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1.  Fetuin-A is related to syndesmophytes in patients with ankylosing spondylitis: a case control study 
Clinics  2014;69(10):688-693.
New bone formation is one of the hallmark characteristics of ankylosing spondylitis, which is thereby associated with syndesmophytes. Fetuin-A is a molecule that is abundantly found in calcified tissues and it shows high affinity for calcium phosphate minerals and related compounds. Considering the role of fetuin-A in the regulation of calcified matrix metabolism, we compared the fetuin-A levels in ankylosing spondylitis patients with syndesmophytes with those in patients without syndesmophytes and in healthy controls. We also studied other biomarkers that are thought to be related to syndesmophytes.
Ninety-four patients (49 patients without syndesmophytes, 67.3% male, 40.7±8.7 years; 45 patients with syndesmophytes, 71.1% M, 43.9±9.9 years) and 68 healthy controls (44.2±10.6 years and 70.6% male) were included in this study. Syndesmophytes were assessed on the lateral radiographs of the cervical and lumbar spine. The serum levels of fetuin-A, dickkopf-1, sclerostin, IL-6, high-sensitivity C-reactive protein and bone morphogenetic protein-7 were measured with an enzyme-linked immunosorbent assay.
Patients with syndesmophytes had significantly higher levels of fetuin-A compared with patients without syndesmophytes and controls (1.16±0.13, 1.05±0.09 and 1.08±0.13 mg/ml, respectively). However, fetuin-A was not different between the patients without syndesmophytes and controls. Bone morphogenetic protein-7 was significantly lower; dickkopf-1 was significantly higher in patients with ankylosing spondylitis compared with controls. The sclerostin concentrations were not different between the groups. In regression analysis, fetuin-A was an independent, significant predictor of syndesmophytes.
Our results suggest that fetuin-A may a role in the pathogenesis of bony proliferation in ankylosing spondylitis.
PMCID: PMC4221327  PMID: 25518021
Ankylosing Spondylitis; Bone Formation; Fetuin-A; Dickkopf-1 Protein Human; Sclerostin Protein Human; Bone Morphogenetic Protein 7
2.  The relationship between inflammation and new bone formation in patients with ankylosing spondylitis 
Arthritis Research & Therapy  2008;10(5):R104.
Spinal inflammation as detected by magnetic resonance imaging and new bone formation as identified by conventional radiographs are characteristic of ankylosing spondylitis. Whether and how spondylitis and syndesmophyte formation are linked are unclear. Our objective was to investigate whether and how spinal inflammation are associated with new bone formation in ankylosing spondylitis.
Spinal magnetic resonance images and conventional radiographs from 39 ankylosing spondylitis patients treated with anti-tumour necrosis factor (anti-TNF) agents at baseline and after 2 years were analysed for syndesmophyte formation at vertebral edges with or without inflammatory lesions at baseline.
Overall, 922 vertebral edges at the cervical and lumbar spine were analysed. At baseline, the proportion of vertebral edges with and without inflammation (magnetic resonance imaging) that showed structural changes (conventional radiographs) was similar (in total, 16.6% of all vertebral edges in 71.4% of patients). From the perspective of syndesmophyte formation (n = 26, 2.9%) after 2 years, there were more vertebral edges without (62%) than with (38%) inflammation at baseline (P = 0.03). From the perspective of spinal inflammation at baseline (n = 153 vertebral edges), more syndesmophytes developed at vertebral edges with (6.5%) than without (2.1%) inflammation (P = 0.002, odds ratio 3.3, 95% confidence interval 1.5 to 7.4). Inflammation persisted in 31% of the initially inflamed vertebral edges (n = 132), and new lesions developed in 8% of the vertebral edges without inflammation at baseline (n = 410). From the perspective of spinal inflammation after 2 years (n = 72 vertebral edges), 5.6% of the vertebral edges showed syndesmophyte development in contrast to 1.9% of the vertebral edges with new syndesmophytes without inflammation (P = 0.06).
These findings obtained in patients treated with anti-TNF agents suggest linkage and some dissociation of inflammation and new bone formation in ankylosing spondylitis. Although syndesmophytes were also found to develop at sites where no inflammation had been seen by magnetic resonance imaging at baseline, it was more likely that syndesmophytes developed in inflamed vertebral edges. More effective suppression of spinal inflammation may be required to inhibit structural damage in ankylosing spondylitis.
PMCID: PMC2592781  PMID: 18761747
3.  Study of Bone Mineral Density in Patients with Ankylosing Spondylitis 
Introduction: Ankylosing spondylitis (AS) is an inflammatory rheumatic disease characterized by spine and sacroiliac joint involvement that mainly affects young male subjects. Bone Mineral Density (BMD) loss occurs in AS disease course. Bone loss in AS appears to be multifactorial and perhaps involves different mechanisms at different stages of disease. The disease typically affects young males and is associated with progressive functional impairment, increased work disability and decreased quality of life. Osteoporosis is frequent in AS and there is a close association of bone mineral density, bone metabolism and inflammatory activity. Osteoporosis is frequently associated with AS and BMD decreased predominantly in patients with active disease.
Aims & Objectives: The aim of the present study was to study bone mineral density in cases of Ankylosing Spondylitis (AS) in comparison to age and sex matched controls.
Material and Methods: The present study was conducted on 100 established cases of AS based on modified New York criteria and 150 controls healthy, age, race, socio-economic matched controls patients. The results were statistically analyzed.
Results: Hundred cases of AS were subjected to undergo BMD by Dual Energy X-ray Absorption (DEXA) scan of different age groups in cases 35.19± 8.23(min age 23- max age 67years) and controls 33.27±5.22(min age 22years - max age 44years) with height observed in cases is 169.67±6-87 and controls 170.99±7.16 with weight varied in cases 65.63±10.27 and controls 70.14±10.67.
