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Northeast Region Meeting AbstractsPlenary Session.

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ACR NORTHEAST REGION MEETING ABSTRACTS: PLENARY SESSION
P1N
P4N
FIBRONECTIN LEVELS IN ANTIGEN-STIMULATED PERIPHERAL BLOOD MONONUCLEAR
CELLS FROM OSTEOARTHRITIS PATIENTS. Ileana Mitrache, Horsy Alsamadisi,
Nassau County Medical Center (NCMC), East Meadow, NY, Steven Carsons,
Winthrop University Hospital, Mineola, NY, Marlanne Frieri, NCMC, State
University of NY at Stony Brook, E. Meadow, Stony Brook. NY.
Recent evidence suggests that inflamnation plays an important role
in osteoarthritis (OA). Synovial mononuclear and mast cells may
Interact with the articular connective tlssue by promoting matrix
component synthesis and release of inflammatory mediators.
We hypothesized that activated peripheral blood mononuclear cells
(PBHC) might display enhanced release of protelns such as fibronectin
(FN) during active Inflammation in OA. PBMC were isolated from 15 OA
patients, clinically evaluated by history, physlcal examination, roentgenography, standard symptom and diary scores. PBMC were stimulated
with either 5ug/ml ConA, 10-4 M histamine. 10 u g h 1 of heparin proteoglycan or type 1 human collagen in the presence or absence of 50 u g h 1
and 100 u g h 1 of flurblprofen. PBMC secreted F N levels from supernatants were detected by Elisa. PBMC secreted FN levels were greater in
OA patients compared to normals (Y=1.4+.87 v5 F=0.47+.09 ng/ml ( p = r . 0 5 ) .
Flurbiprofen partially abrogated the PBMC secreted FN increase
mediated by heparin (53%) and type I human collagen (402). PBMC
secreted FN levels correlated clinically with the intensity of disease
in all OA patients according to symptom and/or diary score assessment
and in 7 of 8 patients evaluated on multiple visits. While inflammation
plays a role in OA, standard perlpheral Indicators of inflamnatory
activity are generally absent. The measurement of PBMC secreted FN may
play a role in the assessment of inflamnatory activity and treatment
in OA.
THE HLA-DRB3 LOCUS SUPERTYPIC ALLELE DIEv52a IS STRONGLY ASSOCIATMI
WITH SYSTEMIC LUPUS ERYTHEMAMSUS (SLE). Ashok Kumar, Priti Kumar,
Peter H . Schur, liarvard Medical School, Boston. Massachusetts.
The predominant qenetic elements contributinq to HLA associated
disease susceptibility for a number of autoimmune diseases have been
localized within the class I1 region of the major histocmpatibilitv
complex. DR3 is associated with SLF: in patients of Enqlish/Ieish
ancestry. The Polymerase Chain Reaction was used to amplifv the
second exon of OR beta qenes of Caucasian SLE patients and non SLE
controls. The amplified DNA was used for Sequence Specific
Oligonucleotide typins under high stringency conditions usinq DRw52a,
DRw52b. DRw52c. and D m 5 3 specific oliqonucleotide probes. 31 S m
patients (20 DR3; 11 nonDR3) and 29 nonSLE controls (19 DR3; 10 non
DR3) were typed. Thirty (97%) SLZ patients had a DRw52 allele. 22
(71%) patients were typed as ORw53. Eiqhteen (62%) nonSLE controls
had a DRw52 allele; 10 (35%) were typed as DRw53. The association of
O m 5 2 with SLB was stronger (RR~18.5) than with DRwS3 (RR=4.0) in a
population selccted to have a RR of 1.0 for OR3.
DRw52a
DRw52b
DRw52C
DRw53
Null
SLE
DR3 (120)
19(95%) 5(25%)
14(70%)
0
nonDR3 (111) 10(91%) 5(45%)
0
8(73%)
0
NonSLE DR3 (919) 17(90%) 1(5%)
0
2(11%l
2(11%1
nonDR3 (810) 1 (10%)
0
n
9(90%)
l(106)
The supertypic allele DRw52a had the stronqest association with SLE.
