Radiographic Progression In Ankylosing Spondylitis Research Articles

DNA methylation of DKK-1 may correlate with pathological bone formation in ankylosing spondylitis.

To investigate DNA methylation (DNAm) status of dickkopf-associated protein 1 (DKK-1) in ossified hip capsule synovium and serum among patients with ankylosing spondylitis (AS). Western blot was applied to detect the level of DKK-1 protein expression in hip joint capsule tissues from four patients with AS as well as four patients with femoral neck fracture (FNF) caused by trauma as control. DKK-1 gene promoter methylation (GPM) was examined by methylation-specific polymerase chain reaction. Reverse transcription-polymerase chain reaction was performed to examine the messenger RNA (mRNA) levels of DKK-1, β-catenin, and Wnt3a in both tissue and serum. The DNAm status of serum DKK-1 was measured among 36 patients with AS and syndesmophytes (AS + syndesmophytes group), 40 patients with AS but no syndesmophyte (AS group), and 42 healthy individuals (control group). Also, the serum levels of DKK-1 were measured by enzyme-linked immunosorbent assay. The modified New York criteria (mNYC) together with the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) were adopted to examine the radiographic progression of AS. The receiver operating characteristic (ROC) curve was applied to investigate the diagnostic value of the methylation rate of DKK-1 with regard to radiographic progression. The expressions of DKK-1 protein and mRNA in hip joint capsule tissues of AS patients were significantly lower, while DKK-1 GPM rate, β-catenin mRNA, and Wnt3a mRNA were markedly higher when compared with FNF group. For serum samples, the DKK-1 methylation rate was significantly higher in AS+ syndesmophytes group in contrast to AS group and healthy controls. Serum levels of DKK-1 protein and mRNA in AS with syndesmophytes group were markedly decreased, while β-catenin mRNA and Wnt3a mRNA expressions were significantly increased than AS with no syndesmophyte group and the healthy control group. AS patients in Grade 4 showed a significantly higher serum DKK-1 GPM rate than those in Grade 3 based on mNYC. Serum DKK-1 GPM level was markedly and positively correlated with mSASSS. Serum levels of DKK-1 in AS+ syndesmophytes group were markedly lower compared with AS but no syndesmophyte group and healthy controls. ROC curve analysis indicated that serum DKK-1 methylation rate serves as a decent indicator for AS radiographic progression. DNAm of DKK-1 may correlate with pathological bone formation in AS, which may provide new strategies for the treatment of AS abnormal bone formation.

Prostaglandin E2/EP4 axis is upregulated in Spondyloarthritis and contributes to radiographic progression

Ankylosing spondylitis (AS) is an inflammatory disease leading to spine ankylosis; however, the mechanisms behind new bone formation are still not fully understood. Single Nucleotide Polymorphisms (SNPs) in PTGER4, encoding for the receptor EP4 of prostaglandin E2 (PGE2), are associated with AS. Since the PGE2-EP4 axis participates in inflammation and bone metabolism, this work aims at investigating the influence of the prostaglandin-E2 axis on radiographic progression in AS.In 185 AS (97 progressors), baseline serum PGE2 predicted progression, and PTGER4 SNP rs6896969 was more frequent in progressors. Increased EP4/PTGER4 expression was observed in AS circulating immune cells, synovial tissue, and bone marrow. CD14highEP4 + cells frequency correlated with disease activity, and when monocytes were cocultured with mesenchymal stem cells, the PGE2/EP4 axis induced bone formation.In conclusion, the Prostaglandin E2 axis is involved in bone remodelling and may contribute to the radiographic progression in AS due to genetic and environmental upregulation.

Platelet-Derived Growth Factor B Is a Key Element in the Pathological Bone Formation of Ankylosing Spondylitis.

