Evidence for uncoupling of inflammation and joint remodeling in a mouse model of spondylarthritis

Lories, Rik; Derese, Inge; Bari, Cosimo De; Luyten, Frank P.

doi:10.1002/art.22372

Cited by 170 publications

(125 citation statements)

References 54 publications

(76 reference statements)

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“…This research has not provided convincing evidence of slowing of radiographic progression, despite anti-TNF treatment for up to 4 years. Explanatory theories suggest that inflammation and bony progression are 2 independent pathways, and that suppression of inflammation may not prevent spinal ankylosis (34). The impact of TNF blockade on new bone formation in the spine has been controversial, and it has been suggested that once inflammation has started, the bony progression cannot be halted with suppression of TNF alone.…”

Section: Discussionmentioning

confidence: 99%

Clinical and imaging efficacy of infliximab in HLA–B27–Positive patients with magnetic resonance imaging–determined early sacroiliitis

Barkham

Keen

Coates

et al. 2009

Arthritis & Rheumatism

268

152

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Objective. To evaluate the efficacy of infliximab in HLA-B27-positive patients with magnetic resonance imaging (MRI)-determined early sacroiliitis, using both clinical and MRI assessments.Methods. Forty patients with recent-onset inflammatory back pain, as assessed by the Calin criteria, HLA-B27 positivity, clinical disease activity as measured by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), pain and morning stiffness, and magnetic resonance imaging (MRI)-determined sacroiliac joint bone edema were randomized in a doubleblind manner to receive infliximab 5 mg/kg or placebo at 0, 2, 6, and 12 weeks. MRI scans were performed at baseline and 16 weeks and scored by 2 observers (blinded to both the order of the scans and to treatment group), using the Leeds scoring system. Clinical assessments included the BASDAI, the Bath Ankylosing Spondylitis Functional Index (BASFI), the Ankylosing Spondylitis Quality of Life (ASQoL) instrument, the ASsessment in Ankylosing Spondylitis International Working Group criteria (ASAS) for improvement, and markers of inflammation.Results. The mean reduction in the total MRI score from week 0 to week 16 was significantly greater in infliximab-treated patients compared with placebotreated patients (P ‫؍‬ 0.033). On average, significantly more lesions resolved in the infliximab group (P < 0.001), while significantly more new lesions developed in the placebo group (P ‫؍‬ 0.004). Significantly greater improvement in the infliximab group versus the placebo group was also observed for changes from week 0 to week 16 in the BASDAI (P ‫؍‬ 0.002), BASFI (P ‫؍‬ 0.004), and ASQoL (P ‫؍‬ 0.007) scores. Responses according to the ASAS criteria for 40% improvement, the ASAS criteria for 20% improvement in 5 of 6 domains, and ASAS partial remission were achieved by 61%, 44%, and 56% of infliximab-treated patients, respectively. Infliximab was well tolerated, and no serious adverse events were observed.Conclusion. Infliximab was an effective therapy for early sacroiliitis, providing a reduction in disease activity by week 16. This study is the first to show that infliximab is effective for reducing clinical and imaging evidence of disease activity in patients with MRIdetermined early axial spondylarthritis.Ankylosing spondylitis (AS), the prototype spondylarthritis (SpA), is increasingly recognized as an important and potentially treatable condition. AS is more common than previously estimated, with some studies suggesting a prevalence similar to that of rheumatoid European Clinical Trials (EudraCT)

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Section: Discussionmentioning

confidence: 99%

Clinical and imaging efficacy of infliximab in HLA–B27–Positive patients with magnetic resonance imaging–determined early sacroiliitis

Barkham

Keen

Coates

et al. 2009

Arthritis & Rheumatism

268

152

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“…However, data from animal models of spondylarthritis (SpA), principally ankylosing enthesitis, directly challenged this hypothesis by demonstrating that anti-tumor necrosis factor ␣ (anti-TNF␣) therapy did not prevent the development of ankylosis (1). An alternative hypothesis was then proposed whereby pathogenetic factors such as altered gene expression, biomechanical factors, and bacteria trigger the concomitant expression of inflammation and new bone formation, which then proceed along essentially autonomous pathways (2).…”