These observations sugqest that DRB3 qenes, in particular the DRw52a
allele, has a stronger association with SLE than DRBl or DRB4 qone
coded alleles.
P2N
A FlNAL. COMMON PATHWAY FOR ANTIINFLAMMATORY AGENTS: INHIBITION OF LBUKOCYTEENDOTHELIAL INTERACTIONS.SC Kimmel. MJ Van de
Stouwc RI Lcvin. G Wekmann. BN Cronstein NYU Medical Center., NYC, NY.
u
n
r(EQ before leaving the vasculature lor
inflamed 'arc& of tihsue injury or inflammation.' Sdicylates and-other nonstcmidal
antiintlammatory drugs NSAIDs) block ehemoattractant-induced (fMLP) PMNPMN
adhesion, an analo uc o$ PMN-EC interaction, by preventing affinity but ~t frequency
modulation of the %MN integrin, CD1lh/CD18. In contrast, cortimtcroids (CS)affect
PMNPMN adhesion only at cxtrcmcly high concentrations. We determined whether
a m m o n mode of action as antiinflammatory agents:
NSAIDs and ~ i c o S t e m K tsharc
s
diminished PMN-ECinteractions. At antiinflammatoryconcentrations(05-lOmM), sodium
salicylate (SAL.), an NSAlD which does not inhibit pmtaglandin synthesis, inhibited
stimulated (fMLP, O.lpM but not unstimulated PMN adhercnffig 30 min) to culturcd
inhibited oxidative
human umbilical vein E& (IC, 1.5mM, n=2). Predictably, S
in stimulated hut not
pharphorylation, as widenced de letion of ATP stores (HP
rating PMN c.g, dccrement $87!*9Spmol/l~PMN
(ImM S ! p<O.Mw)I, n=8 A
metaboliteof A", adenosine, whether endogenouslyreleased or added, inhibits stimukted
PMN adherencc to EC. Adenosine deaminase (ADA, O.I25IU/ml),~which converts
extrwllular adenosine to its inactivc metaholite inosinc, r c v c d inhibition by SAL, of
PMN adherence to EC; an observation which suaests that SAL inhibits PMN adherence
9 $creasing rclcam of adenarinc (from ATP breakdown) from PMN, Ec or both.
Similarly, indomcthacin and pimicam (IO-mpM) inhibited stimuhtcd PMN adherencc to
E C again inhibition was partially reversed by addition of ADA. EC bcwmc more
adtkrcnt rbr resting PMN attcr stimulation with JJS increasing expression of adherence
molcculcs (sclectins) GMP140 wthin minutes) E L (hours) and ICAM (overnight
As expcctcd,more PMN a d h c d AS-prctrcai;ed(lpghnl for 4 h n than to rcsting E k
(40+1 vs. 7 f . 2 PMNhpf, c.001,n=8). Dmmelhasone (ZSnM-ApM), added during
LPS treatment, diminished up to 50% (p<0.001,n=3 ,incrcaaed Ecadheaiveness. The
data suggest that NSAIDs and cortimteroids blunt inhammation by inhihiting PMN-EC
adhesion via thcir ctTccts on integrin/selectin interactions.
MFPHOTREXATE (MIX) THERAPY CAUSES A S I G N I F I M DFCR34SE I N SDLUHIE
INIXRLELXIN-2 m
R
S (SIL-2R) I N PATIENTS W I T H F$EUMWOIDARX-IRITIS
(RA). JOel M. m r , Ralph P. StOCkfX, Richard I. Rynes, David A.
Lawrence, Albany Medical College, Albany, NY
Although s e r i a l mo~su~z?s
of SIL-2R have beon associated with disease
d c t i v i t y i n RA, no reprts of the e f f e c t of MIX or any other s:Low acting anti-rheumtic drug (SAARD) have onerg&.