Conclusion: Osteoporosis is a significant complication in ankylosing spondylitis and needs to be monitored and managed at the earliest. Significant osteoporosis can occur even in early disease. Osteoporosis of spine is much more prevalent than femur.BMD spine is still the most important site to define osteoporosis in ankylosing spondylitis. Rise in BMD in LS spine with duration, is not exclusive for subjects with radiologically evident syndesmophytes. Statistically, presence of syndesmophytes did not affect estimation of osteoporosis of spine.
PMCID: PMC3919376  PMID: 24551650
Ankylosing Spondylitis; Bone Mineral Density; Dual Energy x-ray Absorption
4.  Insight on Bone Morphogenetic Protein 7 in Ankylosing Spondylitis and its association with disease activity and radiographic damage 
Electronic Physician  2016;8(7):2670-2678.
Fusion of joints as well as intervertebral spaces by the formation of bony spurs appearing as syndesmophytes and osteophytes are the hallmark of spondyloarthropathies which accounts for disability. The aim of this study was to assess the serum level of bone morphogenetic protein (BMP)-7 in ankylosing spondylitis and its relationship with disease activity and the radiographic damage.
This longitudinal case control study was conducted in Ain Shams University Hospitals (Egypt). A total of 55 subjects were included in two case groups and one control group. Group I included 20 patients with Ankylosing Spondylitis (AS) assessed at baseline (defined as Ia and after 18 months defined as Ib). Group II included 20 patients with Rheumatoid Arthritis (RA) and Group III included 15 healthy subjects as controls. Patients with other forms of seronegative spondyloarthropathies, bone forming diseases were excluded from the study. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Bath Ankylosing Spondylitis Metrology Index (BASMI) were used to assess disease activity in AS patients. RA disease activity was assessed using the disease activity score 28 (DAS28). Radiographic changes were assessed using the Bath AS Radiographic Index (BASRI) in AS and Larsen scores in RA. Laboratory investigations included: Complete blood picture (CBC), Erythrocyte sedimentation rate (ESR), quantitative CRP, serum calcium, phosphorus and alkaline phosphatase. Determination of serum bone morphogenetic protein-7 level (BMP-7) was done using enzyme linked immunosorbent assay (ELISA). Sample collections, clinical and radiological assessments were performed at baseline for all groups and after a mean follow-up of 18 months for Group I. Data were analyzed by SPSS 17, using t-test, Kruskal-Wallis, Mann-Whitney, Fischer exact test, Chi square, and Pearson Product-Moment Correlation Coefficient.
There were statistically significant differences between the 3 groups as regard baseline BMP-7 levels; the mean BMP-7 level of AS patients was significantly higher than that of RA patients and controls and significantly higher in the RA group than that of controls. BMP-7 levels were not associated with any of the clinical or drug related variables either in AS or RA. In AS BMP-7 levels showed significant increase after follow up and significant positive correlation with serum alkaline phosphatase (both at baseline and after follow up) and BASDAI score (after follow up) respectively. Despite the parallel increase of BMP7 and BASRI score during the follow-up period no statistically significant correlation was detected. There were no significant correlations between BMP7 level and patient’s age or any disease related characteristics in the RA group.
A significant progressive increase in serum BMP-7 was noted in AS patients that correlated with serum markers of bone formation. Such a biomarker measurement may not only act as a surrogate marker for the disease but has the potential to contribute to the pathogenesis of AS that may provide a complementary or alternative therapeutic approach.
PMCID: PMC5014508  PMID: 27648196
Bone morphogenic protein-7; Ankylosing spondylitis; Radiographic changes
5.  Diagnostic imaging of sacroiliac joints and the spine in the course of spondyloarthropathies 
Polish Journal of Radiology  2013;78(2):43-49.
Spondyloarthropathies belong to a group of rheumatic diseases, in which inflammatory changes affect mainly the sacroiliac joints, spine, peripheral joints, tendon, ligaments and capsule attachments (entheses). This group includes 6 entities: ankylosing spondylitis, arthritis associated with inflammatory bowel disease, reactive arthritis, undifferentiated spondyloarthropathy, psoriatic arthritis and juvenile spondyloarthropathy.
In 2009, ASAS (Assessment in SpondyloArthritis international Society) association, published classification criteria for spondyloarthropathies, which propose standardization of clinical-diagnostic approach in the case of sacroiliitis, spondylitis and arthritis.
Radiological diagnosis of inflammatory changes of sacroiliac joints is based on a 4 step radiographic grading method from 1966. According to modified New York criteria, the diagnosis of ankylosing spondylitis is made based on the presence of advanced lesions, sacroiliitis of at least 2 grade bilaterally or 3–4 unilaterally. In case of other types of spondyloarthropathies diagnosis is made based on presence of at least grade 1 changes.
In MRI, active inflammation of sacroiliac joints is indicated by the presence of subchondral bone marrow edema, synovitis, bursitis, or enthesitis.
ASAS discusses only the classic form of axial spondyloarthropathies, which is ankylosing spondylitis. To quantify radiological inflammatory changes in the course of the disease, Stoke Ankylosing spondylitis classification Spinal Score (SASSS) is recommended. The signs of inflammation and scarrying of the spinal cord in the course of ankylosing spondylitis, present in MRI include: bone marrow edema, sclerosis, fat metaplasia, formation of syndesmophytes, and ankylosis.
PMCID: PMC3693836  PMID: 23807884
sacroiliitis; spondyloartropathies; diagnostics; radiograms; magnetic resonance imaging
6.  Baseline new bone formation does not predict bone loss in ankylosing spondylitis as assessed by quantitative computed tomography (QCT) - 10-year follow-up 
To evaluate the relationship between bone loss and new bone formation in ankylosing spondylitis (AS) using 10-year X-ray, dual-energy x-ray absorptiometry (DXA) and quantitative computed tomography (QCT) follow-up.
