R.G. Lambert

Inflammatory lesions of the spine on magnetic resonance imaging predict the development of new syndesmophytes in ankylosing spondylitis: Evidence of a relationship between inflammation and new bone formation

OBJECTIVE To determine whether a vertebral corner that demonstrates an active corner inflammatory lesion (CIL) on magnetic resonance imaging (MRI) in patients with ankylosing spondylitis (AS) is more likely to evolve into a de novo syndesmophyte visible on plain radiography than is a vertebral corner that demonstrates no active inflammation on MRI. METHODS MRI scans and plain radiographs were obtained for 29 patients recruited into randomized placebo-controlled trials of anti-tumor necrosis factor alpha (anti-TNFalpha) therapy. MRI was conducted at baseline, 12 or 24 weeks (n=29), and 2 years (n=22), while radiography was conducted at baseline and 2 years. A persistent CIL was defined as a CIL that was found on all available scans. A resolved CIL was defined as having completely disappeared on either the second or third scan. A validation cohort consisted of 41 AS patients followed up prospectively. Anonymized MRIs were assessed independently by 3 readers who were blinded with regard to radiographic findings. RESULTS New syndesmophytes developed significantly more frequently in vertebral corners with inflammation (20%) than in those without inflammation (5.1%) seen on baseline MRI (P<or=0.008 for all reader pairs). They also developed more frequently in vertebral corners where inflammation had resolved than in those where inflammation persisted after anti-TNF treatment. This was confirmed in the analysis of the prospective cohort, in which significantly more vertebral corners with inflammation (14.3%) compared with those without inflammation (2.9%) seen on baseline MRI developed new syndesmophytes (P<or=0.003 for all reader pairs). CONCLUSION Our findings indicate that a syndesmophyte is more likely to develop from a prior inflammatory lesion, supporting a relationship between inflammation and ankylosis.

The diagnostic utility of magnetic resonance imaging in spondylarthritis: An international multicenter evaluation of one hundred eighty‐seven subjects

OBJECTIVE To systematically assess the diagnostic utility of magnetic resonance imaging (MRI) to differentiate patients with spondylarthritis (SpA) from patients with nonspecific back pain and healthy volunteers, using a standardized evaluation of MR images of the sacroiliac joints. METHODS Five readers blinded to the patients and diagnoses independently assessed MRI scans (T1-weighted and STIR sequences) of the sacroiliac joints obtained from 187 subjects: 75 patients with ankylosing spondylitis (AS; symptom duration ≤ 10 years), 27 patients with preradiographic inflammatory back pain (IBP; mean symptom duration 29 months), 26 patients with nonspecific back pain, and 59 healthy control subjects; all participants were age 45 years or younger. Bone marrow edema, fat infiltration, erosion, and ankylosis were recorded according to standardized definitions using an online data entry system. We calculated sensitivity, specificity, and positive and negative likelihood ratios (LRs) for the diagnosis of SpA based on global assessment of the MRI scans. RESULTS Diagnostic utility was high for all 5 readers, both for patients with AS (sensitivity 0.90, specificity 0.97, positive LR 44.6) and for patients with preradiographic IBP (sensitivity 0.51, specificity 0.97, positive LR 26.0). Diagnostic utility based solely on detection of bone marrow edema enhanced sensitivity (67%) for patients with IBP but reduced specificity (88%); detection of erosions in addition to bone marrow edema further enhanced sensitivity (81%) without changing specificity. A single lesion of the sacroiliac joint on MRI was observed in up to 27% of control subjects. CONCLUSION This systematic and standardized evaluation of sacroiliac joints in patients with SpA showed that MRI has much greater diagnostic utility than has been documented previously. We present for the first time a data-driven definition of MRI-visualized positivity for SpA.

