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

Maksymowych, Walter P.; Morency, Nathalie; Conner‐Spady, Barbara; Lambert, Robert G.

doi:10.1136/annrheumdis-2011-200859

Cited by 180 publications

(104 citation statements)

References 26 publications

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“…Recently published MRI data suggest that resolution of inflammation (i.e., bone marrow edema) in the spine may be associated with the development of fat metaplasia in the same area and later also with the development of new syndesmophytes (5)(6)(7). The sequence of events seen on MRI that lead to the development of ankylosis in the SI joints has not yet been established, but it has been assumed based on radiography that ankylosis follows resolution of erosion.…”

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confidence: 99%

Fat Metaplasia and Backfill Are Key Intermediaries in the Development of Sacroiliac Joint Ankylosis in Patients With Ankylosing Spondylitis

Maksymowych

Wichuk

Chiowchanwisawakit

et al. 2014

Arthritis & Rheumatology

125

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Objective. Fat metaplasia in bone marrow on T1-weighted magnetic resonance imaging (MRI) scans may develop after resolution of inflammation in patients with ankylosing spondylitis (AS) and may predict new bone formation in the spine. Similar tissue, termed backfill, may also fill areas of excavated bone in the sacroiliac (SI) joints and may reflect resolution of inflammation and tissue repair at sites of erosions. The purpose of this study was to test our hypothesis that SI joint ankylosis develops following repair of erosions and that tissue characterized by fat metaplasia is a key intermediary step in this pathway.Methods. We used the Spondyloarthritis Research Consortium of Canada (SPARCC) SI structural lesion score (SSS) method to assess fat metaplasia, erosions, backfill, and ankylosis on MRIs of the SI joints in 147 patients with AS monitored for 2 years. Univariate and multivariate regression analyses focused first on identifying significant MRI predictors of new backfill and fat metaplasia. We then assessed the role of backfill and fat metaplasia in the development of new ankylosis. All analyses were adjusted for demographic features, treatment, and baseline and 2-year change in SSS values for parameters of inflammation and MRI structural lesions.Results. Resolution of inflammation and reduction of erosions were each independently associated with the development of new backfill and fat metaplasia at 2 years on multivariate analyses. Multivariate regression analysis that included demographic features, baseline and 2-year change in parameters of inflammation and MRI structural lesion showed that reduction in erosions (P ‫؍‬ 0.0005) and increase in fat metaplasia (P ‫؍‬ 0.002) at 2 years was each independently associated with the development of new ankylosis.Conclusion. Our data support a disease model whereby ankylosis develops following repair of erosions, and fat metaplasia and backfill are key intermediary steps in this pathway.Spondyloarthritis (SpA) is an inflammatory disorder primarily of the axial spine that typically begins with sacroiliitis. The first sign of disease on radiography is the appearance of erosion of the subchondral bone of the ilium, which is seen as a blurred cortical outline. Progression results in more extensive erosion involving the sacral bone and the appearance of pseudowidening. Subsequent features include bone sclerosis and, finally, ankylosis across the joint. Magnetic resonance imaging (MRI) constitutes a major advance in the field through its ability to demonstrate active inflammation on fatsuppressed sequences, such as short tau inversion recovery (STIR), and structural lesions, such as fat metaplasia, erosions, and ankylosis, on T1-weighed sequences (1).

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confidence: 99%

Fat Metaplasia and Backfill Are Key Intermediaries in the Development of Sacroiliac Joint Ankylosis in Patients With Ankylosing Spondylitis

Maksymowych

Wichuk

Chiowchanwisawakit

et al. 2014

Arthritis & Rheumatology

125

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“…Some more recent data suggest that osteoplastic changes in ankylosing spondylitis develop as independent reparative processes in the sites where the inflammatory changes ("early lesions") reached the limits of irreversible changes ("advanced lesions") (7). Early lesions were defined by an increased signal on STIR MR sequences; an advanced lesion is indicated by a decrease in the increased signal in STIR sequences from the apex of the vertebral corner and changes in T1 weighed scans in this localization (erosion, sclerotization, fat infiltration).…”

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confidence: 99%

“…By the action of various regulatory mechanisms there then develops proliferation of the bone, which then may take place independently of the presence or absence of inflammation. New syndesmophytes have been demonstrated to develop unequivocally more often in the sites of these "advanced lesions" (7).…”

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confidence: 99%

The Vegf and BMP-2 Levels in Patients With Ankylosing Spondylitis and the Relationship to Treatment With Tumour Necrosis Factor Alpha Inhibitors

Tošovský

Bradna

Andrýs

et al. 2014

Acta Med. (Hradec Kralove, Czech Repub.)