Fifteen AS patients free from medical conditions and drugs affecting bone metabolism underwent X-ray, DXA and QCT in 1999 and 2009.
In spine QCT a statistically significant (p = 0,001) decrease of trabecular bone mineral content (BMC) was observed (change ± SD: 18.0 ± 7.3 mg/cm3). In contrast, spine DXA revealed a significant increase of bone mineral density (change ± SD: -0.15 ± 0.14 g/cm2). The mean BMC, both at baseline and follow-up was significantly lower (p = 0.02 and p = 0.005, respectively) in advanced radiological group as compared to early radiological group. However, in multiple regression model after adjustment for baseline BMC, the baseline radiological scoring did not influence the progression of bone loss as assessed with QCT (p = 0.22, p for BMC*X-ray syndesmophyte scoring interaction = 0.65, p for ANOVA-based X-ray syndesmophyte scoring*time interaction = 0.39). Baseline BMC was the only significant determinant of 10-year BMC change, to date the longest QCT follow-up data in AS.
In AS patients who were not using antiosteoporotic therapy spine trabecular bone density evaluated by QCT decreased over 10-year follow-up and was not related to baseline radiological severity of spine involvement.
PMCID: PMC3118153  PMID: 21627836
7.  Osteoporosis in ankylosing spondylitis - prevalence, risk factors and methods of assessment 
Arthritis Research & Therapy  2012;14(3):R108.
Osteoporosis can be a complication of ankylosing spondylitis (AS), but diagnosing spinal osteoporosis can be difficult since pathologic new bone formation interferes with the assessment of the bone mineral density (BMD). The aims of the current study were to investigate prevalence and risk factors for reduced BMD in a Swedish cohort of AS patients, and to examine how progressive ankylosis influences BMD with the use of dual-energy x-ray absorptiometry (DXA) of the lumbar spine in different projections.
Methods of assessment were questionnaires, back mobility tests, blood samples, lateral spine radiographs for syndesmophyte grading (mSASSS), DXA of the hip, radius and lumbar spine in anteroposterior (AP) and lateral projections with estimation of volumetric BMD (vBMD).
AS patients (modified New York criteria), 87 women and 117 men, mean age 50 ± 13 years and disease duration 15 ± 11 years were included. According to World Health Organization (WHO) criteria 21% osteoporosis and 44% osteopenia was diagnosed in patients > = 50 years. Under age 50 BMD below expected range for age was found in 5%. Interestingly lateral lumbar DXA showed significantly lower BMD and revealed significantly more cases with osteoporosis as compared with AP DXA. Lumbar vBMD was not different between sexes, but women had significantly more lumbar osteoporosis measured with AP DXA (P < 0.001). Men had significantly higher mSASSS (P < 0.001). Low BMD was associated with high age, disease duration, mSASSS, Bath Ankylosing Spondylitis Metrology Index (BASMI), inflammatory parameters and low body mass index (BMI). Increasing mSASSS correlated significantly with decreasing lateral and volumetric lumbar BMD, while AP lumbar BMD showed tendency to increase.
Osteoporosis and osteopenia is common in AS and associated with high disease burden. Lateral and volumetric lumbar DXA are more sensitive than AP DXA in detecting osteoporosis and are less affected by syndesmophyte formation.
PMCID: PMC3446485  PMID: 22569245
8.  The effect of two golimumab doses on radiographic progression in ankylosing spondylitis: results through 4 years of the GO-RAISE trial 
Annals of the Rheumatic Diseases  2013;73(6):1107-1113.
To evaluate radiographic progression in patients with ankylosing spondylitis (AS) receiving two different doses of the tumour necrosis factor antagonist golimumab.
356 patients with AS were randomly assigned to placebo, or golimumab 50 mg or 100 mg every 4 weeks (wks). At wk16, patients with inadequate response early escaped with blinded dose adjustments (placebo→golimumab 50 mg, 50 mg→100 mg). At wk24, patients still receiving placebo crossed over to golimumab 50 mg. Lateral view radiographs of the cervical/lumbar spine were obtained at wk0, wk104 and wk208, and scored (two blinded readers, modified Stoke AS Spine Score (mSASSS)). Observed data were used for wk104 analyses; missing wk208 scores were linearly extrapolated.
Wk104 changes from baseline in mSASSS averaged 1.6±4.6 for placebo crossover, 0.9±2.7 for 50 mg and 0.9±3.9 for 100 mg. By wk208, following golimumab therapy for 3.5–4 years, mean changes in mSASSS were 2.1±5.2 for placebo crossover, 1.3±4.1 for 50 mg and 2.0±5.6 for 100 mg. Less than a third of patients (placebo crossover, 19/66 (28.8%); 50 mg, 29/111 (26.1%); 100 mg, 35/122 (28.7%)) had a definitive change from baseline mSASSS (>2). Less radiographic progression was observed through wk208 in patients without baseline syndesmophytes (0.2 vs 2.8 in patients with ≥1 syndesmophyte; p<0.0001) and with baseline C-reactive protein (CRP) levels ≤1.5 mg/dl (0.9 vs 2.9 with CRP >1.5 mg/dl; p=0.0004).
No difference in mSASSS change was observed between golimumab 50 mg and 100 mg. The radiographic progression rate remained stable at years 2 and 4, suggesting no acceleration of new bone formation over time. Golimumab-treated AS patients with no syndesmophytes and less systemic inflammation at baseline had considerably less radiographic progression.
PMCID: PMC4033110  PMID: 23644549
Ankylosing Spondylitis; TNF-alpha; Anti-TNF; Spondyloarthritis
9.  Does the KIR2DS5 Gene Protect from Some Human Diseases? 
PLoS ONE  2010;5(8):e12381.
KIR2DS5 gene encodes an activating natural killer cell receptor whose ligand is not known. It was recently reported to affect the outcome of hematopoietic stem cell transplantation.