Enthesophyte formation plays a crucial role in the development of spinal ankylosis in ankylosing spondylitis (AS). We aimed to investigate the role of platelet-derived growth factor B (PDGFB) in enthesophyte formation of AS using in vitro and in vivo models and to determine the association between PDGFB and spinal progression in AS. Serum PDGFB levels were measured in AS patients and healthy controls (HC). Human entheseal tissues attached to facet joints or spinous processes were harvested at the time of surgery and investigated for bone-forming activity. The impact of a pharmacological agonist and antagonist of platelet-derived growth factor B receptor (PDGFRB) were investigated respectively in curdlan-treated SKG mice. PDGFB levels were elevated in AS sera and correlated with radiographic progression of AS in the spine. Mature osteoclasts secreting PDGFB proteins were increased in the AS group compared with HC and were observed in bony ankylosis tissues of AS. Expression of PDGFRB was significantly elevated in the spinous enthesis and facet joints of AS compared with controls. Moreover, recombinant PDGFB treatment accelerated bone mineralization of enthesis cells, which was pronounced in AS, whereas PDGFRB inhibition efficiently reduced the PDGFB-induced bone mineralization. Also, PDGFRB inhibition attenuated the severity of arthritis and enthesophyte formation at the joints of curdlan-treated SKG mice. This study suggests that regulating PDGFB/PDGFRB signaling could be a novel therapeutic strategy to block key pathophysiological processes of AS. © 2022 American Society for Bone and Mineral Research (ASBMR).

Conventional disease-modifying antirheumatic drugs therapy may not slow spinal radiographic progression in ankylosing spondylitis: results from an 18-year longitudinal dataset.

Objectives:The clinical benefit of conventional disease-modifying antirheumatic drugs (cDMARDs) for treating ankylosing spondylitis (AS) is generally limited to improvements in peripheral arthritis. However, cDMARDs could be conditionally considered as alternatives to established drugs for improving axial manifestations in exceptional circumstances. However, there are few studies of the impact of cDMARDs on radiographic progression outcomes. Therefore, we investigated the effectiveness of cDMARDs on radiographic progression in AS.Methods:Among 1280 AS patients at a single hospital from 2000 to 2018, 301 who had been treated with sulfasalazine (SSZ) or methotrexate (MTX) were enrolled. For each patient, the entire follow-up period was split into 1-year intervals. Each interval was classified as either an “on-cDMARD” interval, which was a period of treatment with SSZ alone, MTX alone, or a combination of SSZ and MTX, or an “off-cDMARD” interval, which was a period without cDMARD treatment. Radiographic progression was scored using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). The relationship between cDMARD use and radiographic progression within the intervals, defined as the rate of mSASSS progression, was investigated using linear models with adjustment for potential confounding covariates and for clustering among observations from the same patient.Results:The 732 on-cDMARD intervals and 1027 off-cDMARD intervals were obtained from enrolled patients. In multivariable regression analysis, there was no significant association between cDMARDs and the rate of mSASSS progression (β = −0.081, p = 0.418). The mean adjusted mSASSS change per year was 0.610 from on-cDMARD intervals and 0.691 from off-cDMARD intervals.Conclusion:Treatment with cDMARDs may not reduce radiographic progression in AS patients.

HLA-B27-mediated activation of TNAP phosphatase promotes pathogenic syndesmophyte formation in ankylosing spondylitis.

Ankylosing spondylitis (AS) is a type of axial inflammation. Over time, some patients develop spinal ankylosis and permanent disability; however, current treatment strategies cannot arrest syndesmophyte formation completely. Here, we used mesenchymal stem cells (MSCs) from AS patients (AS MSCs) within the enthesis involved in spinal ankylosis to delineate that the HLA-B27-mediated spliced X-box-binding protein 1 (sXBP1)/retinoic acid receptor-β (RARB)/tissue-nonspecific alkaline phosphatase (TNAP) axis accelerated the mineralization of AS MSCs, which was independent of Runt-related transcription factor 2 (Runx2). An animal model mimicking AS pathological bony appositions was established by implantation of AS MSCs into the lumbar spine of NOD-SCID mice. We found that TNAP inhibitors, including levamisole and pamidronate, inhibited AS MSC mineralization in vitro and blocked bony appositions in vivo. Furthermore, we demonstrated that the serum bone-specific TNAP (BAP) level was a potential prognostic biomarker to predict AS patients with a high risk for radiographic progression. Our study highlights the importance of the HLA-B27-mediated activation of the sXBP1/RARB/TNAP axis in AS syndesmophyte pathogenesis and provides a new strategy for the diagnosis and prevention of radiographic progression of AS.

Modified stoke ankylosing spondylitis spinal score as an outcome measure to assess the impact of treatment on structural progression in ankylosing spondylitis.