W e measured SIL-2R by an
ELISA syston (T c e l l Sciences) i n patients ( p t s ) with PA p r i o r t o
receiving MIX and at 6 month intervals a f t e r s t a r t i n g t h e drug. A t the
t h of the follow-up m e a s u m n t s , SIL-2R was measurcd j u s t p r i o r to a
&ly
dose of MIX ( 7 days a f t e r the l a s t dofe) and 24 hrs l a t e r i n
order to detennine i f weckly MIX dosing had any acute e f f e c t on levels
of SIL-2R. Pts reported a r e part of a larger cohort being studied to
determine the long-term h n e e f f e c t s of MIX i n RA.
11 p t s consuned a mean weekly dose of MIX of 14.3 mg (range [ r ]=
12.5-20 rig). Mean age was 61.7 years (r-40-76) and mean disease duration p r i o r t o s t a r t i n g MIXwas 100.1 nws (r.23-336). P t s had been on
other SMFm p i o r t o receiving MIX. The m a n duration of fol.10~-up
f o r moasunment of SIL-2R is 11.5 m (r=B-lB).
SIL-2Rs d e c r r ~ s c ds i g n i f i c a n t l y f r a n b a r l i n e t o last moasuLmy?nt
fmn a m a n of 2456.1 u n i t s (+1769) to 966.1 unite (+Bog) p.02. No
difference was observed i n m ~ s u r m E l t sobtained jusF p r i o r t o t4lX or
24 hrs a f t e r receiving t h e drug. No s t a t i s t i c a l l y significant L u r e l a tions wese observed between decreases in SIL-2and n u l t i p l e simultanmusly m u r e d c l i n i c a l and l a b o r a t q p r m t e r s . We conclude t h a t
MIX therapy of RA is associated with a significant f a l l i n SIL-2Rs.
The association of t h i s observation with the mechanism of action i n RA
is presently unclear.
P3N
COGNITIVE IMPAIRMENT IN UNSELECTED PATIENTS WITH
SYSTEMIC LUPUS ERYTHEMATOSUS (SLE). John G Hanlv. Glenda
,'&wood.
John V Jones. Brian.
John D Fisk. Victoria
General Hospital and Dalhousie University, Halifax, Nova Scotid, Canada.
Central nervous system manifestations of SLE include cognitive deficits.
The aim of this study was to examine cognitive impairment in an unselected
population of SLE patients.
Seventy SLE patients, 20 patients with
rheumatoid arthritis (RA) and 21 healthy subjects (age and sex matched) were
evaluated using the WAISR, the WMS-R, the California Verbal Learning Test
and the National Adult Reading Test-R to identify impairment in verbdl
abstraction, visual construction, p!ychomotor speed, attention-concentration,
global, short-term. delayed (20 minutes) and retrieval memory. Cumulative
disease manifestations were documented and disease activity was expressed
using the SLE disease activity index (SLEDAI). 15/70 (21%) SLE patients
were impaired compared to 1/25 (4%) R A patients and 1/21 (5%) healthy
subjects (pc0.05). Impairment was most common in patients with clinically
overt neuropsychiatric (NP) SLE (2/5,40%) but was also increased in patients
with inactive NP-SLE (2/9,22%) and in those who never had NP-SLE (11/56,
20%). A history of serositis was more frequent in patients with cofinitive
impairment (53% vs 18%, p<O.O2) but there was no difference in the
frequency of skin disease (73% vs 80%), arthritis (73% vs 76%), mucmitia
(27% vs 29%) or nephritis (33% vs 24%). SLEDAI scores were higher in
patients with cognitive impairment (9.8 f 1.7 vs 5.4 f 0.8, p<0.05). There
was no difference in the dose (mg) of prednisone (18.4 f 7 vs 14.0 f 4).