Methodology/Principal Findings
In our studies on KIR2DS5 gene associations with human diseases, we compared the frequencies of this gene in patients and relevant controls. Typing for KIR2DS5 gene was performed by either individual or multiplex polymerase chain reactions which, when compared in the same samples, gave concordant results. We noted an apparently protective effect of KIR2DS5 gene presence in several clinical conditions, but not in others. Namely, this effect was observed in ankylosing spondylitis (p = 0.003, odds ratio [OR] = 0.47, confidence interval [CI] = 0.28–0.79), endometriosis (p = 0.03, OR = 0.25, CI = 0.07–0.82) and acute rejection of kidney graft (p = 0.0056, OR = 0.44, CI = 0.24–0.80), but not in non-small-cell lung carcinoma, rheumatoid arthritis, spontaneous abortion, or leukemia (all p>0.05). In addition, the simultaneous presence of KIR2DS5 gene and HLA-C C1 allotype exhibited an even stronger protective effect on ankylosing spondylitis (p = 0.0003, OR = 0.35, CI = 0.19–0.65), whereas a lack of KIR2DS5 and the presence of the HLA-C C2 allotype was associated with ankylosing spondylitis (p = 0.0017, OR = 1.92, CI = 1.28–2.89), whereas a lack of KIR2DS5 and presence of C1 allotype was associated with rheumatoid arthritis (p = 0.005, OR = 1.47, CI = 1.13–1.92). The presence of both KIR2DS5 and C1 seemed to protect from acute kidney graft rejection (p = 0.017, OR = 0.47, CI = 0.25–0.89), whereas lack of KIR2DS5 and presence of C2 seemed to favor rejection (p = 0.0015, OR = 2.13, CI = 1.34–3.37).
Our results suggest that KIR2DS5 may protect from endometriosis, ankylosing spondylitis, and acute rejection of kidney graft.
PMCID: PMC2928722  PMID: 20865034
10.  Progression of radiographic damage in patients with ankylosing spondylitis: defining the central role of syndesmophytes 
Annals of the Rheumatic Diseases  2007;66(7):910-915.
Structural changes such as erosions, syndesmophytes and ankylosis are characteristic of ankylosing spondylitis (AS). These can be quantified by the modified Stokes Anklylosing Spondylitis Spinal Score (mSASSS). It is unknown which radiographic feature is most relevant for the assessment of change and the prediction of future damage in AS.
To analyse radiographic progression in AS by using different assessments to define the most important changes.
Spinal radiographs of 116 patients with AS were scored by the mSASSS at baseline (BL) and after 2 years. Radiographic progression was assessed by differentiating (1) any change; (2) progression to syndesmophytes/ankylosis (definite change); and (3) changes exceeding the smallest detectable change (SDC) as predefined. A growth angle of 45° was used to differentiate syndesmophytes from spondylophytes.
Some radiographic progression after 2 years was detected in 42% of patients, novel syndesmophytes in 31% of patients, and, using the SDC (calculated at 2 mSASSS units) as cut‐off, progression was seen in 28% of patients. Thus, in 74% of the patients changes were because of syndesmophytes and/or ankylosis. Using the predefined cut‐off, only 12% of all syndesmophytes were spondylophytes. Patients with such changes were of older age. Definite radiographic progression was found in 44% of the patients with syndesmophytes/ankylosis at BL (n = 57) versus 19% (p = 0.03) of the patients without such changes (n = 59).
Syndesmophytes and ankylosis are the most relevant structural changes in AS, and also in the mSASSS. Development of just one syndesmophyte within 2 years indicates progression of structural changes in AS; this is relevant for clinical practice. Syndesmophytes are the best predictors of radiographic progression.
PMCID: PMC1955120  PMID: 17329306
11.  Syndesmophyte Growth in Ankylosing Spondylitis 
Current opinion in rheumatology  2015;27(4):326-332.
Purpose of review
Syndesmophytes are characteristic components of the spine pathology of ankylosing spondylitis (AS). Understanding their growth may reveal insights to pathogenesis and potential treatment. We review recent studies on rates of development of syndesmophytes, patient characteristics associated with more rapid syndesmophyte growth, local vertebral abnormalities that precede syndesmophytes, systemic biomarkers of syndesmophytes, and studies of medications.
Recent findings
New syndesmophytes develop in one-third of patients over two years. Consistent clinical predictors are male gender, elevated serum C-reactive protein levels, and pre-existing syndesmophytes. Concomitant vertebral inflammation and fat dysplasia on magnetic resonance imaging predict future syndesmophytes at the same vertebral location, but most syndesmophytes do not have recognized antecedents. Associations with serum levels of Wnt pathway proteins are inconsistent, as are the results of observational studies of tumor necrosis factor-alpha inhibitors.
Although there is better understanding of the frequency of syndesmophyte development, the pathogenesis of syndesmophytes remains unclear.
PMCID: PMC4478446  PMID: 26002023
ankylosing spondylitis; syndesmophytes; magnetic resonance imaging; computed tomography; tumor necrosis factor-alpha inhibitors
12.  Computer Aided Evaluation of Ankylosing Spondylitis Using High-Resolution CT 
IEEE transactions on medical imaging  2008;27(9):1252-1267.
Ankylosing Spondylitis is a disease characterized by abnormal bone structures (syndesmophytes) growing at intervertebral disk spaces. Because this growth is so slow as to be undetectable on plain radiographs taken over years, it is desirable to resort to computerized techniques to complement qualitative human judgment with precise quantitative measures. We developed an algorithm with minimal user intervention that provides such measures using high-resolution computed tomography (CT) images. To the best of our knowledge it is the first time that determination of the disease’s status is attempted by direct measurement of the syndesmophytes. The first part of our algorithm segments the whole vertebral body using a 3-D multiscale cascade of successive level sets. The second part extracts the continuous ridgeline of the vertebral body where syndesmophytes are located. For that we designed a novel level set implementation capable of evolving on the isosurface of an object represented by a triangular mesh using curvature features. The third part of the algorithm segments the syndesmophytes from the vertebral body using local cutting planes and quantitates them. We present experimental work done with 10 patients from each of which we processed five vertebrae. The results of our algorithm were validated by comparison with a semi-quantitative evaluation made by a medical expert who visually inspected the CT scans. Correlation between the two evaluations was found to be 0.936 (p < 10−18).