In ankylosing spondylitis (AS), structural damage that occurs as a result of syndesmophyte formation and ankylosis of the vertebral column is irreversible. Structural damage is currently assessed by conventional radiography and scoring systems that reliably assess radiographic structural damage are needed to capture the differential effects of drugs on structural damage progression. The validity of the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) as a primary outcome measure in evaluating the effect of AS treatments on radiographic progression rates was assessed in this review. The mSASSS has not been used, to date, as a primary outcome measure in a prospective randomized controlled clinical trial of biologic therapy in AS. This review of the medical literature confirmed that the mSASSS is the most validated and widely used method for assessing radiographic progression in AS, correlating with worsening measures of disease signs and symptoms, spinal mobility and physical function, with a 2-year interval being required to ensure sufficient sensitivity to change.

The Paradox of Bone Formation and Bone Loss in Ankylosing Spondylitis: Evolving New Concepts of Bone Formation and Future Trends in Management.

The purpose of the study is to briefly review the molecular mechanisms that leads to structural damage in ankylosing spondylitis (AS), defined as new bone formation resulting in complete or incomplete ankylosis of the spine, and the impact of treatment with biologics to retard this process. The understanding of molecular mechanisms leading to new bone formation in AS has significantly improved but is still incomplete. Availability of biologics has greatly enhanced the treatment of patients with AS, but its impact on slowing the structural damage is still a matter of debate, although a few observational studies have shown that long term use of TNF-α blockers may slow radiographic progression. The availability of newer biologics targeting IL-17/1L23 has shown some promising results in slowing radiographic progression in AS. Although the availability of TNF-inhibitors has greatly enhanced the treatment options for patients with AS, their impact on slowing the structural damage is still not clearly established. However, preliminary results using newer biologics targeting IL-17/1L23 axis are more encouraging but longer follow-up is needed.

Effects of tumor necrosis factor-α inhibitors on new bone formation in ankylosing spondylitis

ObjectivesTo better understand the effect of TNF-α inhibitors (TNFi) on new bone formation in ankylosing spondylitis (AS) patients. MethodsWe systematically searched the articles in EMBASE and PubMed. ResultsFifteen articles were enrolled. In all the 9 TNFi-treated cohorts, the vertebral corners with inflammatory lesions at baseline were at higher risk to develop new syndesmophytes than those without inflammatory lesions, although a few syndesmophytes also developed at the vertebral corners without inflammatory lesions at baseline. The advanced inflammatory lesions including fat deposition on baseline MRI showed a higher risk for syndesmophyte formation than the acute inflammatory lesions. Because the number of analyzed vertebral corners were too small, it might not be true that new syndesmophytes developed more frequently at the corners with inflammatory lesions completely resolved than those with persistent inflammation after TNFi treatment. Four studies with 2-year follow-up revealed null effect of TNFi on radiographic progression compared with historical controls with lower disease activity, and 3 studies with ≥4-year follow-up proved inhibitory effect of TNFi on new bone formation in AS patients. Patients with a delay of >10 years in starting TNFi therapy were more likely to experience radiographic progression as compared to those who started earlier. ConclusionsIn TNFi treated AS patients, baseline inflammation is linked with syndesmophyte development. An earlier initiation of TNFi therapy may slow the radiographic progression in AS, and TNFi may lose its benefit of retarding new bone formation at advanced stage of AS especially after the focal fat infiltration or syndesmophyte formation.

Decreased local and systematic matrix Gla protein (MGP) expression and its link to radiographic progression in ankylosing spondylitis patients.

Decreased serum levels of uncarboxylated matrix Gla-protein (ucMGP) have been detected in Ankylosing Spondylitis (AS) patients. The current study was to investigate the expression of MGP in AS tissues as well as the relationship between serum ucMGP (an inactive form of MGP) levels and radiographic severity in AS patients. Local MGP expression were assessed by Western blot and RT-PCR in hip synovial tissues from patients with AS and control subjects. In addition, the serum level of ucMGP was assessed by enzyme-linked immunosorbent assay in 68 healthy subjects and 62 patients with AS. The radiographic progression of AS was classified according to the radiographic events of modified New York Criteria for sacroiliac joint evaluation and modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) system for spine assessment. MGP expression was downregulated in AS patients compared to controls in hip tissues. Decreased levels of ucMGP in serum were found in AS patients compared with healthy controls. ucMGP levels in serum of AS patients were significantly negatively correlated with the disease radiographic severity evaluated by modified New York grading criteria (r = -0.293, p = 0.045) and mSASSS system (r = -0.361, p = 0.03). MGP expression is impaired in patients with AS. A low serum level of ucMGP in the setting of AS is linked to increased structural damage, emphasizing the role of MGP in the suppression of new bone formation.