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Summary:Introduction: Ankylosing spondylitis (AS) is an inflammatory rheumatic disease characterized by the development of osteoproductive changes in the spine which could possibly result in ankylosis. Treatment with tumour necrosis factor alpha (TNFα) inhibitors has proved to be an important step forward in the treatment of this disease, but for the time being it is not clear whether it favourably influences radiographic progression of the disease. Vascular endothelial growth factor most probably plays a role in the development of osteoproductive changes and recently its predictive influence on radiographic progression has been demonstrated. Bone morphogenic protein 2 (BMP-2) participates in the regulation of bone proliferation and its increased serum level has been demonstrated in patients with advanced AS and correlated with the degree of radiographic changes. Aim: The study aims to evaluate the VEGF and BMP-2 levels in patients with ankylosing spondylitis and how these levels relate to the concurrent treatment with TNFα inhibitors. Methods: Sera were evaluated from patients at the Rheumatologic Clinic of the Hradec Králové Faculty Hospital who fulfilled the modified New York Criteria for AS (n = 55). In these patients, the parameters of the activity of the disease (BASDAI = Bath Ankylosing Spondylitis Disease Activity Index, CRP = C-reactive protein) and the concurrent therapy (TNFα inhibitors, n = 21, vs. non-anti TNFα, n = 34) were recorded. The levels of VEGF and BMP-2 were analyzed using the ELISA method. Results: In patients treated with TNFα inhibitors, a significantly lower VEGF level was found when compared to untreated patients (140.3 (109.4; 262.2) vs. 261 (172.4; 396.6) pg/ml; p = 0.02). No difference was found between BMP-2 levels in both groups (treated vs. untreated patients) (254.8 (2301; 267.3) vs. 261.1 (248.6; 273.5) pg/ml; p = 0.24). A correlation analysis did not reveal any relationship between VEG F and BMP-2 (r = 0.057; p = 0.68). Serum levels of VEGF correlated with serum levels of CRP (r = 0.56; p = 0.00001) and the BASDAI value (r = 0.33; p = 0.015). Conclusion: Significantly lower VEGF levels were found in patients treated with TNFα inhibitors versus the untreated patients. These findings are in harmony with some hitherto published analyses and may give evidence of a favourable effect of TNFα inhibitors on radiographic progression. Neither influence on the BMP-2 level by treatment with TNFα inhibitors nor correlation with VEGF levels was demonstrated.

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“…The objective of preventing or slowing the development of structural damage assessed by radiographic ossification is difficult to attain. Recent studies suggest that early effective treatment may influence radiographic outcome [11,12], even if data about benefit of a tight control strategy in axial SpA are lacking. Identification of patients with poor prognosis is another need, and the ongoing prospective cohorts of patients with early axial SpA [13] will hopefully bring some answers in this field.…”

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confidence: 99%

Treating to target in axial spondyloarthritis: defining the target and the arrow

Wendling

2015

Expert Review of Clinical Immunology

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

Abstract: 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.

Cited by 180 publications

References 26 publications

Fat Metaplasia and Backfill Are Key Intermediaries in the Development of Sacroiliac Joint Ankylosis in Patients With Ankylosing Spondylitis

Fat Metaplasia and Backfill Are Key Intermediaries in the Development of Sacroiliac Joint Ankylosis in Patients With Ankylosing Spondylitis

The Vegf and BMP-2 Levels in Patients With Ankylosing Spondylitis and the Relationship to Treatment With Tumour Necrosis Factor Alpha Inhibitors

Treating to target in axial spondyloarthritis: defining the target and the arrow

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