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01.06.2014 | Research article | Ausgabe 3/2014 Open Access

Arthritis Research & Therapy 3/2014

Synovial explant inflammatory mediator production corresponds to rheumatoid arthritis imaging hallmarks: a cross-sectional study

Zeitschrift:
Arthritis Research & Therapy > Ausgabe 3/2014
Autoren:
Martin Andersen, Mikael Boesen, Karen Ellegaard, Robin Christensen, Kalle Söderström, Niels Søe, Pieter Spee, Ulrik GW Mørch, Søren Torp-Pedersen, Else Marie Bartels, Bente Danneskiold-Samsøe, Nina Vendel, Lars Karlsson, Henning Bliddal
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​ar4557) contains supplementary material, which is available to authorized users.

Competing interests

During the course of this study Martin Andersen, Kalle Söderstöm, Pieter Spee, Ulrik GW Mørch, and Lars Karlsson were employed at Novo Nordisk. Kalle Söderstöm, Pieter Spee, Ulrik GW Mørch, and Lars Karlsson owned stocks in Novo Nordisk. MA, KS, UGWM, PS and LK were all employed by Novo Nordisk during the patient recruitment period. KS, PS, UGWM and LK owned stocks in Novo Nordisk.

Abstract

Introduction

Despite the widespread use of magnetic resonance imaging (MRI) and Doppler ultrasound for the detection of rheumatoid arthritis (RA) disease activity, little is known regarding the association of imaging-detected activity and synovial pathology. The purpose of this study was to compare site-specific release of inflammatory mediators and evaluate the corresponding anatomical sites by examining colour Doppler ultrasound (CDUS) and MRI scans.

Methods

RA patients were evaluated on the basis of CDUS and 3-T MRI scans and subsequently underwent synovectomy using a needle arthroscopic procedure of the hand joints. The synovial tissue specimens were incubated for 72 hours, and spontaneous release of monocyte chemoattractant protein 1 (MCP-1), interleukin 6 (IL-6), macrophage inflammatory protein 1β (MIP-1β) and IL-8 was measured by performing multiplex immunoassays. Bone marrow oedema (BME), synovitis and erosion scores were estimated on the basis of the rheumatoid arthritis magnetic resonance imaging score (RAMRIS). Mixed models were used for the statistical analyses. Parsimony was achieved by omitting covariates with P > 0.1 from the statistical model.

Results

Tissue samples from 58 synovial sites were obtained from 25 patients. MCP-1 was associated with CDUS activity (P = 0.009, approximate Spearman’s ρ = 0.41), RAMRIS BME score (P = 0.01, approximate Spearman’s ρ = 0.42) and RAMRIS erosion score (P = 0.03, approximate Spearman’s ρ = 0.31). IL-6 was associated with RAMRIS synovitis score (P = 0.04, approximate Spearman’s ρ = 0.50), BME score (P = 0.04, approximate Spearman’s ρ = 0.31) and RAMRIS erosion score (P = 0.03, approximate Spearman’s ρ = 0.35). MIP-1β was associated with CDUS activity (P = 0.02, approximate Spearman’s ρ = 0.38) and RAMRIS synovitis scores (P = 0.02, approximate Spearman’s ρ = 0.63). IL-8 associations with imaging outcome measures did not reach statistical significance.