PMCID: PMC2832317  PMID: 18779065
Level sets on nonplanar manifolds; multiscale vertebra segmentation; ridgelines/crestlines; semi-synthetic digital phantoms
13.  The prevalence of clinically diagnosed ankylosing spondylitis and its clinical manifestations: a nationwide register study 
Prevalence estimates of ankylosing spondylitis vary considerably, and there are few nationwide estimates. The present study aimed to describe the national prevalence of clinically diagnosed ankylosing spondylitis in Sweden, stratified according to age, sex, geographical, and socio-economic factors, and according to subgroups with ankylosing spondylitis-related clinical manifestations and pharmacological treatment.
All individuals diagnosed with ankylosing spondylitis according to the World Health Organization International Classification of Disease codes, between 1967 and 2009, were identified from the National Patient Register. Data regarding disease manifestations, patient demographics, level of education, pharmacological treatment, and geographical region were retrieved from the National Patient Register and other national registers.
A total of 11,030 cases with an ankylosing spondylitis diagnosis (alive, living in Sweden, and 16 to 64 years old in December 2009) were identified in the National Patient Register, giving a point prevalence of 0.18% in 2009. The prevalence was higher in northern Sweden, and lower in those with a higher level of education. Men had a higher prevalence of ankylosing spondylitis (0.23% versus 0.14%, P < 0.001), a higher frequency of anterior uveitis (25.5% versus 20.0%, P < 0.001) and were more likely to receive tumor necrosis factor inhibitors than women (15.6% versus 11.8% in 2009, P < 0.001). Women were more likely than men to have peripheral arthritis (21.7% versus 15.3%, P < 0.001), psoriasis (8.0% versus 6.9%, P = 0.03), and treatment with oral corticosteroids (14.0% versus 10.4% in 2009, P < 0.001).
This nationwide, register-based study demonstrated a prevalence of clinically diagnosed ankylosing spondylitis of 0.18%. It revealed phenotypical and treatment differences between the sexes, as well as geographical and socio-economic differences in disease prevalence.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-015-0627-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4424886  PMID: 25956915
14.  Quantitative measurement of syndesmophyte volume and height in ankylosing spondylitis using CT 
Annals of the rheumatic diseases  2013;73(3):544-550.
Syndesmophyte growth in ankylosing spondylitis can be difficult to measure using radiographs because of poor visualisation and semiquantitative scoring methods. We developed and tested the reliability and validity of a new computer-based method that fully quantifies syndesmophyte volumes and heights on CT scans.
In this developmental study, we performed lumbar spine CT scans on 38 patients and used our algorithm to compute syndesmophyte volume and height in four intervertebral disk spaces. To assess reliability, we compared results between two scans performed on the same day in nine patients. To assess validity, we compared computed measures to visual ratings of syndesmophyte volume and height on both CT scans and radiographs by two physician readers.
Coefficients of variation for syndesmophyte volume and height, based on repeat scans, were 2.05% and 2.40%, respectively. Based on Bland–Altman analysis, an increase in syndesmophyte volume of more than 4% or in height of more than 0.20 mm represented a change greater than measurement error. Computed volumes and heights were strongly associated with physician ratings of syndesmophyte volume and height on visual examination of both the CT scans (p<0.0001) and plain radiographs (p<0.002). Syndesmophyte volumes correlated with the Schober test (r=−0.48) and lateral thoracolumbar flexion (r=−0.60).
This new CT-based method that fully quantifies syndesmophytes in three-dimensional space had excellent reliability and face and construct validity. Given its high precision, this method shows promise for longitudinal clinical studies of syndesmophyte development and growth.
PMCID: PMC5071781  PMID: 23345598
15.  Improved precision of syndesmophyte measurement for the evaluation of ankylosing spondylitis using CT: a phantom and patient study 
Physics in medicine and biology  2012;57(14):4683-4704.
Ankylosing spondylitis is a disease characterized by abnormal bone formation (syndesmophyte) at the margins of intervertebral disk spaces. Syndesmophyte growth is currently typically monitored by visual inspection of radiographs. The limitations inherent to the modality (2D projection of a 3D object) and rater (qualitative human judgment) may compromise sensitivity. With newly available treatments, more precise measures of syndesmophytes are needed to determine if treatment can slow rates of syndesmophyte growth. We previously presented a computer algorithm measuring syndesmophyte volumes and heights in the 3D space of CT scans. In this study we present improvements to the original algorithm and evaluate the gain in precision as applied to an anthropomorphic vertebral phantom and patients. Each patient was scanned twice in one day, thus providing two syndesmophyte volume and height measures. The difference between those two measures (ideally zero) determines our algorithm’s precision. The technical improvements to the algorithm decreased the mean volume difference (standard deviation) between scans from 3.01% (2.83%) to 1.31% (0.95%) and the mean height difference between scans from 3.16% (2.99%) to 1.56% (1.13%). The high precision of the improved algorithm holds promise for application to longitudinal clinical studies.
PMCID: PMC3427026  PMID: 22750760
16.  Symptomatic improvement in function and disease activity in a patient with ankylosing spondylitis utilizing a course of chiropractic therapy: a prospective case study 
There is limited outcome measure support for chiropractic manipulative therapy in the management of ankylosing spondylitis. An improvement in specific indices for both function and disease activity during chiropractic therapy for ankylosing spondylitis has not previously been reported.
