PMID- 18346273
OWN - NLM
STAT- MEDLINE
DCOM- 20080923
LR  - 20220227
IS  - 1478-6362 (Electronic)
IS  - 1478-6354 (Print)
IS  - 1478-6354 (Linking)
VI  - 10
IP  - 2
DP  - 2008
TI  - Systemic TNF blockade does not modulate synovial expression of the 
      pro-inflammatory mediator HMGB1 in rheumatoid arthritis patients--a prospective 
      clinical study.
PG  - R33
LID - 10.1186/ar2387 [doi]
AB  - 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.
FAU - Sundberg, Erik
AU  - Sundberg E
AD  - Department of Woman and Child Health, Pediatric Rheumatology Research Unit, 
      Karolinska Institutet/Karolinska University Hospital, Stockholm, Sweden. 
      erik.sundberg@ki.se
FAU - Grundtman, Cecilia
AU  - Grundtman C
FAU - Af Klint, Erik
AU  - Af Klint E
FAU - Lindberg, Johan
AU  - Lindberg J
FAU - Ernestam, Sofia
AU  - Ernestam S
FAU - Ulfgren, Ann-Kristin
AU  - Ulfgren AK
FAU - Harris, Helena Erlandsson
AU  - Harris HE
FAU - Andersson, Ulf
AU  - Andersson U
LA  - eng
PT  - Clinical Trial
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20080317
PL  - England
TA  - Arthritis Res Ther
JT  - Arthritis research & therapy
JID - 101154438
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antirheumatic Agents)
RN  - 0 (HMGB1 Protein)
RN  - 0 (RNA, Messenger)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - B72HH48FLU (Infliximab)
SB  - IM
CIN - Arthritis Res Ther. 2008;10(3):111. PMID: 18557992
MH  - Adult
MH  - Aged
MH  - Antibodies, Monoclonal/*therapeutic use
MH  - Antirheumatic Agents/*therapeutic use
MH  - Arthritis, Rheumatoid/drug therapy/*metabolism
MH  - Arthroscopy
MH  - Female
MH  - Gene Expression
MH  - HMGB1 Protein/*biosynthesis/drug effects
MH  - Humans
MH  - Immunohistochemistry
MH  - Infliximab
MH  - Knee Joint/drug effects/metabolism
MH  - Male
MH  - Middle Aged
MH  - Pilot Projects
MH  - RNA, Messenger/analysis/drug effects
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Synovial Membrane/drug effects/*metabolism
MH  - Tumor Necrosis Factor-alpha/*antagonists & inhibitors/drug effects
PMC - PMC2452983
EDAT- 2008/03/19 09:00
MHDA- 2008/09/24 09:00
PMCR- 2008/03/17
CRDT- 2008/03/19 09:00
PHST- 2007/11/21 00:00 [received]
PHST- 2008/02/26 00:00 [revised]
PHST- 2008/03/17 00:00 [accepted]
PHST- 2008/03/19 09:00 [pubmed]
PHST- 2008/09/24 09:00 [medline]
PHST- 2008/03/19 09:00 [entrez]
PHST- 2008/03/17 00:00 [pmc-release]
AID - ar2387 [pii]
AID - 10.1186/ar2387 [doi]
PST - ppublish
SO  - Arthritis Res Ther. 2008;10(2):R33. doi: 10.1186/ar2387. Epub 2008 Mar 17.