Suppression of inflammation and effects on new bone formation in ankylosing spondylitis: evidence for a window of opportunity in disease modification

Objectives Although MRI data supports a link between spinal inflammation and formation of new bone in ankylosing spondylitis, anti-tumour necrosis factor α therapies have not been shown to prevent new bone formation. The authors aimed to demonstrate that while acute lesions resolve completely, more advanced lesions, characterised by evidence of reparation, are associated with new bone formation. Methods MRI scans were performed at baseline, 12 and 52 weeks in 76 ankylosing spondylitis patients recruited to a placebo-controlled trial of adalimumab therapy. New syndesmophytes were assessed on lateral radiographs of the cervical and lumbar spine at baseline and 104 weeks. Anonymised MRI scans were read independently by two readers who recorded the presence/absence of acute (type A) and advanced (type B) vertebral corner inflammatory lesions (CIL) and fat lesions. The authors used generalised linear latent and mixed models analysis to adjust for the extent of syndesmophytes/ankylosis at baseline. Results New syndesmophytes developed significantly more frequently from type B CIL (16.7%) compared with type A CIL (2.9%) (p=0.002) or no CIL (2.5%) (p<0.0001). This was also observed for both baseline and new vertebral corner fat lesions evolving over 52 weeks (11.1% (p<0.001) and 6.8% (p=0.03), respectively). The association with type B CIL (OR (95% CI 3.88, 1.20 to –12.57) and fat (OR 95% CI 4.83, 2.38– to 9.80), p<0.0001) was significant after adjustment for the extent of syndesmophytes/ankylosis at baseline. Conclusions Our data supports the hypothesis that new bone formation is more likely in advanced inflammatory lesions and proceeds through a process of fat metaplasia, supporting a window of opportunity for disease modification.

Focal fat lesions at vertebral corners on magnetic resonance imaging predict the development of new syndesmophytes in ankylosing spondylitis

OBJECTIVE Focal fat infiltration is frequently visible on magnetic resonance imaging (MRI) of the spine in patients with ankylosing spondylitis (AS) and likely reflects postinflammatory tissue metaplasia. To support the concept of coupling between inflammation and new bone formation, we tested the hypothesis that focal fat infiltration at a vertebral corner is more likely to evolve into a de novo syndesmophyte. METHODS MRI scans were obtained at baseline and radiographs were obtained at baseline and 2 years in 100 AS patients from 2 cohorts: a clinical trial cohort (n = 38) and an observational cohort (n = 62). In the clinical trial cohort, patients were randomized to receive anti-tumor necrosis factor (anti-TNF) therapy or placebo for 12-24 weeks and then open-label treatment for 2 years. In the observational cohort, patients received either standard therapy (n = 36) or anti-TNF therapy (n = 26) for 2 years. Vertebral corner inflammation and fat infiltration were assessed independently by pairs of readers who were blinded with regard to the radiographic findings. RESULTS New syndesmophytes developed significantly more frequently in vertebral corners with fat in both the clinical trial (10.2%) and the observational (6.5%) cohort as compared to those without either feature on baseline MRI (3.1% [P = 0.008] and 1.4% [P = 0.0002], respectively). Adjusting for within-patient variations in baseline syndesmophytes/ankylosis, vertebral corners that were fat-positive/inflammation-positive significantly predicted new syndesmophytes, with an odds ratio (OR) of 7.6 (95% confidence interval [95% CI] 1.5-38.5 [P = 0.01]), while a model that included baseline variations in both fat and inflammation showed an OR of 5.8 (95% CI 2.2-15.3 [P < 0.001]) for inflammation and an OR of 1.9 (95% CI 0.9-4.1 [P = 0.1]) for fat. CONCLUSION Our data lend support to the hypothesis that inflammatory lesions evolve into new bone through a process of tissue metaplasia that includes fat infiltration.

Assessment of structural lesions in sacroiliac joints enhances diagnostic utility of magnetic resonance imaging in early spondylarthritis

To compare the diagnostic utility of T1‐weighted and STIR magnetic resonance imaging (MRI) sequences in early spondylarthritis (SpA) using a standardized approach to the evaluation of sacroiliac (SI) joints, and to test whether systematic calibration of readers directed at recognition of abnormalities on T1‐weighted MRI would enhance diagnostic utility.

Resolution of inflammation following treatment of ankylosing spondylitis is associated with new bone formation.

