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Systemic TNF blockade does not modulate synovial expression of the pro-inflammatory mediator HMGB1 in rheumatoid arthritis patients--a prospective clinical study.
Arthritis Res Ther. 2008; 10(2):R33.AR

Abstract

INTRODUCTION

High-mobility group box chromosomal protein 1 (HMGB1) has recently been identified as an endogenous mediator of arthritis. TNF and IL-1beta, pivotal cytokines in arthritis pathogenesis, both have the ability to induce the release of HMGB1 from myeloid and dendritic cells. It was, therefore, decided to investigate whether treatment based on TNF blockade in rheumatoid arthritis (RA) affects the expression of synovial HMGB1.

METHODS

Repeated arthroscopy-guided sampling of synovial tissue was performed in nine patients with RA before and nine weeks after initiation of anti-TNF mAb (infliximab) therapy. Synovial biopsy specimens were analysed for HMGB1 protein by immunohistochemical staining and for HMGB1 mRNA expression by real-time reverse transcriptase PCR (RT-PCR). Statistical evaluations were based on Wilcoxon's signed rank tests or Spearman rank sum tests.

RESULTS

Aberrant, extranuclear HMGB1 and constitutive nuclear HMGB1 expression, with histological signs of inflammation, were evident in all biopsies obtained before infliximab therapy. Signs of inflammation were still evident in the second biopsies obtained nine weeks after initiation of infliximab therapy. The cytoplasmic and extracellular expression of HMGB1 decreased in five patients, remained unchanged in one patient and increased in three patients, making the overall change in HMGB1 protein expression not significant. No correlation between the clinical response, as measured by disease activity score calculated for 28 joints (DAS28) or the American College of Rheumatology response criteria (ACR 20, 50, and 70), and the direction of change of HMGB1 expression in individual patients could be discerned. In addition, infliximab therapy did not alter HMGB1 mRNA synthesis.

CONCLUSION

Pro-inflammatory HMGB1 expression during rheumatoid synovitis was not consistently influenced by TNF-blocking therapy with infliximab. This suggests that TNF is not the main inducer of extranuclear HMGB1 during synovitis and that HMGB1 may represent a TNF-independent molecule that could be considered as a possible target for future therapeutic intervention in RA.

Authors+Show Affiliations

Department of Woman and Child Health, Pediatric Rheumatology Research Unit, Karolinska Institutet/Karolinska University Hospital, Stockholm, Sweden. erik.sundberg@ki.seNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18346273

Citation

Sundberg, Erik, et al. "Systemic TNF Blockade Does Not Modulate Synovial Expression of the Pro-inflammatory Mediator HMGB1 in Rheumatoid Arthritis Patients--a Prospective Clinical Study." Arthritis Research & Therapy, vol. 10, no. 2, 2008, pp. R33.
Sundberg E, Grundtman C, Af Klint E, et al. Systemic TNF blockade does not modulate synovial expression of the pro-inflammatory mediator HMGB1 in rheumatoid arthritis patients--a prospective clinical study. Arthritis Res Ther. 2008;10(2):R33.
Sundberg, E., Grundtman, C., Af Klint, E., Lindberg, J., Ernestam, S., Ulfgren, A. K., Harris, H. E., & Andersson, U. (2008). Systemic TNF blockade does not modulate synovial expression of the pro-inflammatory mediator HMGB1 in rheumatoid arthritis patients--a prospective clinical study. Arthritis Research & Therapy, 10(2), R33. https://doi.org/10.1186/ar2387
Sundberg E, et al. Systemic TNF Blockade Does Not Modulate Synovial Expression of the Pro-inflammatory Mediator HMGB1 in Rheumatoid Arthritis Patients--a Prospective Clinical Study. Arthritis Res Ther. 2008;10(2):R33. PubMed PMID: 18346273.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Systemic TNF blockade does not modulate synovial expression of the pro-inflammatory mediator HMGB1 in rheumatoid arthritis patients--a prospective clinical study. AU - Sundberg,Erik, AU - Grundtman,Cecilia, AU - Af Klint,Erik, AU - Lindberg,Johan, AU - Ernestam,Sofia, AU - Ulfgren,Ann-Kristin, AU - Harris,Helena Erlandsson, AU - Andersson,Ulf, Y1 - 2008/03/17/ PY - 2007/11/21/received PY - 2008/02/26/revised PY - 2008/03/17/accepted PY - 2008/3/19/pubmed PY - 2008/9/24/medline PY - 2008/3/19/entrez SP - R33 EP - R33 JF - Arthritis research & therapy JO - Arthritis Res Ther VL - 10 IS - 2 N2 - INTRODUCTION: High-mobility group box chromosomal protein 1 (HMGB1) has recently been identified as an endogenous mediator of arthritis. TNF and IL-1beta, pivotal cytokines in arthritis pathogenesis, both have the ability to induce the release of HMGB1 from myeloid and dendritic cells. It was, therefore, decided to investigate whether treatment based on TNF blockade in rheumatoid arthritis (RA) affects the expression of synovial HMGB1. METHODS: Repeated arthroscopy-guided sampling of synovial tissue was performed in nine patients with RA before and nine weeks after initiation of anti-TNF mAb (infliximab) therapy. Synovial biopsy specimens were analysed for HMGB1 protein by immunohistochemical staining and for HMGB1 mRNA expression by real-time reverse transcriptase PCR (RT-PCR). Statistical evaluations were based on Wilcoxon's signed rank tests or Spearman rank sum tests. RESULTS: Aberrant, extranuclear HMGB1 and constitutive nuclear HMGB1 expression, with histological signs of inflammation, were evident in all biopsies obtained before infliximab therapy. Signs of inflammation were still evident in the second biopsies obtained nine weeks after initiation of infliximab therapy. The cytoplasmic and extracellular expression of HMGB1 decreased in five patients, remained unchanged in one patient and increased in three patients, making the overall change in HMGB1 protein expression not significant. No correlation between the clinical response, as measured by disease activity score calculated for 28 joints (DAS28) or the American College of Rheumatology response criteria (ACR 20, 50, and 70), and the direction of change of HMGB1 expression in individual patients could be discerned. In addition, infliximab therapy did not alter HMGB1 mRNA synthesis. CONCLUSION: Pro-inflammatory HMGB1 expression during rheumatoid synovitis was not consistently influenced by TNF-blocking therapy with infliximab. This suggests that TNF is not the main inducer of extranuclear HMGB1 during synovitis and that HMGB1 may represent a TNF-independent molecule that could be considered as a possible target for future therapeutic intervention in RA. SN - 1478-6362 UR - https://www.unboundmedicine.com/medline/citation/18346273/Systemic_TNF_blockade_does_not_modulate_synovial_expression_of_the_pro_inflammatory_mediator_HMGB1_in_rheumatoid_arthritis_patients__a_prospective_clinical_study_ L2 - https://arthritis-research.biomedcentral.com/articles/10.1186/ar2387 DB - PRIME DP - Unbound Medicine ER -