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Introduction Ankylosing spondylitis (AS) is unique in its pathology where inflammation commences at the entheses before progressing to an osteoproliferative phenotype generating excessive bone formation that can result in joint fusion. The underlying mechanisms of this progression are poorly understood. Recent work has suggested that changes in Wnt signalling, a key bone regulatory pathway, may contribute to joint ankylosis in AS. Using the proteoglycan-induced spondylitis (PGISp) mouse model which displays spondylitis and eventual joint fusion following an initial inflammatory stimulus, we have characterised the structural and molecular changes that underlie disease progression. Methods PGISp mice were characterised 12 weeks after initiation of inflammation using histology, immunohistochemistry (IHC) and expression profiling. Results Inflammation initiated at the periphery of the intervertebral discs progressing to disc destruction followed by massively excessive cartilage and bone matrix formation, as demonstrated by toluidine blue staining and IHC for collagen type I and osteocalcin, leading to syndesmophyte formation. Expression levels of DKK1 and SOST, Wnt signalling inhibitors highly expressed in joints, were reduced by 49% and 63% respectively in the spine PGISp compared with control mice (P < 0.05) with SOST inhibition confirmed by IHC. Microarray profiling showed genes involved in inflammation and immune-regulation were altered. Further, a number of genes specifically involved in bone regulation including other members of the Wnt pathway were also dysregulated. Conclusions This study implicates the Wnt pathway as a likely mediator of the mechanism by which inflammation induces bony ankylosis in spondyloarthritis, raising the potential that therapies targeting this pathway may be effective in preventing this process.

Endothelial cell stimulating angiogenesis factor (ESAF) is raised in conditions of neovascularization, such as may occur at the endochondral surface of the bone growth plate or in association with syndesmophyte formation. Syndesmophytes are formed in response to chronic enthesitis. Twenty unselected patients with AS were studied and enthesitis was measured clinically using a previously validated enthesitis index. Biochemical and haematological markers of disease activity were measured along with ESAF. Radiographs were scored for the degree of sacroiliitis and syndesmophyte formation and all these measurements were correlated to the enthesitis index. ESAF was raised in AS compared with normal controls. ESAF correlated positively with the enthesitis index but not with any of the biochemical or haematological indices. Higher levels of ESAF were found in those with more advanced sacroiliitis. High ESAF activity may be reflecting the angiogenic process involved in new bone formation associated with sacroiliitis and syndesmophyte formation. ESAF may be a biochemical marker for disease activity in AS.

OBJECTIVE--To examine the relationship between disease severity and bone density as well as vertebral fracture risk in patients with ankylosing spondylitis (AS). METHODS--Measurements were taken for bone mineral density (BMD) and vertebral fracture rates in 87 patients with AS. BMD was measured at the hip (femoral neck -FN), lumbar spine (L1-L4-LS) and for the whole body using a hologic-QDR-1000/W absorptiometer. An algorithm based on normal female ranges of vertebral heights was used to define a fracture as occurring when two vertebral ratios were each three standard deviations below the calculated mean of the controls. RESULTS--Patients with AS had significantly lower FN-BMD in proportion to disease severity (based on a Schober index) and disease duration. LS-BMD was also reduced in early disease, but in patients with advanced AS it had increased considerably. Nine vertebral fractures (10.3%) were identified which was considerably higher than expected when compared with a fracture of 1.9% in a control population of 1035 females of a similar age range. Patients with AS with fractures were significantly older, more likely to be male, had longer disease duration and more advanced spinal limitation with less mobility. There was no significant reduction in lumbar spine or femoral neck bone density in the fracture group. CONCLUSIONS--Vertebral fractures that result from osteoporosis are a feature of longstanding AS. BMD used as a measure of osteoporosis of the spine in advanced AS is unreliable probably as a result of syndesmophyte formation and does not predict the risk of vertebral fracture. Alternative sites such as the neck of the femur should be used for sequential assessment of BMD in AS.