Objective. To test the hypothesis that in patients with ankylosing spondylitis (AS) a vertebral corner inflammatory lesion (CIL) visible on magnetic resonance imaging (MRI) that completely resolves following treatment with anti-tumor necrosis factor-α (TNF-α) agents is more likely to develop into a de novo syndesmophyte visible on a radiograph as compared to a vertebral corner with no CIL. Methods. Fifty patients with AS, who had MRI at baseline and at followup (mean 19.2 months), and spinal radiography at baseline and after 2 years, were followed prospectively. A persistent CIL was defined as being present on both MRI, while a resolved CIL was defined as present at baseline MRI and completely disappeared at followup MRI. Two readers read the MRI independently, and analyses were done for areas with agreement (concordant reads) and for individual reads. Results. For patients receiving anti-TNF therapy (n = 23), new syndesmophytes developed more frequently from vertebral corners where a CIL had completely resolved on followup MRI (42.9% on concordant reads) as compared to vertebral corners where no CIL was demonstrable on either the baseline or followup MRI (2.4%; p < 0.0001). Results from individual readers showed similar differences. For patients receiving standard treatment (n = 27), the same pattern, although nonsignificant, was observed (20% vs 3.3%; p = 0.16) on concordant reads, as well as on individual reads. Conclusion. Our study of AS spines documents that MRI findings predict new bone formation on radiograph. Demonstration of an increased likelihood of developing new bone following resolution of inflammation after anti-TNF therapy supports the theory that TNF-α acts as a brake on new bone formation. Because the number of new syndesmophytes was low, further study is necessary to make firm conclusions.

Defining active sacroiliitis on MRI for classification of axial spondyloarthritis: update by the ASAS MRI working group

Objectives To review and update the existing definition of a positive MRI for classification of axial spondyloarthritis (SpA). Methods The Assessment in SpondyloArthritis International Society (ASAS) MRI working group conducted a consensus exercise to review the definition of a positive MRI for inclusion in the ASAS classification criteria of axial SpA. Existing definitions and new data relevant to the MRI diagnosis and classification of sacroiliitis and spondylitis in axial SpA, published since the ASAS definition first appeared in print in 2009, were reviewed and discussed. The precise wording of the existing definition was examined in detail and the data and a draft proposal were presented to and voted on by the ASAS membership. Results The clear presence of bone marrow oedema on MRI in subchondral bone is still considered to be the defining observation that determines the presence of active sacroiliitis. Structural damage lesions seen on MRI may contribute to a decision by the observer that inflammatory lesions are genuinely due to SpA but are not required to meet the definition. The existing definition was clarified adding guidelines and images to assist in the application of the definition. Conclusion The definition of a positive MRI for classification of axial SpA should continue to primarily depend on the imaging features of ‘active sacroiliitis’ until more data are available regarding MRI features of structural damage in the sacroiliac joint and MRI features in the spine and their utility when used for classification purposes.

ASDAS, BASDAI and different treatment responses and their relation to biomarkers of inflammation, cartilage and bone turnover in patients with axial spondyloarthritis treated with TNFα inhibitors

Objectives To investigate the relation between ankylosing spondylitis disease activity score (ASDAS), Bath ankylosing spondylitis disease activity index (BASDAI) and treatment response and biomarkers of inflammation (C-reactive protein (CRP), interleukin-6 (IL-6), YKL-40), angiogenesis (vascular endothelial growth factor (VEGF)), cartilage (C-terminal crosslinking telopeptide of type II collagen (CTX-II), matrix metalloproteinase-3 (MMP-3), total aggrecan, cartilage oligomeric matrix protein) and bone (C-terminal crosslinking telopeptide of type I collagen, osteocalcin) turnover in 60 patients with axial spondyloarthritis initiating tumour necrosis factor alpha (TNFα) inhibitor therapy. Methods ASDAS (CRP-based), BASDAI and biomarkers were determined before and seven times during 46 weeks of TNFα inhibitor therapy. Results Very high ASDAS were associated with high levels of inflammatory biomarkers, while high BASDAI were not related to any biomarkers. Mixed modeling demonstrated significant longitudinal associations between ASDAS and IL-6, VEGF, MMP-3 and osteocalcin and between BASDAI and CRP, IL-6 and VEGF. Major improvement in ASDAS was associated with larger percentage decreases in biomarkers of inflammation, angiogenesis, MMP-3 and increases in aggrecan and osteocalcin. BASDAI response was associated with larger decreases in CRP and IL-6. Biomarkers with moderate/high differences in responsiveness for major versus no/clinically important improvement in ASDAS were CRP, IL-6, VEGF, aggrecan and osteocalcin, and VEGF and CTX-II for BASDAI response versus non-response. Conclusion Levels and changes of 10 biomarkers in patients with axial spondyloarthritis during anti-TNFα therapy were documented. Construct validity and responsiveness of IL-6, VEGF, MMP-3, total aggrecan and osteocalcin were demonstrated. ASDAS was more associated with these biomarkers than BASDAI, and may better reflect the inflammatory disease processes. ClinicalTrials.gov identifier NCT00133315.