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

Background and ObjectNearly 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.MethodsA 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.ResultsWe 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.ConclusionThis 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.

The effect of tumor necrosis factor-blockade on new bone formation in ankylosing spondylitis: what is the evidence?

Treatment of ankylosing spondylitis (AS) has seen remarkable advances since the introduction of therapies targeting tumor necrosis factor-alfa (TNFα). In addition to the excellent disease control achieved by these agents, recent evidence points to a possible disease-modifying potential of the drug. This novel finding can potentially change the landscape of AS treatment. In this review, existing knowledge on mechanisms of new bone formation and ways to quantify and prevent progression are discussed. Evidence for disease-modifying potential of NSAIDs, short-term and long-term studies on TNFα inhibitors, and AS progression are discussed. A follow-up of more than 4 years is required to study disease modification in AS. Early and long-term therapy with tumor necrosis factor inhibitors appears to slow radiographic progression in AS. New evidence for a disease-modifying potential of tumor necrosis factor inhibitors can change the AS treatment paradigm. http://links.lww.com/COR/A16.

Serum functional dickkopf-1 levels are inversely correlated with radiographic severity of ankylosing spondylitis.

Dickkopf-1 (DKK-1) has been proved dysfunctional in ankylosing spondylitis (AS), and decreased serum functional DKK-1 levels have been identified to be decreased in AS patients. This study aims to examine the relation of binding (functional) DKK-1 levels in serum with the radiographic severity of AS. Total Dkk1 levels were assessed by commercial sandwich enzyme-linked immunosorbent assay and functional DKK-1 levels of serum were measured using functional enzyme-linked immunosorbent assay method in 84 patients with AS and 79 healthy controls. The radiographic progression of AS was classified according to the radiographic events of modified New York Criteria for sacroiliac joints evaluation and modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) system for spine assessment. No significant difference was seen between AS patients and healthy controls for total Dkk1 levels (p = 0.273). Decreased levels of functional DKK-1 in serum were found in AS patients compared with healthy controls 17.24 (1.24-11.15) vs. 9.15 (5.33-13.35) pg/mL, p < 0.001]. Functional DKK-1 levels in serum of AS patients were significantly associated with the disease radiographic severity evaluated by modified New York grading criteria (r = -0.236, p = 0.04) and mSASSS system (r = -0.389, p = 0.025). Serum functional DKK-1 levels showed an independent and negative correlation with radiographic severity of the disease in patients with AS. Functional DKK-1 in serum might serve as a potential biomarker for reflecting the progression of ankylosing spondylitis.

Evolution of radiographic damage in ankylosing spondylitis: a 12 year prospective follow-up of the OASIS study

ObjectivesTo describe the evolution of radiographic abnormalities of the spine in patients with ankylosing spondylitis (AS).MethodsPatients with AS were followed prospectively with 2 yearly radiographs for 12 years. The modified...

FRI0468 Socioeconomic status predicts radiographic progression in ankylosing spondylitis

BackgroundLower socioeconomic status (SES) is associated with worse outcomes in several rheumatic diseases. In Ankylosing Spondylitis (AS), SES has been associated with poorer functional outcomes and certain physical activities with...

HLA-B27 homozygosity has no influence on radiographic damage in ankylosing spondylitis: Observation Study of Korean spondyloArthropathy Registry (OSKAR) data

ObjectivesTo evaluate the influence of homozygosity for HLA-B27 on the radiographic damage in ankylosing spondylitis (AS). MethodsA total of 368 AS patients with positive HLA-B27 status from the Observation Study of Korean spondyloArthropathy Registry (OSKAR) cohort were recruited for this study. HLA-B27 positive patients out of all AS patients were assessed for whether they had homozygosity or heterozygosity for HLA-B27. First, all data were stratified in relation to the carrier state of positive HLA-B27 for cross-sectional survey. Then we compared the radiographic damage score between groups. Second, we evaluated collected clinical and radiographic parameters at two different time points. Then we compared radiographic progression between groups. To use the mSASSS, cervical and lumbar spinal radiographs were examined by two experienced bone and joint radiologists (S. Lee, K.B. Joo). ResultsThe agreement between the two readers regarding mSASSS was very good: ICC coefficient 0.70 (95% CI 0.60–0.81). The mean age (SD) of the AS patients was 37.0 (9.2) years, and the mean disease duration (SD) was 15.6 (9.1) years. Of these patients, 34.5% (127 patients) had HLA-B27 homozygosity. The mean mSASSS unit (SEM) was not significantly different between groups (homozygosity 28.57±4.12 vs heterozygosity 23.34±3.44, P=0.344) on cross-sectional survey. When it comes to radiographic progression between groups over 5years, there was no significant difference in spite of adjusting for confounding variable (homozygosity 4.98±0.98 vs heterozygosity 4.21±0.82, P=0.562). ConclusionThe carrier state of positive HLA-B27 plays no role in determining the radiographic progression in AS.

