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Bone morphogenetic protein 6 polymorphisms are associated with radiographic progression in ankylosing spondylitis.

ABSTRACT: Nearly 25 genetic loci associated with susceptibility to ankylosing spondylitis (AS) have been identified by several large studies. However, there have been limited studies to identify the genes associated with radiographic severity of the disease. Thus we investigated which genes involved in bone formation pathways might be associated with radiographic severity in AS.A total of 417 Korean AS patients were classified into two groups based on the radiographic severity as defined by the modified Stoke' Ankylosing Spondylitis Spinal Score (mSASSS) system. Severe AS was defined by the presence of syndesmophytes and/or fusion in the lumbar or cervical spine (n = 195). Mild AS was defined by the absence of any syndesmophyte or fusion (n = 170). A total of 251 single nucleotide polymorphisms (SNPs) within 52 genes related to bone formation were selected and genotyped. Odds ratios (OR) and 95% confidence interval (95% CI) were analysed by multivariate logistic regression controlling for age at onset of symptoms, sex, disease duration, and smoking status as covariates.We identified new loci of bone morphogenetic protein 6 (BMP6) associated with radiographic severity in patients with AS that passed false discovery rate threshold. Two SNPs in BMP6 were significantly associated with radiologic severity [rs270378 (OR 1.97, p = 6.74 × 10(-4)) and rs1235192 [OR 1.92, p = 1.17 × 10(-3)]) adjusted by covariates.This is the first study to demonstrate that BMP6 is associated with radiographic severity in AS, supporting the role wingless-type like/BMP pathway on radiographic progression in AS.

SUBMITTER: Joo YB

PROVIDER: S-EPMC4133264 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Bone morphogenetic protein 6 polymorphisms are associated with radiographic progression in ankylosing spondylitis.

Joo Young Bin YB Bang So-Young SY Kim Tae-Hwan TH Shim Seung-Cheol SC Lee Seunghun S Joo Kyung Bin KB Kim Jong Heon JH Min Hye Joon HJ Rahman Proton P Inman Robert D RD

PloS one 20140814 8

<h4>Background and object</h4>Nearly 25 genetic loci associated with susceptibility to ankylosing spondylitis (AS) have been identified by several large studies. However, there have been limited studies to identify the genes associated with radiographic severity of the disease. Thus we investigated which genes involved in bone formation pathways might be associated with radiographic severity in AS.<h4>Methods</h4>A total of 417 Korean AS patients were classified into two groups based on the radi ...[more]

PMID: 25121767

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Project description:To study the effect of tumor necrosis factor ? (TNF?) inhibitors on progressive spinal damage in patients with ankylosing spondylitis (AS).All AS patients meeting the modified New York criteria who had been monitored prospectively and had at least 2 sets of spinal radiographs a minimum of 1.5 years apart were included in the study (n=334). The patients received standard therapy, which included nonsteroidal antiinflammatory drugs and TNF? inhibitors. Radiographic severity was assessed by the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Patients with a rate of AS progression that was ?1 mSASSS unit/year were considered progressors. Univariable and multivariable regression analyses were done. Propensity score matching and sensitivity analysis were performed. A zero-inflated negative binomial (ZINB) model was used to analyze the effect of TNF? inhibitors on the change in the mSASSS with varying followup periods. Potential confounders, such as disease activity (as assessed by the Bath Ankylosing Spondylitis Disease Activity Index), the erythrocyte sedimentation rate, C-reactive protein level, HLA-B27 positivity, sex, age at onset, smoking burden (number of pack-years), and baseline damage, were included in the model.TNF? inhibitor treatment was associated with a 50% reduction in the odds of progression, with an odds ratio (OR) of 0.52 (95% confidence interval [95% CI] 0.30-0.88, P=0.02). Patients with a delay of >10 years in starting therapy were more likely to experience progression as compared to those who started earlier (OR 2.4 [95% CI 1.09-5.3], P=0.03). In the ZINB model, the use of TNF? inhibitors significantly reduced disease progression when the gap between radiographs was >3.9 years. The protective effect of TNF? inhibitors was stronger after propensity score matching.Treatment with TNF? inhibitors appears to reduce radiographic progression in AS patients, especially with early initiation and with longer duration of followup.