Radiographic progression is associated with resolution of systemic inflammation in patients with axial spondylarthritis treated with tumor necrosis factor α inhibitors: a study of radiographic progression, inflammation on magnetic resonance imaging, and circulating biomarkers of inflammation, angiogenesis, and cartilage and bone turnover.

OBJECTIVE To investigate the relationship of circulating biomarkers of inflammation (C-reactive protein [CRP], interleukin-6 [IL-6], and YKL-40), angiogenesis (vascular endothelial growth factor), cartilage turnover (C-terminal crosslinking telopeptide of type II collagen [CTX-II], total aggrecan, matrix metalloproteinase 3 [MMP-3], and cartilage oligomeric matrix protein [COMP]), and bone turnover (CTX-I and osteocalcin) to inflammation on magnetic resonance imaging (MRI) and radiographic progression in patients with axial spondylarthritis (SpA) beginning tumor necrosis factor α (TNFα) inhibitor therapy. METHODS MRIs were evaluated according to the Berlin sacroiliac (SI) joint and spine inflammation scoring method at baseline, week 22, and week 46. Radiographs were evaluated using the modified Stoke Ankylosing Spondylitis Spine Score at baseline and week 46. Patients with new syndesmophytes were identified. Biomarker levels in patients were compared to levels in healthy subjects. RESULTS Higher pretreatment MRI inflammation scores for SI joints and/or lumbar spine were associated with higher baseline CTX-II levels, but not with higher levels of biomarkers of inflammation and bone turnover. During treatment with TNFα inhibitors, a decrease in MRI inflammation scores from baseline to week 22 was associated with larger percentage decreases in and a normalization of CRP and IL-6 levels as compared to an increase or no change in MRI scores. Development of new syndesmophytes was associated with larger percentage decreases in CRP and IL-6 levels and an increase in osteocalcin level, and with normalization of CRP and IL-6 levels from baseline to week 22. Persistent systemic inflammation was associated with radiographic nonprogression. CONCLUSION Our findings indicate that inflammation on baseline MRI is associated with higher CTX-II levels. Radiographic progression is associated with decreased systemic inflammation, as assessed by IL-6 and CRP levels and MRI, supporting the notion of a link between the resolution of inflammation and new bone formation in SpA patients during anti-TNFα therapy.

Can erosions on MRI of the sacroiliac joints be reliably detected in patients with ankylosing spondylitis? - A cross-sectional study

IntroductionErosions of the sacroiliac joints (SIJ) on pelvic radiographs of patients with ankylosing spondylitis (AS) are an important feature of the modified New York classification criteria. However, radiographic SIJ erosions are often difficult to identify. Recent studies have shown that erosions can be detected also on magnetic resonance imaging (MRI) of the SIJ early in the disease course before they can be seen on radiography. The goals of this study were to assess the reproducibility of erosion and related features, namely, extended erosion (EE) and backfill (BF) of excavated erosion, in the SIJ using a standardized MRI methodology.MethodsFour readers independently assessed T1-weighted and short tau inversion recovery sequence (STIR) images of the SIJ from 30 AS patients and 30 controls (15 patients with non-specific back pain and 15 healthy volunteers) ≤45 years old. Erosions, EE, and BF were recorded according to standardized definitions. Reproducibility was assessed by percentage concordance among six possible reader pairs, kappa statistics (erosion as binary variable) and intraclass correlation coefficient (ICC) (erosion as sum score) for all readers jointly.ResultsSIJ erosions were detected in all AS patients and six controls by ≥2 readers. The median number of SIJ quadrants affected by erosion recorded by four readers in 30 AS patients was 8.6 in the iliac and 2.1 in the sacral joint portion (P < 0.0001). For all 60 subjects and for all four readers, the kappa value for erosion was 0.72, 0.73 for EE, and 0.63 for BF. ICC for erosion was 0.79, 0.72 for EE, and 0.55 for BF, respectively. For comparison, the kappa and ICC values for bone marrow edema were 0.61 and 0.93, respectively.ConclusionsErosions can be detected on MRI to a comparable degree of reliability as bone marrow edema despite the significant heterogeneity of their appearance on MRI.