To measure changes in function and disease activity in a patient with ankylosing spondylitis during a course of chiropractic therapy. The clinical management of ankylosing spondylitis, including chiropractic manipulative therapy and the implications of this case study are discussed.
Clinical Features
A 34-year-old male with a 10 year diagnosis of ankylosing spondylitis sought chiropractic treatment for spinal pain and stiffness. His advanced radiographic signs included an increased atlantodental interspace and cervical vertebral ankylosis.
Intervention and outcome
The Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), finger-tip-to-floor distance and chest expansion were assessed during an 18 week course of chiropractic spinal manipulation and mobilization therapy. There was a 90% improvement in the disease activity index and an 85% improvement in the functional index from the pre-treatment baseline, as measured by the BASDAI and BASFI respectively. Spinal flexibility and chest expansion also improved.
To the authors knowledge this is the first study to incorporate ankylosing spondylitis specific indices, for both disease activity and function, to objectively support the use of chiropractic manipulative therapy in the management of ankylosing spondylitis. More intensive research is suggested.
PMCID: PMC1840019  PMID: 17549197
ankylosing spondylitis; chiropractic; manipulation; Bath Ankylosing Spondylitis Functional Index (BASFI); Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)
17.  Bone Morphogenetic Protein 6 Polymorphisms Are Associated with Radiographic Progression in Ankylosing Spondylitis 
PLoS ONE  2014;9(8):e104966.
Background and Object
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.
PMCID: PMC4133264  PMID: 25121767
18.  Iatrogenic fractures in ankylosing spondylitis—a report of two cases 
European Spine Journal  2005;15(1):100-104.
Study design: Two cases of intraoperative, iatrogenic cervical spine fractures in patients with ankylosing spondylitis are reported. Objective: To describe the uncommon complication of iatrogenic cervical spine fractures occurring during spine surgery in patients with ankylosing spondylitis. Summary of background data: To our knowledge, this is the first report on this rare complication. Methods: A 39-year-old patient (1) with ankylosing spondylitis was operated on for cervical stenosis due to C1/2 anterolisthesis. Fifteen hours postoperatively, he developed acute quadriplegia. MRI revealed a fracture/dislocation of C6 on C7 and compression of the spinal cord at this level. Revision was performed with decompression and instrumentation from the occiput to T3. A 55-year-old patient (2) with ankylosing spondylitis and thoracic hyperkyphosis underwent a correction procedure consisting of costotransversectomy, anterior cage implantation at T8/9, and posterior instrumentation from T4 to L1. Halo traction was temporarily applied for correction. At the end of the operation, with the patient still under anesthesia, increased mobility of the cervical spine was noticed. Emergent MRI revealed a fracture of the anterior structures of C6/7. Posterior instrumentation from C5 to T1 was then performed. Results: Quadriplegia persisted in patient 1 until his death secondary to further complications. Patient 2 was mobilized without any neurologic deficits. The fracture healed in good alignment. Conclusions: Iatrogenic fractures of the cervical spine during surgery in ankylosing spondylitis patients are a rare but potentially severe complication. Early diagnosis and therapy are necessary before dislocation, cord compression, and subsequent neurologic impairment occur.
PMCID: PMC3454562  PMID: 16032433
Ankylosing spondylitis; Iatrogenic fracture; Cervical spine fracture
19.  Low grade radiographic sacroiliitis as prognostic factor in patients with undifferentiated spondyloarthritis fulfilling diagnostic criteria for ankylosing spondylitis throughout follow up 
Annals of the Rheumatic Diseases  2005;65(5):642-646.
To determine the rate and factors associated with ankylosing spondylitis in a cohort of patients with undifferentiated spondyloarthritides (SpA).
62 consecutive patients with undifferentiated SpA seen between 1998 and 1999 underwent clinical and imaging evaluations throughout follow up. The main outcome measure was a diagnosis of ankylosing spondylitis.
50 patients with peripheral arthritis (n = 35) and inflammatory back pain (n = 24) (26 male; mean (SD) age at onset, 20.4 (8.8) years; disease duration 5.4 (5.7) years) were followed up for 3–5 years. At baseline, >90% of patients had axial and peripheral disease, while 38% had radiographic sacroiliitis below the cut off level for a diagnosis of ankylosing spondylitis (BASDAI 3.9, BASFI 2.9). At the most recent evaluation, 21 patients (42%) had ankylosing spondylitis. Two factors were associated with a diagnosis of ankylosing spondylitis in multivariate analysis: radiographic sacroiliitis grade <2 bilateral, or grade <3 unilateral (odds ratio (OR) = 11.18 (95% confidence interval, 2.59 to 48.16), p = 0.001), particularly grade 1 bilateral (OR = 12.58 (1.33 to 119.09), p = 0.027), and previous uveitis (OR = 19.25 (1.72 to 214.39), p = 0.001). Acute phase reactant levels, juvenile onset, and HLA‐B27 showed a trend to linkage with ankylosing spondylitis (NS).
Low grade radiographic sacroiliitis is a prognostic factor for ankylosing spondylitis in patients originally classified as having undifferentiated SpA. Low grade radiographic sacroiliitis should be regarded as indicative of early ankylosing spondylitis in patients with undifferentiated SpA.
PMCID: PMC1798115  PMID: 16219705
ankylosing spondylitis; spondyloarthritis; sacroiliitis; HLA‐B27
20.  Might axial myofascial properties and biomechanical mechanisms be relevant to ankylosing spondylitis and axial spondyloarthritis? 
