis interobserver reliability exercise--the INSPIRE study: II. Assessment of peripheral joints, enthesitis, and dactylitis.

OBJECTIVE: To determine whether the assessments of peripheral joints and enthesitis were reproducible for both AS and PsA with axial disease, and whether dactylitis assessment is reproducible in patients with PsA. METHODS: A group of 20 rheumatologists from 11 countries with expertise in spondyloarthritis (SpA) met for a combined physical examination exercise to assess 10 patients with PsA with axial involvement (9 men, 1 woman, mean age 52 yrs, disease duration 17 yrs) and 9 patients with AS (7 men, 2 women, mean age 38 yrs, disease duration 16 yrs). A modified Latin-square design that enabled assessment of patient, assessor, and order effect was used. Measures included were number of tender and swollen joints, presence of enthesitis using 6 different indices, and dactylitis score. Data were analyzed using intraclass correlation (ICC) adjusted for order of measurements. RESULTS: The majority of the variance was contributed by the patients. There was no order effect. The assessment of tender joints (ICC 0.69) was more reliable than the assessment of swollen joints (ICC 0.54). Moreover, there was better agreement in patients with PsA (ICC 0.78) than in patients with AS (ICC 0.62). There was excellent agreement on the number of active enthesitis sites (ICC 0.86). All the enthesitis indices provided substantial to excellent agreement among observers. Agreement for the dactylitis score was substantial (ICC 0.70). CONCLUSION: The assessment of peripheral joints is more reliable in patients with PsA. Enthesitis instruments can be used reliably in patients with AS and patients with PsA with spinal involvement. The Leeds dactylitis instrument functions well in PsA.

Juvenile-onset ankylosing spondylitis is associated with worse functional outcomes than adult-onset ankylosing spondylitis.

OBJECTIVE: To compare functional outcome of patients with juvenile-onset ankylosing spondylitis (JoAS; defined as AS with symptom onset before 16 years of age) with that of patients with adult-onset AS (AoAS) and to identify variables associated with a poor functional outcome of JoAS. METHODS: A cross-sectional study was performed of 326 JoAS patients who participated in a postal survey conducted by the Spondylitis Association of America. This cohort was compared with 2,021 AoAS patients who participated in the same survey. Simple and multiple logistic regression analyses were performed to identify differences with respect to clinical features, demographic features, and functional outcome (defined by the Bath Ankylosing Spondylitis Functional Index [BASFI]) between the 2 groups. A validation cohort of 255 AS patients was also surveyed. RESULTS: The mean +/- SD BASFI score (controlled for disease duration) for JoAS was 51.3 +/- 1.5 compared with 46.4 +/- 0.6 for AoAS (P < 0.0001). Multiple logistic regression identified only age (P < 0.0001) and income status (P < 0.0001) as factors associated with functional impairment. CONCLUSION: It appears that JoAS is a progressive disease and is associated with significant delay in diagnosis and worse functional outcome compared with AoAS. Furthermore, women do worse than men with JoAS. This would argue for the importance of early diagnosis and treatment of AS, particularly in the subgroup of patients with JoAS.

Spondyloarthritis Research Consortium of Canada magnetic resonance imaging index for assessment of spinal inflammation in ankylosing spondylitis.

OBJECTIVE: To develop a feasible magnetic resonance imaging (MRI)-based scoring system for spinal inflammation in patients with spondylarthropathy that requires minimal scan time, does not require contrast enhancement, evaluates the extent of lesions in 3 dimensional planes, and limits the number of vertebral levels that are scored because MRI demonstrates characteristic inflammatory lesions in the spine of patients with ankylosing spondylitis (AS) prior to the development of typical features on plain radiographic. METHODS: Our scoring method was based entirely on the assessment of increased signal denoting bone marrow edema on T2-weighted STIR sequences. Blinded MRI films were assessed in random order at 2 sites by 3 blinded readers at each of the 2 sites (the Universities of Alberta and Toronto). Intra- and interreader reliability was assessed by intraclass correlation coefficient. The 24-week response of patients with AS randomized to infliximab:placebo (8:3) was assessed by effect size and standardized response mean. RESULTS: An initial analysis of all discovertebral units (DVUs) in the spine of 11 patients demonstrated a mean of 3.2 (95% confidence interval 3.2, 5.2) affected units, while limiting the scoring to a maximum of 6 units captured most of the affected units. We scanned 11 patients with AS with clinically active disease and 20 additional patients randomized to a 24-week trial of either infliximab or placebo. Intraobserver reproducibility for the 6-DVU STIR score ranged from 0.93 to 0.98 (P < 0.0001). Interobserver reproducibility of scores by readers from both sites was 0.79 (P < 0.0001) for status score and 0.82 (P < 0.0001) for change score. Analysis of pretreatment and posttreatment scores for all 20 patients randomized to infliximab/placebo showed a large degree of responsiveness (standardized response mean = 0.87). Reproducibility and responsiveness were only slightly improved by using contrast enhancement with gadolinium diethylenetriaminepentaacetic acid. CONCLUSION: The Spondyloarthritis Research Consortium of Canada MRI index is a feasible, reproducible, and responsive index for measuring spinal inflammation in AS.