OBJECTIVE. We assessed the prevalence, severity, and anatomic distribution of ankylosing spondylitis (AS)-related osteopenia (OP). METHODS. We studied 70 patients (60 males, 10 premenopausal females) with AS (according to the New York criteria) to determine the frequency of OP. Bone mass was measured by plain radiographs of the spine, by single-photon absorptiometry (SPA) of the distal and midshaft of the radius on the nondominant side, by dual-photon absorptiometry (DPA) of the lumbar spine (L2-L4), and by quantitative computed tomography (QCT) of the lumbar spine. RESULTS. SPA values for the radius mass were normal in males and in females, both at the distal and midshaft sites. In contrast, spine radiographs showed diminished density of the vertebral bodies in 69% of the males and 50% of the premenopausal females. Two male patients had had a vertebral compression fracture, and one female patient had had two. DPA values for the spine mass were significantly diminished in the male patients compared with the controls, but not in the female patients. Males with less severe AS also had the largest reduction in lumbar bone mineral content. In patients with more severe disease, lumbar bone mineral content was not statistically different from that in controls. QCT of the lumbar spine performed in 10 patients disclosed low density of the trabecular bone of the vertebral bodies, more so in those with more severe AS and syndesmophyte formation and/or apophyseal joint fusion, which contrasts with the normal values on DPA in these patients. CONCLUSION. Male patients with AS have axial osteopenia. In those who have very severe AS with new bone formation, DPA demonstrates normal values as a result of two opposite trends: central osteopenia (as assessed from QCT) and peripheral new-bone formation, which transforms vertebral bodies into long bones. This could modify the mechanical resistance of the spine and account for the propensity for anteroposterior transvertebral and transdiscal fractures after trauma in AS.

Erosive changes and syndesmophyte formation, characteristics of spondyloarthropathy, were present in 79/2906 skeletons in the Todd Collection. Holistic assessment of this defined population allowed it to be distinguished from rheumatoid and other erosive forms of arthritis. Characterization of the nature and distribution of osseous alterations in a contemporary skeletal population allowed development of a standard for recognition of the disease in skeletal populations.

Introduction 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. Methods 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. Results 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). Conclusions 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.

A seropositive white man had follow-up for 16 years with a diagnosis of palindromic rheumatism. Treatment had included parenteral gold, methotrexate, prednisone, hydroxychloroquine sulfate, and penicillamine before diarrhea led to a biopsy-proven diagnosis of Whipple's disease. Clinical and radiographic criteria for ankylosing spondylitis were met. In addition to classic Whipple's arthropathy, he had the combined but singular findings of pancarpal destruction and cervical apophyseal fusion. HLA typing revealed the B7 antigen. This case illustrates the pitfalls in diagnosis of a chronic polyarthritis that has, as a typical feature, a long latency before manifesting its more specific signs and symptoms (ie, diarrhea, malabsorption, and hyperpigmentation). Care should be taken during evaluation of any disease with atypical and nonspecific features (eg, positive rheumatoid factor in a patient with polyarthritis) and one should continue to reevaluate the original impression, while confirmatory evidence is lacking. Moreover, the roentgenographic findings of pancarpal narrowing, apophyseal fusion, and advanced iliofemoral joint disease, in addition to sacroiliitis and syndesmophyte formation, challenge the generally held notion that Whipple's arthropathy is a nondestructive joint disease.

We read with great interest the editorial article by Schett et al ,1 where the authors discuss the role of tumour necrosis factor (TNF) α blockers in reducing new bone formation in ankylosing spondylitis (AS). They described the pathophysiological process, where TNF-α is a key proinflammatory cytokine, but is also a potent inhibitor of bone formation. Therefore, it is unlikely that TNF-α blockers are effective in reducing syndesmophyte growth and bridging. In other words, would TNF-α blockers inhibit the progression of structural damage even though they are proven to be very efficient in diminishing the clinical parameters of AS activity, acute-phase reactants and also active …