These results suggest that cognitive deficits in SLE may occur in patients with
and without clinically overt NP-SLE. They are more common in patients with
generalised active disease and are independent of corticosteroid medication.
. ,
DEFECT
IN IFN-v
__.__.
.
... , GENE EXPRESSION IN RHEUMATOID ARTHRITIS.
Esther Sotp, University of Toronto, Toronto, Edward C. KevgtME The Wellesley
Hospital. Toronto, Eleanor N. Fish,University of Toronto, Toronto.
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic
inflammatory lesions of synovial joints. The synovium is infilmted by aciivatcd Tcells that are thought to mediate the synovitis by their secreted cytokines.
However, the cytokine profile of synovialT-cells in RA remains controversial.
We have examined cytokine gene expression in fmhly isolated RA synovial fluid
(SF) and synovial tissue (ST) T-cells by quantitative polymeruse chain reaction
amplification. SF and autologous peripheral blood mononuclear (PBM) T-cells
demonsmtcddetestablelcvels of interleukin-2 OL-2) and interleukin-2 ruxptor (IL
2R) mRNA. Significantlyhigher levels werc detcctrd in ST T-cells. In S of 9 RA
PBM samples and 6 of 10 paired SF samples, 1L2 mRNA levels were less than
10% of the levels in PHA stimulated conml PBM. Similarly, in 6 of 9 RA PBM
samples and 7 of 10 RA SF samples L 2 R mRNA levels wen less than 10%of the
levels in stimulated conmls. For the two ST analyzed, I L 2 mRNA levels were
41% and 76% of stimulated control expression levels. while IL-2R mRNA levels
were 43% and 2% nspcctively. IFN-y gene expression was not detected in any of
the three compartments. SF T-cells from patients with arthritides other than RA,
were also assessed and similar results wen obtained.
The level of gene expression found in the ST nhtivc to SF suggests that !he SF
compartment may not accurately reflect the pathophysiological processes of RA.
The absence of IFN-ymRNA in RA SP and RA ST T-cells may be a consequence
of an inninsic defect in synovial T-cells at least at the level of gene expression for
IFN-y. Taken together, the results are consistent with the concept that
uncoordinated regulation of cytokine gene expression in RA contributes to
pupctuation of disease.
~~
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~~~~
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~~
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RHEUMATOID ARTHRITIS IS CHARACTERIZED BY AN EXPANDED
POPULATION OF CD7-NAIVE T CELLS IN THE PERIPHERAL BLOOD AND
CDI- MEMORY CELLS IN THE SYNOVIUM.
&I. La zarovits. M.J.
m t e and J. I(Knh. Robarts Research Institute and
University of Western Ontario, London and University of
Ottawa, Ontario, Canada.
Rheumatoid Arthritis (RA) is characterized by decreased
expression of CD7 on T cells in the peripheral blood (PBL)
and in the synovium. In order to identify the basis for
this low expression we evaluated PBL of normal controls and
patients with RA and Systemic Lupus Erythematosus (SLE) and
T cell lines derived from rheumatoid synovium using 3 colour
FACS analysis. Patients' medications included only NSAID,
hydroxychloroquine and/or low dose prednisone. All 3 groups
demonstrated heterogeneous CD7 expression on CD4+ memory
(CD29) PBL. Whereas normals and most SLE patients expressed
homogeneous bright CD7 on CD4r naive (CD45RA) PBL, RA
demonstrated clearly a CD7-subpopulation.
T cell lines
derived from RA synovium demonstrated a striking deficiency
of CD7 on the CD4+ memory cells which was not seen in T cell
lines derived from PBL of normal controls. Naive RA CD4+
PBL matured after activation in vitro (obtained by FACS) to
a memory cell phenotype, but this induced increased
expression of CD7. Thus the low CD7 expression in RA is not
merely a manifestation of activation. Rather an expansion
of CD7- T cells may be part of the RA disease process.
R38
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