Cartilage biomarkers in ankylosing spondylitis: relationship to clinical variables and treatment response.

OBJECTIVE: Ankylosing spondylitis (AS) is a progressive disease in which chronic inflammation can lead to extensive new bone formation throughout the spine. At present, few measures of the activity or extent of the disease are available. In this study, we sought to determine whether markers of cartilage synthesis and degradation could provide such quantitative measures. METHODS: Serum samples from 23 patients receiving infliximab treatment for AS were obtained at baseline and at weeks 2, 6, 14, and 22. Patients were stratified with respect to joint involvement and baseline levels of inflammatory markers, and responders were defined according to the Assessments in Ankylosing Spondylitis 20% criteria. Serial measurements of interferon-gamma, tumor necrosis factor alpha, transforming growth factor beta (TGFbeta), interleukin-10 (IL-10), and IL-1 were done at each time point. The following biomarkers were measured by enzyme-linked immunosorbent assay: the proteoglycan aggrecan 846 epitope, a marker of cartilage turnover; C-propeptide of type II collagen (CPII), a biosynthesis marker; and the Col2-3/4(long mono) (C2C) and Col2-3/4(short) (C1-2C) neoepitopes, reflecting collagen cleavage of type II collagen and type I/type II collagen, respectively. RESULTS: At baseline, patients with AS demonstrated significant elevations in serum levels of CPII, the 846 epitope, and the CPII-to-C2C (CPII:C2C) ratio (but not C2C or C1-2C) compared with normal controls. Of the biomarkers examined, only CPII:C2C showed a correlation with the C-reactive protein (CRP) level. Among the biomarker-cytokine relationships, TGFbeta demonstrated a trend toward a positive correlation with the 846 epitope. CONCLUSION: In AS, elevated serum levels of CPII and the 846 epitope may be related to biosynthetic turnover of hyaline cartilage and the intervertebral discs but may also reflect progressive bone formation as a result of endochondral ossification. The correlation of the CPII:C2C ratio with CRP suggests that the CPII:C2C ratio might prove to be a useful marker of disease activity in AS.

Interleukin 1 and nuclear factor-kappaB polymorphisms in ankylosing spondylitis in Canada and Korea.

OBJECTIVE: The interleukin 1alpha and 1beta (IL-1alpha, IL-1beta) are potent mediators of inflammation and immunity. IL-1 receptor antagonist (IL-1Ra) is a protein that binds to IL-1 receptors and competitively inhibits the binding of IL-1alpha and IL-1beta. There are reports of IL-1 complex gene polymorphisms in ankylosing spondylitis (AS), but the results have been inconsistent. NFKB1 encodes the genes for the p50 and p101 nuclear factor-kappaB (NF-kappaB) isoforms, which are recognized as critical to inflammatory disease. To date there have been no reports examining an association between NFKB1 and AS. We investigated polymorphisms of IL-1 complex and NF-kappaB1 with 2 genetically and geographically different populations. METHODS: Subjects with AS satisfied modified New York criteria for AS. Healthy controls were recruited at each respective site. Subjects with AS were genotyped for the following: IL-1alpha-889 single nucleotide polymorphism (SNP); IL-1beta +3953 SNP; IL-1Ra (86 base pair variable number tandem repeat within intron 2); and NFKB1 (-94 insertion/deletion polymorphism). RESULTS: In total, 205 subjects with AS and 200 controls from Seoul, Korea, and 68 subjects with AS and 164 controls from Toronto, Canada, were genotyped for the IL-1alpha and IL-1beta polymorphisms and 115 controls for the IL-1Ra and NF-kappaB polymorphisms. There were no differences of IL-1alpha, IL-1beta, IL-1Ra, and NF-kappaB polymorphisms between AS patients and controls in these populations. CONCLUSION: Our analysis of these SNP in the IL-1 complex and NF-kappaB genes does not support a major role for either in AS susceptibility in the Seoul and Toronto populations.