mentioning

confidence: 99%

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

Chiowchanwisawakit

Lambert

Conner‐Spady

et al. 2011

Arthritis & Rheumatism

181

117

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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 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.A hallmark of ankylosing spondylitis (AS) is the development of new bone in the spine, which typically leads to ankylosis across the disc spaces. Bone proliferation typically starts at the vertebral rim and grows in the direction of the anulus fibrosus, parallel to the vertebral axis. Ossification may extend across the vertical length of the anulus and becomes visible on radiographs as a syndesmophyte.Until recently, it was hypothesized that ankylosis occurred in response to inflammation and following a reparative process that included cartilage metaplasia. However, data from animal models of spondylarthritis (SpA), principally ankylosing enthesitis, directly challenged this hypothesis by demonstrating that anti-tumor necrosis factor ␣ (anti-TNF␣) therapy did not prevent the development of ankylosis (1). An alternative hypothesis was then proposed whereby pathogenetic factors such as altered gene expression, biomechanical factors, and bacteria trigger the concomitant expression of inflammation and new bone formation, which then proceed

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“…The Luyten's group has characterized the spondyloarthropathy-like arthritis that spontaneously develops in aging DBA/1 mice. 2,3 In this mouse model, new bone formation starts at the enthesis and occurs through endochondral ossification. 2 On the other hand, Benjamin and McGonagle have thoroughly studied the age-related enthesophyte formation in the Achilles tendon in both rodents and humans.…”

mentioning

confidence: 99%

“…10 Moreover, although anti-tumor necrosis factor a (anti-TNF-a) therapies have been shown to improve most symptoms in AS patients, they have proven unsuccessful to block the progression of bone spurs both in patients with AS, 7,10 and in the DBA/1 model of spondyloarthropathy. 3 The fact that anti-TNF treatments do not significantly alter the course of syndesmophyte formation may be due to the fact that TNF-a likely displays both stimulatory and inhibitory effects, as it does in endochondral ossification during bone healing. [11][12][13] It is also possible that other cytokines are involved in syndesmophyte formation.…”

mentioning

confidence: 99%

Cell-specific effects of TNF-α and IL-1β on alkaline phosphatase: implication for syndesmophyte formation and vascular calcification

Lencel

Delplace

Pilet

et al. 2011

Laboratory Investigation

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Tumor necrosis factor (TNF)-a and interleukin (IL)-1b stimulate tissue non-specific alkaline phosphatase (TNAP) activity and mineralization in cultures of vascular smooth muscle cells (VSMCs). They are, therefore, considered as stimulators of vascular calcification in the context of atherosclerosis and diabetes type 2. In contrast, although ankylosing spondylitis (AS) leads to the formation of syndesmophytes, which are ectopic ossifications from entheses (where ligaments, tendons and capsules are attached to bone), anti-TNF-a therapies fail to block bone formation in this disease. In this context, our aims were to compare the effects of TNF-a and IL-1b on TNAP activity and mineralization in entheseal cells and VSMCs. Organotypic cultures of mouse ankle entheses were treated or not with TNF-a and IL-1b for 5 days. Micro-computed tomography was performed to determine trabecular bone parameters, and histology to assess TNAP activity and mineralization. Human mesenchymal stem cells cultured in pellets in chondrogenic conditions and human VSMCs were also used to determine the effects of cytokines on TNAP activity and expression, measured by quantitative PCR. In organotypic cultures, TNF-a and IL-1b significantly reduced the tibia BV/TV ratio. They also inhibited TNAP activity in entheseal chondrocytes in situ, and in mouse and human chondrocytes in vitro. In contrast, TNF-a stimulated TNAP expression and activity in human VSMCs. These differences were likely due to cell-specific effects of peroxisome proliferator-activated receptor g (PPARg), which is inhibited by TNF-a. Indeed, in human chondrocytes and VSMCs, the PPARg inhibitor GW-9662 displayed the same opposite effects as TNF-a on TNAP expression. In conclusion, whereas TNF-a and IL-1b stimulate TNAP activity in VSMCs, they inhibit it in entheseal cells in situ and on chondrocytes in vitro. The identification of PPARg as a likely mediator of cytokine effects deserves consideration for future research on the mechanisms of ectopic ossification.

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Evidence for uncoupling of inflammation and joint remodeling in a mouse model of spondylarthritis

Cited by 170 publications

References 54 publications

Clinical and imaging efficacy of infliximab in HLA–B27–Positive patients with magnetic resonance imaging–determined early sacroiliitis

Clinical and imaging efficacy of infliximab in HLA–B27–Positive patients with magnetic resonance imaging–determined early sacroiliitis

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

Cell-specific effects of TNF-α and IL-1β on alkaline phosphatase: implication for syndesmophyte formation and vascular calcification

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