Project description:ObjectiveThe aim of this study was to compare radiographic progression in patients with ankylosing spondylitis (AS) treated for up to 2 years with secukinumab (MEASURE 1) with a historical cohort of biologic-naïve patients treated with NSAIDs (ENRADAS).MethodsBaseline and 2-year lateral cervical and lumbar spine radiographs were independently evaluated using mSASSS by two readers, who were blinded to the chronology and cohort of the radiographs. The primary endpoint was the proportion of patients with no radiographic progression (mSASSS change ≤ 0 from baseline to year 2). The Primary Analysis Set included patients with baseline (≤ day 30) and post-baseline day 31-743 radiographs. Sensitivity analyses were performed to assess the robustness of the comparison between the two cohorts, as follows: Sensitivity Analysis Set 1 included all patients with baseline (≤ day 30) and year 2 (days 640-819) radiographs; Sensitivity Analysis Set 2 included all patients with baseline and post-baseline (> day 30) radiographs.ResultsA total of 168 patients (84%) from the MEASURE 1 cohort and 69 (57%) from the ENRADAS cohort qualified for the Primary Analysis Set. Over 2 years, the LS (SE) mean change from baseline in mSASSS for the primary analysis was 0.55 (0.139) for MEASURE 1 vs 0.89 (0.216) for ENRADAS (p = 0.1852). Mean changes from baseline in mSASSS were lower in MEASURE 1 vs ENRADAS for the primary and sensitivity analyses. The proportion of patients with no radiographic progression was consistently higher in the MEASURE 1 vs ENRADAS cohort across all cutoffs for no radiographic progression (change in mSASSS from baseline to year 2 of ≤ 0, ≤ 0.5, ≤ 1, and ≤ 2), but the differences were not statistically significant.ConclusionSecukinumab-treated patients demonstrated a numerical, but statistically non-significant, higher proportion of non-progressors and lower change in mSASSS over 2 years versus a cohort of biologic-naïve patients treated with NSAIDs.

Project description:Objective This study aimed to identify trajectories of radiographic progression of the spine over time and use them, along with associated clinical factors, to develop a prediction model for patients with ankylosing spondylitis (AS). Methods Data from the medical records of patients diagnosed with AS in a single center were extracted between 2001 and 2018. Modified Stoke Ankylosing Spondylitis Spinal Scores (mSASSS) were estimated from cervical and lumbar radiographs. Group-based trajectory modeling classified patients into trajectory subgroups using longitudinal mSASSS data. In multivariate analysis, significant clinical factors associated with trajectories were selected and used to develop a decision tree for prediction of radiographic progression. The most appropriate group for each patient was then predicted using decision tree analysis. Results We identified three trajectory classes: class 1 had a uniformly increasing slope of mSASSS, class 2 showed sustained low mSASSS, and class 3 showed little change in the slope of mSASSS but highest mSASSS from time of diagnosis to after progression. In multivariate analysis for predictive factors, female sex, younger age at diagnosis, lack of eye involvement, presence of peripheral joint involvement, and low baseline erythrocyte sedimentation rate (log) were significantly associated with class 2. Class 3 was significantly associated with male sex, older age at diagnosis, presence of ocular involvement, and lack of peripheral joint involvement when compared with class 1. Six clinical factors from multivariate analysis were used for the decision tree for classifying patients into three trajectories of radiographic progression. Conclusion We identified three patterns of radiographic progression over time and developed a decision tree based on clinical factors to classify patients according to their trajectories of radiographic progression. Clinically, this model holds promise for predicting prognosis in patients with AS.

Dataset Information

Bone morphogenetic protein 6 polymorphisms are associated with radiographic progression in ankylosing spondylitis.

Publications

Bone morphogenetic protein 6 polymorphisms are associated with radiographic progression in ankylosing spondylitis.

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