Conclusions

The association between imaging activity and synovial inflammatory mediators underscores the high sensitivity of CDUS and MRI in the evaluation of RA disease activity. The associations found in our present study have different implications for synovial mediator releases and corresponding imaging signs. For example, MCP-1 and IL-6 were associated with both general inflammation and bone destruction, in contrast to MIP-1β, which was involved solely in general synovitis. The lack of association of IL-8 with synovitis was likely underestimated because of a large proportion of samples above assay detection limits among the patients with the highest synovitis scores.
Zusatzmaterial
Additional file 1: Table depicting the anatomic landmarks defining each ultrasound scan position. Standardized ultrasound scanning planes, image selection, and image quantification. Description of data: overview of the standardized ultrasound scanning planes and description of the colour Doppler quantification method. (DOCX 14 KB)
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Additional file 2: Table giving an overview of the multiplex panel chosen for the supernatant analysis and description of the multiplex panel and rationale behind the selection of synovial mediators used in the study. (RTF 14 KB)
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Additional file 3: Figure showing scatterplots of statistically insignificant associations of synovial mediator release and CF max and RAMRIS synovitis score. Scatterplots depict synovitis, defined as synovial perfusion by colour fraction max (CFmax) and the RAMRIS synovitis score vs. synovial explant release (in pg/ml) after 72 hours of culture that did not reach a statistically significant association. For CFmax: (a) IL-6 (P = 0.23, approximated ρ = 0.22). (b) IL-8 (P = 0.09, approximated ρ = 0.27). For the RAMRIS synovitis score: (c) MCP-1 (P = 0.17, approximated ρ = 0.48). (d) IL-8 (P = 0.05, approximated ρ = 0.58). IL, Interleukin; MCP-1, Monocyte chemoattractant protein 1; RAMRIS, Rheumatoid arthritis magnetic resonance imaging score. (TIFF 1 MB)
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Additional file 4: Figure showing scatterplots of statistically insignificant associations of synovial mediator release and RAMRIS BME and RAMRIS erosion scores. Scatterplots depict bone erosion measured by the RAMRIS bone marrow oedema (BME) and bone erosion score vs. synovial explant release (pg/ml) after 72 hours in culture that did not reach statistical significance. RAMRIS BME: (a) IL-8 (P = 0.16, approximated ρ = 0.27). (b) MIP-1β (P = 0.95, approximated ρ = 0.35). RAMRIS erosion: (c) IL-8 (P = 0.07, approximated ρ = 0.43). (d) MIP-1β (P = 0.62, approximated ρ = 0.30). IL, Interleukin; MIP-1β, Monocyte inflammatory protein 1β; RAMRIS, Rheumatoid arthritis magnetic resonance imaging score. (TIFF 517 KB)
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Additional file 5: Table providing an overview of the stepwise covariate elimination in the statistical models with regard to synovial mediator production and CDUS activity. This table depicts the statistical associations between colour Doppler ultrasound (p = CDUS) activity and synovial explant mediator release after 72 hours in culture. A mixed model has been used for the statistical analysis. P < 0.05 was considered significant. In the reduced model, covariates were excluded if the P-value was >0.10. All of the four prespecified covariates tested in the models are shown. (DOC 54 KB)
13075_2013_4274_MOESM5_ESM.doc
Additional file 6: Table giving an overview of the stepwise covariate elimination in the statistical models with regard to synovial mediator production and RAMRIS synovitis score. This table depicts the statistical associations between the rheumatoid arthritis magnetic resonance imaging synovitis score (RAMRIS) component in the part of the joint that was synovectomised and synovial explant mediator release after 72 hours in culture. A mixed model was used for the statistical analysis. P < 0.05 was considered significant. In the reduced model, covariates were excluded when P-values were >0.10. All of the four prespecified covariates tested in the models are shown. (DOC 53 KB)
13075_2013_4274_MOESM6_ESM.doc
Additional file 7: Table providing an overview of the stepwise covariate elimination in the statistical models with regard to synovial mediator production and RAMRIS BME score. This table depicts the statistical associations between the rheumatoid arthritis magnetic resonance imaging bone marrow oedema score (focal RAMRIS BME) component and synovial explant mediator release after 72 hours in culture. A mixed model was used for the statistical analysis. P < 0.05 was considered significant. In the reduced model, covariates were excluded if P-values were >0.10. All of the four prespecified covariates tested in the models are shown. (DOC 53 KB)
13075_2013_4274_MOESM7_ESM.doc
Additional file 8: Table depicting the statistical associations between the rheumatoid arthritis magnetic resonance imaging erosion score (RAMRIS) component in the part of the joint that was synovectomised and synovial explant mediator release after 72 hours in culture. Overview of the stepwise covariate elimination in the statistical models with regards to synovial mediator production and the RAMRIS erosion score. A mixed model was used for the statistical analysis. P < 0.05 was considered significant. In the reduced model, covariates were excluded if P > 0.10. All of the four prespecified covariates tested in the models are shown. (DOC 54 KB)
13075_2013_4274_MOESM8_ESM.doc
Authors’ original file for figure 1
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Authors’ original file for figure 2
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Authors’ original file for figure 3
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