A 76-year-old man with a history of ankylosing spondylitis (AS) was evaluated for possible Paget's disease (PD) based on an elevated alkaline phosphatase level of 197 U/I (normal, 36 to 126 U/I) and a urinary hydroxyproline level of 68 mg per 24 hours (normal, 5 to 65 mg). Roentgenograms of the posteroanterior and lateral chest, lateral lumbar spine, and sacroiliac joints revealed marked kyphosis within the thoracic spine and a flowing anterior syndesmophyte and ankylosis of the sacroiliac joints consistent with AS. The films also showed expansion, prominent trabecula, end cortical thickening of affected thoracic ribs, and L2-L3 vertebral bodies, consistent with PD. Additional changes of PD were seen in the T7-T10 vertebral bodies and the anterior syndesmophyte bridging these levels. Anterior and posterior whole-body scintiscans were obtained after intravenous administration of 25 mCi Tc-99m MDP. The scintigrams showed typical increased uptake in the T7-T11 and L2-L3 vertebrae, consistent with PD. In addition, they demonstrated increased uptake in the posterior seventh through tenth ribs bilaterally, corresponding in location to the pagetoid changes seen on the roentgenograms. This bone scan appearance is unusual in that unlike the typical PD presentation (i.e., extension distally from the articular surface of the bone without crossing of the joint), PD in this case extended across joints fused by AS.

Nine radiodiagnostic rules are drawn from the X-rays of 2125 ankylosing spondylitis patients. The significance of early diagnosis of the ‘multicolored’ sacroiliac X-ray is looked onto; the syndesmophyte, squaring-phenomenon, barrel-shaped vertebra, Romanus and Andersson lesions, and the ossification of ligaments are discussed. The changes at the apophyseal and the costovertebral joints, unimportant for early diagnosis, are explored.

A grading system involving six stages of arthritis from grade 0 = normal joints to grade V = extensive bony ankylosis in the sacro-iliac joints and a scheme applicable for quantitative registration of the radiographic findings of the spine in ankylosing spondylitis (AS) are detailed. These radiographic grading systems were used in a study comprising 48 patients with psoriasis (group A), 19 patients with AS and psoriasis (group B), 103 patients with AS (group C) and 231 first-degree relatives of the patients belonging to groups B and C (group D). Radiographic abnormalities of the spine were found totally in 80 per cent of the patients belonging to groups B and C. In these groups sclerotic anterior borders of vertebrae (SABS) and/or straightened anterior surfaces of vertebrae were seen totally in 66 per cent. SABS were earlier findings than syndesmophyte formation which was found in 60 per cent of the patients belonging to groups B and C. Except for ankylosis of the apophyseal joints and ossified interspinous ligament most frequently found in the lower lumbar region in patients with duration of disease more than 20 years, all abnormalities of the spine were most frequent in the dorsolumbar junction. Grade V sacro-iliitis was associated with ankylosis of two or more segments of the spine. Such spinal changes were infrequently seen in patients with grade IV sacro-iliitis. This finding supports the previous notion that among patients fulfilling the criteria for AS, there is a group with a non-ankylosing disease. Thus two different subgroups of AS could be identified. Except for frequent unilateral sacro-iliitis and slight changes of the spine in group A no radiographic differences were found between the groups A, B and C. Sacro-iliitis was found in 22 (9%) in group D, and 11 of those with sacro-iliitis had abnormalities of the spine compatible with AS.

The enthesopathic lesion of ankylosing spondylitis consists of a nonspecific, nongranulomatous inflammatory lesion which leads to destruction of the attachment of ligament to bone. Resulting erosion leads to reactive bone formation which may form a new enthesis and around the outer fibres of the annulus may lead to syndesmophyte formation. What determines the distribution of the enthesopathy and ankylosis is not known.

The radiological and scintigraphic findings in the skeletons of patients with psoriasis and psoriatic arthropathy are described. The results indicate that is it possible to detect inflammatory disease in joints by scintigraphy in patients who have not yet developed symptoms. The effect of treatment can be satisfactorily followed by serial scans. Further investigations and observations will be required to show whether the paravertebral calcification and syndesmophyte formation which has been described is really pathognomonic for psoriatic arthropathy.

Fifty two patients with psoriatic spondyloarthropathy were monitored prospectively over a mean of 57 months (range 30-107). A comprehensive protocol was used to assess clinical and radiological features of disease activity and severity. Serial radiographs showed a significant increase in the number of patients with syndesmophyte formation and sacroiliitis. In contrast, there was no significant increase in the number of patients with inflammatory neck pain or stiffness, back pain or stiffness, cervical spine limitation, or sacroiliac tenderness. Similarly, there were no significant changes in any of the direct or indirect measurements of thoracolumbar spine mobility. The presence of HLA-B27 did not appear to influence disease progression. These results suggest that although patients with psoriatic spondyloarthropathy have radiological progression of their disease, this remains clinically silent and does not compromise spinal mobility.

