RESEARCH - TNF blockade does not modulate synovial expression of HMGB1 in RA

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Arthritis Research & Therapy 2008, 10:R33doi:10.1186/ar2387

Published: 17 March 2008

Systemic TNF blockade does not modulate synovial expression of the

pro-inflammatory mediator HMGB1 in rheumatoid arthritis patients - a

prospective clinical study

Sundberg , Cecilia Grundtman , af Klint , Johan Lindberg ,

Sofia Ernestam , Ann- Ulfgren , Helena Erlandsson and

Ulf Andersson

Abstract (provisional)

Background

High mobility group box chromosomal protein 1 (HMGB1) has recently

been identified as an endogenous mediator of arthritis. Both tumour

necrosis factor (TNF) and IL-1beta, pivotal cytokines in arthritis

pathogenesis, have the ability to induce HMGB1 release from myeloid

and dendritic cells. We therefore decided to investigate whether

treatment based on TNF blockade in rheumatoid arthritis (RA) affects

the expression of synovial HMGB1.

Methods

Repeated arthroscopy-guided samplings of synovial tissue were

performed in nine RA patients before and nine weeks after initiation

of anti-TNF monoclonal antibody (Infliximab) therapy. Synovial biopsy

specimens were analysed for HMGB1 protein by immunohistochemical

staining and for HMGB1 mRNA expression by real-time reverse

transcriptase polymerase chain reaction (RT-PCR). Statistical

evaluations were based on Wilcoxon's signed rank test or Spearman rank

sum test.

Results

Aberrant, extranuclear HMGB1 and constitutive nuclear HMGB1 expression

along with histological signs of inflammation were evident in all

biopsies obtained prior to infliximab therapy. Signs of inflammation

were still evident in the second biopsies obtained after nine weeks of

infliximab therapy. The cytoplasmic and extracellular expression of

HMGB1 decreased in five patients, remained unchanged in one patient

and increased in three patients, rendering the overall change in HMGB1

protein expression not significant. No correlation between the

clinical response (DAS28 and ACR20, 50 & 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.

Conclusions

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.

http://arthritis-research.com/content/10/2/R33/abstract

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