ANNUAL REVIEW master Final3a - St Vincent's University Hospital

in patients with RA following withdrawal of their anti-TNFα therapy, by substituting optimal DMARD therapy.
We propose to identify predictive markers of relapse and identify a genetic profile associated with relapse.
Dr Ceara Walsh (clinical fellow), led by Prof Barry Bresnihan and Dr Ursula Fearon, is examining the role
NK/NKT/NKR+ cells in the patients with active RA compared with those in remission following anti-TNFα
therapy. To date results have shown an expansion of inhibitory receptor CD94/NKG2A in remission
associated with an increase in the CD8+ T cell population. Loss of this expansion may predict disease
relapse and therefore allow modification of dosing schedule with important health-economic and patient
related benefits. Furthermore we are showing a distinct population in the joint of RA and PsA patients
compared to the peripheral circulation with expansion of CD56high NK cells with an activated phenotype
(upregulation of activatory CD69 and HLA-DR and inhibition of CD158 KIR and apoptotic CD57). This
upregulation of CD56high NK cells has increased immunomodulatory function with a significant increase in
proinflammatory cytokine release (interferon-gamma and tumour necrosis factor-alpha) from T cells and
increased cytotoxicity of synovial fluid derived CD3+ cells against the leukaemia cell line K562 compared
with matched peripheral blood. Furthermore we are also examining the immunological effects of kineret
monotherapy and kineret in combination with anti-TNF· therapy (SPECTRA) and comparing this to anti-TNFα
monotherapy.
Rituximab is a recently licensed therapy, targeting CD20+ B cells, which is increasingly used in the treatment
of refractory RA. We have demonstrated the presence of CD20+ cells in the synovium of patients with RA
resistant to anti-TNFα therapies. Complete depletion of synovial B cells following treatment with rituximab is
associated with an excellent clinical response. Early depletion of synovial B cells precedes a decrease in local
inflammation leading to clinical improvement.
Biomarkers and predictors of disease
OMERACT project is an international study examining changes in synovial sublining CD68 in RA as a
biomarker of treatment response. This work is being carried out by Dr Eliza Pontifex and lead by Prof Barry
Bresnihan. 22 patients with RA have undergone synovial biopsies pre and post treatment with rituximab.The
slides obtained from this tissue have been stained for CD68 and are being quantitatively scored by digital
image analysis (DIA) in 2 different centres – AMC in Amsterdam (Prof PPTak) and SVUH in Dublin (Prof B
Bresnihan). Each of these centres uses slightly different staining and DIA techniques.These same slides will
then be swapped and sent to the centre in which they were NOT stained to be reanalyzed by DIA.The aim is
to determine the degree of correlation between the results of the 2 different centres, and thus possibly
validate the method of staining and quantification of sublining CD68 in RA despite the use of slightly
different techniques in different centres. Eliza is also examining if change in CD3 positive cell infiltration in
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