Seventeen patients with Reiter's disease who were included in an earlier prospective study, were reviewed 21 years after their initial episode. Two patients had active synovitis and this correlated with the duration of the initial episode, the extent of the initial synovitis and the peak ESR. In contrast the risk of developing ankylosing spondylitis, present in five patients, was unrelated to the duration of the initial episode or the extent of the initial peripheral synovitis but was greatest in those with a higher peak ESR. A comparison of radiological features at the onset and later showed that five patients had developed bilateral sacroiliac joint fusion although two of these had some sclerosis around the sacroiliac joints at the onset. Eight patients had multifocal marginal syndesmophytes which, in four, occurred without sacroiliac changes. Plantar spur formation and hip and shoulder disease were associated with spondylitis while destructive small joint changes were a feature of Reiter's disease itself. Ten patients were HLA B27 positive. The clinical features at onset were unrelated to the B27 type. Sacroiliitis, osteitis pubis, pelvic whiskering and vertebral squaring were only present in B27 positive patients but syndesmophyte formation was unrelated to B27 type.

Background To compare the glycosaminoglycan (GAG) content of lumbar intervertebral disks (IVDs) of patients with ankylosing spondylitis (AS) and healthy volunteers and to investigate the association of GAG depletion and disease-related clinical and imaging features. Methods Lumbar spines of 50 AS patients (mean age 50 ± 10.5 years) and 30 age-matched volunteers were studied with 3-T magnetic resonance imaging (MRI) and conventional radiographs (CR). The MRI protocol included high-resolution morphological sequences and the compositional GAG chemical exchange saturation transfer imaging technique (gagCEST). Morphological images were analyzed by three raters for inflammatory activity, fat deposition, disk degeneration, and structural changes on CR. Clinical and serological measures included the Bath AS Disease Activity (BASDAI) and Bath AS Function (BASFI) Indices and C-reactive protein (CRP) levels. GagCEST values of both groups were compared using a linear mixed model. Kendall-Tau correlation analyses were performed. Results GagCEST values were significantly lower in AS patients (2.0 ± 1.7%) vs. healthy volunteers (2.4 ± 1.8%), p = 0.001. Small, yet significant correlations were found between gagCEST values and CRP levels (τ = − 0.14, p = 0.007), BASFI (τ = − 0.18, p τ = − 0.17, p = 0.001). No significant correlations were found with BASDAI, inflammation, and fat deposition MRI scores. Conclusions Lumbar spines of r-AS patients undergo significant GAG depletion, independently associated with syndesmophyte formation, functional disability, and increased serological inflammation markers. Beyond establishing a pathophysiological role of the cartilage in AS, these findings suggest that gagCEST imaging may have an adjunct confirmatory role in the assessment of disease-related pathological MRI findings in axial spondyloarthritis. Trial registration 3980 (https://studienregister.med.uni-duesseldorf.de)

Objectives Accurate measurement of syndesmophyte development and growth in ankylosing spondylitis (AS) is needed for studies of biomarkers and of treatments to slow spinal fusion. We tested the longitudinal validity and sensitivity to change of quantitative measurement of syndesmophytes using CT. Methods We performed lumbar spine CT scans on 33 patients with AS at baseline, 1 year and 2 years. Volumes and heights of syndesmophytes were computed in four intervertebral disk spaces. We compared the computed changes to a physician9s ratings of change based on CT scan inspection. Sensitivity to change of the computed measures was compared with that of the modified Stoke AS Spinal Score (radiography) and a scoring method based on MRI. Results At years 1 and 2, respectively 24 (73%) and 26 (79%) patients had syndesmophyte volume increases by CT. At years 1 and 2, the mean (SD) computed volume increases per patient were, respectively 87 (186) and 201 (366) mm3. Computed volume changes were strongly associated with the physician9s visual ratings of change (p Conclusions CT-based syndesmophytes measurements had very good longitudinal validity and better sensitivity to change than radiography or MRI. This method shows promise for longitudinal clinical studies of syndesmophyte development and growth.

Introduction: 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: 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). Results: 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. Conclusions: 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.