RESEARCH - Overexpression of synoviolin in peripheral blood and synoviocytes from RA patients, Remicade nonresponders

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Arthritis Rheum. 2006 Jun 26;54(7):2109-2118 [Epub ahead of print]

Overexpression of synoviolin in peripheral blood and synoviocytes from

rheumatoid arthritis patients and continued elevation in nonresponders to

infliximab treatment.

Toh ML, Marotte H, Blond JL, Jhumka U, Eljaafari A, Mougin B, Miossec P.

Unite Mixte Hospices Civils de Lyon-BioMerieux, Hopital Edouard Herriot,

Lyon, France.

OBJECTIVE: Synoviolin is a novel E3 ubiquitin ligase that has been

implicated in the pathogenesis of rheumatoid arthritis (RA). The purpose of

this study was to examine the expression and regulation of synoviolin by

tumor necrosis factor alpha (TNFalpha), both in vivo and in vitro. METHODS:

A total of 54 RA patients and 23 healthy control subjects were analyzed

before, 4 hours after the first infusion, and at week 22 of infliximab

treatment. Clinical response was assessed by the American College of

Rheumatology criteria for 20% improvement and the Disease Activity Score in

28 joints (DAS28) at 6 months. Synoviolin messenger RNA expression was

measured by real-time reverse transcription-polymerase chain reaction in

peripheral blood (PB) and fibroblast-like synoviocytes (FLS) and with and

without TNFalpha or interleukin-1beta (IL-1beta) stimulation. RESULTS:

Synoviolin expression was increased in whole PB obtained from RA patients as

compared with that from healthy controls and was significantly reduced early

and late after infliximab treatment in responders, but in not nonresponders.

Reduction in synoviolin expression was associated with reduced levels of

markers of disease activity, including C-reactive protein levels.

Nonresponders to infliximab therapy had significantly higher synoviolin

expression at baseline as compared with responders, and this elevation

persisted despite infliximab therapy. PB CD14+ monocytes expressed increased

synoviolin levels compared with CD3+ lymphocytes, and TNFalpha or IL-1beta

induced a further increase in expression in CD3+ cells. TNFalpha or IL-1beta

induced sustained synoviolin expression in RA FLS.

CONCLUSION: Elevated PB levels of synoviolin were identified in circulating

PB mononuclear cells and were associated with nonresponse to infliximab

treatment. Sustained up-regulation of synoviolin by IL-1beta and TNFalpha

may contribute to prolonged survival of immune cells and dysregulated FLS

proliferation, leading to RA chronicity.

PMID: 16802346

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=PubMed & list_uids=1\

6802346

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