Ankylosing spondylitis and axial spondyloarthropathy have characteristic age- and sex-specific onset patterns, typical entheseal lesions, and marked heritability, but the integrative mechanisms causing the pathophysiological and structural alterations remain largely undefined. Myofascial tissues are integrated in the body into webs and networks which permit transmission of passive and active tensional forces that provide stabilizing support and help to control movements. Axial myofascial hypertonicity was hypothesized as a potential excessive polymorphic trait which could contribute to chronic biomechanical overloading and exaggerated stresses at entheseal sites. Such a mechanism may help to integrate many of the characteristic host, pathological, and structural features of ankylosing spondylitis and axial spondyloarthritis. Biomechanical stress and strain were recently documented to correlate with peripheral entheseal inflammation and new bone formation in a murine model of spondyloarthritis. Ankylosing spondylitis has traditionally been classified by the modified New York criteria, which require the presence of definite radiographic sacroiliac joint lesions. New classification criteria for axial spondyloarthritis now include patients who do not fulfill the modified New York criteria. The male-to-female sex ratios clearly differed between the two patient categories - 2:1 or 3:1 in ankylosing spondylitis and 1:1 in non-radiographic axial spondyloarthritis - and this suggests a spectral concept of disease and, among females, milder structural alterations. Magnetic resonance imaging of active and chronic lesions in ankylosing spondylitis and axial spondyloarthritis reveals complex patterns, usually interpreted as inflammatory reactions, but shows similarities to acute degenerative disc disease, which attributed to edema formation following mechanical stresses and micro-damage. A basic question is whether mechanically induced microinjury and immunologically mediated inflammatory mechanisms operate in both ankylosing spondylitis and degenerative disc disease but differ in relative degrees. The hypothesized biomechanical properties raised in this commentary require documentation of their association with the onset risk and course of ankylosing spondylitis and axial spondyloarthritis. If particular subsets of ankylosing spondylitis and axial spondyloarthritis patients are confirmed to have altered axial myofascial properties, their biological basis and underlying biomechanical mechanisms promise to become clarified. Understanding how biomechanical and physical properties can affect symptomatic and structural manifestations of these disorders could also improve their management.
PMCID: PMC4060468  PMID: 25166000
21.  T lymphocyte subset imbalances in patients contribute to ankylosing spondylitis 
Ankylosing spondylitis is a chronic inflammatory rheumatic disease, which is characterized by inflammation of the spine and the sacroiliac joints. To date, the disease etiology remains unclear. In the present study, the correlation of T lymphocyte subset changes with the progression of ankylosing spondylitis was investigated. A total of 55 patients with ankylosing spondylitis (22 severe and 23 mild cases) and 20 healthy individuals were selected. Firstly, the punctured cells in the lesions and the serum were collected, and the lymphocytes and the peripheral blood mononuclear cells were prepared. Secondly, quantitative PCR, ELISA and flow cytometry analyses were carried out to detect the levels of a series of immunoglobulins, complements, helper T cells, cytotoxic T cells, regulatory cells and cytokines. The expression levels of α-globulin, γ-globulin, immunoglobulin (Ig)G, IgA, IgM, serum complement C3, and complement C4 were found to be significantly increased in ankylosing spondylitis patients. In addition, the percentage of Th1 and Th17 cells was found to be significantly higher in the ankylosing spondylitis groups (mild and severe) compared with the healthy individuals. As a result, the Th1/Th2 and Th17/Treg ratios were significantly higher in patients with ankylosing spondylitis. In addition, T lymphocyte subset ratio imbalances contributed to an increased expression of immune mediators, including interferon (IFN)-γ and interleukin (IL)-17A. The mRNA and protein expression levels of IFN-γ and IL-17A were found to be higher in the ankylosing spondylitis groups compared with the control group. The present study provided further evidence on the function and underlying mechanism of T lymphocyte subsets, which may be useful in the diagnosis and treatment of ankylosing spondylitis.
PMCID: PMC4247318  PMID: 25452811
ankylosing spondylitis; T lymphocyte subsets; cytokines; imbalance; inflammation
22.  Spinal Radiographic Progression in Patients with Ankylosing Spondylitis Treated with TNF-α Blocking Therapy: A Prospective Longitudinal Observational Cohort Study 
PLoS ONE  2015;10(4):e0122693.
To evaluate spinal radiographic damage over time and to explore the associations of radiographic progression with patient characteristics and clinical assessments including disease activity in ankylosing spondylitis (AS) patients treated with tumor necrosis factor-alpha (TNF-α) blocking therapy in daily clinical practice.
Consecutive outpatients from the Groningen Leeuwarden AS (GLAS) cohort were included based on the availability of cervical and lumbar radiographs before start of TNF-α blocking therapy and after 2, 4, and/or 6 years of follow-up. Clinical data were assessed at the same time points. Radiographs were scored by two independent readers using the modified Stoke AS Spine Score (mSASSS). Spinal radiographic progression in relation to clinical assessments was analyzed using generalized estimating equations.
176 AS patients were included, 58% had syndesmophytes at baseline. Median mSASSS increased significantly from 10.7 (IQR: 4.6–24.0) at baseline to 14.8 (IQR: 7.9–32.8) at 6 years. At the group level, spinal radiographic progression was linear with a mean progression rate of 1.3 mSASSS units per 2 years. Both spinal radiographic damage at baseline and radiographic progression were highly variable between AS patients. Male gender, older age, longer disease duration, higher BMI, longer smoking duration, high CRP, and high ASDAS were significantly associated with syndesmophytes at baseline. Significantly more radiographic progression was seen in patients with versus without syndesmophytes (2.0 vs. 0.5 mSASSS units per 2 years) and in patients >40 versus ≤40 years of age (1.8 vs. 0.7 mSASSS units per 2 years). No longitudinal associations between radiographic progression and clinical assessments were found.
This prospective longitudinal observational cohort study in daily clinical practice shows overall slow and linear spinal radiographic progression in AS patients treated with TNF-α blocking therapy. At the individual level, progression was highly variable. Patients with syndesmophytes at baseline showed a 4-fold higher radiographic progression rate than patients without syndesmophytes.