Imaging of axial spondyloarthritis including ankylosing spondylitis

New bone formation of the vertebral column is pathognomonic for ankylosing spondylitis (AS), while acute and/or chronic changes in the sacroiliac joints are relevant for diagnosis.The ‘gold standard’ for assessment...

Development of a radiographic scoring tool for ankylosing spondylitis only based on bone formation: Addition of the thoracic spine improves sensitivity to change

The modified Stokes Ankylosing Spondylitis Spinal Score (mSASSS) quantifies radiographic changes in the cervical spine (C-spine) and the lumbar spine (L-spine), but not in the thoracic spine (T-spine). Our objective was to study the contribution of the lower part of the T-spine to structural damage in patients with ankylosing spondylitis (AS). Radiographs of 80 AS patients obtained at baseline and after 2 years were scored by 2 readers using the mSASSS. In addition, changes in the lower T-spine (T10-T12) were quantified. On this basis, a new scoring tool was developed: the Radiographic Ankylosing Spondylitis Spinal Score (RASSS). The RASSS includes 2 changes: no scoring of erosions in order to confine the scoring to new bone formation, and no scoring of squaring in the C-spine for anatomic and feasibility reasons. The mean +/- SD change was 0.9 +/- 2.5 units using the mSASSS and 1.6 +/- 2.8 units using the RASSS (P < 0.001). Although the mSASSS identified new syndesmophytes in mean +/- SD 1.4 +/- 2.9 vertebral edges over 2 years, an additional 0.6 +/- 1.2 vertebral edges were seen in the lower T-spine. New syndesmophytes or ankylosis were found in 15 patients (21.4%; 95% confidence interval [95% CI] 13.1-32.4%) in the C-spine/L-spine and in 6 patients (8.6%; 95% CI 3.8-17.2%) in the T-spine alone. The reliability of the RASSS and the agreement between readers was excellent. The lower T-spine improves the sensitivity to change of scoring radiographic progression in AS. The tool developed in this study, the RASSS, showed better face and content validity than the mSASSS and was proven to be superior in the quantification of new bone formation in AS.

Unfair to Baboons

<h3>Objective.</h3> To describe the natural course of radiographic progression and to differentiate rates of progression in patients with ankylosing spondylitis (AS). <h3>Methods.</h3> Overall, 146 patients with AS who had never received anti-tumor necrosis factor therapy were analyzed in this retrospective cohort study. The main inclusion criterion was the availability of complete sets of cervical and lumbar radiographs from at least 2 timepoints within 6 years. Using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS), we quantified the structural changes and assessed different rates of radiographic progression based on development of new syndesmophytes/year. <h3>Results.</h3> The mean followup time was 3.8 ± 1.7 years (range 1–6) and the mean number of consecutive radiographs was 2.7 (range 2–6) per patient. The mean mSASSS change/year was 1.3 ± 2.5 units. Radiographic progression showed much variability, since 43% of patients showed a 4-fold greater rate of progression than the mean, and 23% had no progression. The data-based definition for “fast progression” was calculated as a change &gt; 5 mSASSS units or &gt; 2 new syndesmophytes; for “moderate progression” as change of 2.0–5.0 mSASSS units or &lt; 2 new syndesmophytes; and for “slow progression” as change of &lt; 2 mSASSS units or no more than 1 new syndesmophyte within 2 years. The only factor to predict future radiographic progression was the number of syndesmophytes at baseline. <h3>Conclusion.</h3> Radiographic progression in AS is rather variable and many patients show high rates of progression. On the basis of this retrospective dataset we propose to differentiate patients on an individual level according to their progression rates: patients with fast, moderate, and slow radiographic progression, assessed by counting new syndesmophytes. Predicting radiographic progression remains difficult; only the prevalence of syndesmophytes at baseline is predictive of future damage.