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.

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.

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.

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.

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.

The clinical assessment of patients with psoriatic arthritis: results of a reliability study of the spondyloarthritis research consortium of Canada.

OBJECTIVES: To evaluate whether rheumatologists experienced in psoriatic arthritis (PsA) assess peripheral and axial involvement in the same way and to consider core clinical measurements that should be included in clinical trials in PsA. METHODS: Ten patients with PsA, representing a broad range of joint inflammation, joint damage, and spinal involvement, were selected for the study. Each patient was examined by each of 10 rheumatologists, members of the Spondyloarthritis Research Consortium of Canada, according to a Latin Square design. Assessments included scoring actively inflamed joints and damaged joints, dactylitis, enthesitis, and spinal measurements. Variance components analyses were conducted for continuous measurements based on models with observer, patient, and order effects. Estimates of intraclass correlation coefficients and associated 95% confidence intervals were obtained. RESULTS: There was substantial reliability in the assessment of the number of actively inflamed joints and excellent agreement in the number of damaged joints. Only moderate agreement was found for the number of digits with dactylitis. There was excellent agreement among observers in the intermalleolar distance measurements, but there was not as good agreement in the other measurements of spinal mobility. There was good agreement among the observers in detecting plantar fasciitis, however, the other entheses did not fare as well. CONCLUSION: In this first multicenter study of the assessment of clinical evaluation of patients with PsA we found that the assessment of peripheral joint disease is reliable although training should be performed prior to initiation of drug trials or comparative studies in this disease. The assessment of back measurements in PsA and other spondyloarthritis requires further study.

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.