PMCID: PMC4400173  PMID: 25879956
23.  Stem cell transplant: An experience from eastern India 
Hematopoietic stem cell transplant using human leukocyte antigen (HLA)-matched sibling or unrelated bone marrow, or related or unrelated cord blood has been performed successfully to treat patients with different types of hematological malignancies, genetic disorders and hereditary immune deficiencies. Since 1983, stem cell transplantation has been carried out in different institutes of India. But, till then, no transplantation was performed in eastern India.
Materials and Methods:
Our present study is reporting for the first time stem cell transplantation in eastern India. From August 2000 to June 2011 (with a 3-year gap for up-gradation), we have performed a total of 22 transplants. Thirteen patients (M:F:9:4) with indications of aplastic anemia, thalassaemia, acute myeloid leukemia and chronic myeloid leukemia underwent allogenic transplant, whereas autologous transplant was performed for nine patients (M:F:2:1) of multiple myeloma, Hodgkin's and non-Hodgkin's lymphoma and neuroblastoma. The median age of the patients was 19.6 years, with a range of 5 years 8 months to 52 years. Fourteen patients received myeloablative conditioning regime whereas eight patients received immunosuppressive and less myeloablative protocol. Sources of stem cells in case of allogenic transplant are bone marrow and related or unrelated umbilical cord blood and in case of autologous transplant, these are peripheral blood stem cells or self-bone marrow. Standard prophylactic medication was followed prior to transplants.
A disease-free survival of 68.18% and overall survival of 86.3% were seen at the median follow-up period of 4.6 years. Common post-transplant complications were mucositis, infection, venoocclusive disease, graft versus host disease, hemorrhagic cystitis, etc.
The use of cord blood as a source of stem cells has been proved inferior as compared with the bone marrow stem cell source in cases of thalassaemia in our institute and thus is not recommended for thalassaemia. But, it has been proved to be a very useful and effective stem cell source (both related and unrelated cord blood) in cases of aplastic anemia and other immunological disorders.
PMCID: PMC3618641  PMID: 23580820
Aplastic anemia; bone marrow transplantation; cord blood transplantation; eastern Indian data; stem cell transplantation; thalassaemia
24.  Duration of remission after halving of the etanercept dose in patients with ankylosing spondylitis: a randomized, prospective, long-term, follow-up study 
The aim of this study was to evaluate the proportion of patients with ankylosing spondylitis maintaining clinical remission after reduction of their subcutaneous etanercept dose to 50 mg every other week compared with that in patients receiving etanercept 50 mg weekly.
In the first phase of this randomized, prospective, follow-up study, all biologic-naïve patients identified between January 2005 and December 2009 as satisfying the modified New York clinical criteria for ankylosing spondylitis treated with etanercept 50 mg weekly were evaluated for disease remission in January 2010. In the second phase, patients meeting the criteria for remission were randomized to receive subcutaneous etanercept as either 50 mg weekly or 50 mg every other week. The randomization allocation was 1:1. Remission was defined as Bath Ankylosing Spondylitis Disease Activity Index < 4, no extra-axial manifestations of peripheral arthritis, dactylitis, tenosynovitis, or iridocyclitis, and normal acute-phase reactants. The patients were assessed at baseline, at weeks 4 and 12, and every 12 weeks thereafter. The last visit constituted the end of the follow-up.
During the first phase, 78 patients with ankylosing spondylitis (57 males and 21 females, median age 38 years, median disease duration 12 years) were recruited. In January 2010, after a mean follow-up of 25 ± 11 months, 43 (55.1%) patients achieving clinical remission were randomized to one of the two treatment arms. Twenty-two patients received etanercept 50 mg every other week (group 1) and 21 received etanercept 50 mg weekly (group 2). At the end of follow-up, 19 of 22 (86.3%) subjects in group 1 and 19 of 21 (90.4%) in group 2 were still in remission, with no significant difference between the two groups. The mean follow-up duration in group 1 and group 2 was 22 ± 1 months and 21 ± 1.6 months, respectively.
Remission of ankylosing spondylitis is possible in at least 50% of patients treated with etanercept 50 mg weekly. After halving of the etanercept dose, remission is maintained in a high percentage of patients during long-term follow-up, with important economic implications.
PMCID: PMC3540908  PMID: 23319853
ankylosing spondylitis; anti-tumor necrosis factor; etanercept; remission; dose reduction
25.  The prevalence of moderate to severe radiographic sacroiliitis and the correlation with health status in elderly Swedish men – The MrOS study 
Ankylosing Spondylitis (AS) is a chronic inflammatory disease with onset in young adults, but little is known about the prevalence in older age groups. Furthermore, there is very limited information of health status of elderly patients with AS. Our objective was to estimate the prevalence of moderate to severe radiographic sacroiliitis in elderly men and its impact on health.
A cross-sectional, population-based survey, that included 1005 men aged 69-81 years old, with the primary aim to study risk factors for osteoporosis (MrOS), was used. X-rays of the pelvis and spine were done for the whole population and then examined by two readers. The prevalences of grade 3-4 sacroiliitis, syndesmophytes and spondylophytes were ascertained. Using a self-administered questionnaire, information was obtained on physical activity (PASE), functional status (IADL items), health related quality of life - QoL (SF-12) and back pain (pain question, Quebec Pain Disability Scale items).
Fourteen cases with grade 3-4 sacroiliitis were identified, corresponding to a prevalence of 1.4% (95%CI: 0.7-2.4). Eight of the patients with sacroiliitis had both AS-typical and degenerative changes in the spine, 4 had only degenerative changes and 2 had only AS-related changes. There were no statistically significant differences between those with and without radiographic sacroiliitis regarding demographics, anthropometric measures, smoking status or health status, reflected by measures on physical activity, functional status, health related QoL and back pain.
The prevalence of moderate to severe radiographic sacroiliitis was estimated to be 1.4% among elderly men in Sweden. Self-reported health was only slightly different in those with sacroiliitis, suggesting that the relative impact of AS is modest in this age group.
PMCID: PMC3878735  PMID: 24330533

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