Spondyloarthritis research Consortium of Canada magnetic resonance imaging index for assessment of sacroiliac joint inflammation in ankylosing spondylitis.

OBJECTIVE: To develop a feasible magnetic resonance imaging (MRI)-based scoring system for sacroiliac joint inflammation in patients with ankylosing spondylitis (AS) that requires minimal scan time, does not require contrast enhancement, evaluates lesions separately at each articular surface, and limits the number of sacroiliac images that are scored. METHODS: A scoring method based on the assessment of increased signal denoting bone marrow edema on T2-weighted STIR sequences was used. MRI films were assessed blindly in random order at 2 sites by multiple readers. Intra- and interreader reliability was assessed by intraclass correlation coefficient (ICC); the 24-week response of patients with AS randomized to placebo:infliximab (3:8) was assessed by effect size and standardized response mean. The reliability and responsiveness of the scoring method were compared for STIR and gadolinium diethylenetriaminepentaacetic (Gd-DTPA)-enhanced MRI sequences. RESULTS: We scanned 11 patients with AS with clinically active disease and 11 additional patients randomized to the trial of infliximab therapy. ICC for total sacroiliac joint STIR score ranged from 0.90 to 0.98 (P < 0.00001) and interobserver ICC for combined readers from the 2 sites was 0.84 (P < 0.0001). ICC for change scores was lower for STIR (ICC 0.53) than for Gd-DTPA-enhanced sequences (ICC 0.79). Responsiveness was poor, although fusion was evident in one-third of patients who received treatment (placebo:infliximab) and inflammation scores were low. CONCLUSION: The Spondyloarthritis Research Consortium of Canada MRI index is a feasible and reproducible index for measuring sacroiliac joint inflammation in patients with AS.

Recent advances in the treatment of the spondyloarthropathies.

PURPOSE OF REVIEW: Recently, there has been renewed interest in the spondyloarthropathy family of chronic inflammatory rheumatic conditions, which has been fueled to a large extent by the biologic era. Over the period of the past 2 years in particular, there have been several notable advances. First, there have been a number of large, high-quality randomized controlled trials evaluating the tumor necrosis factor (TNF) blockers and conservative treatments such as physiotherapy and nonsteroidal anti-inflammatory drugs for use in spondyloarthropathy. This has paved the way for the development of better tools to assess outcome in these patients both in daily practice and in the context of clinical trials. This review uses a systematic approach to outline the most recent (within the last 2 years) and the most pertinent advances in the treatments of the spondyloarthropathies, with particular emphasis on ankylosing spondylitis and psoriatic arthritis. RECENT FINDINGS: Supervised group exercise programs maintain flexibility and posture in patients with ankylosing spondylitis, and spa therapy is a cost-effective treatment option in ankylosing spondylitis. Nonsteroidal anti-inflammatory drugs have a role in symptom modification and, more importantly, may prevent structural disease progression in patients with ankylosing spondylitis when administered continuously at a fixed dose. TNF blockers have been evaluated in a number of randomized controlled trials in ankylosing spondylitis and psoriatic arthritis and have been demonstrated to be safe and effective in the short-term management of these diseases. Longer-term trials are awaited with radiographic outcomes to comment on their disease-modifying properties and their long-term safety and efficacy profiles. SUMMARY: There has been renewed interest in the spondyloarthropathy family of disorders, with an explosion in the number of trials evaluating outcome with the TNF blockers. To date, no cure has been found for the disease, but these agents are emerging as the best therapeutic option available for patients with ankylosing spondylitis and psoriatic arthritis to date.