GRANULOMATOSI DI WEGENER E VASCULITI NECROTIZZANTI
[618] EPIDEMIOLOGY OF SYSTEMIC RHEUMATOID
VASCULITIS (SRV) - A TEN YEAR STUDY.R A Watts, S
E Lane, G Bentham, D GI Scott. Ipswich, Suffolk, United
Kingdom, Norwich, Norfolk, United Kingdom, Norwich,
Norfolk, United Kingdom.
Systemic rheumatoid vasculitis (SRV)is a rare
complication of rheumatoid arthritis. Previous reports
have suggested SRV has become more common since the
1970s. Our institution has been the focus of other
epidemiological studies including RA and systemic
vasculitis. It serves as the central referral hospital
for a stable population. We have since 1988 documented
all cases of SRV occurring in this population.
The aim of this study was to determine the incidence of
SRV over a 10 year period with particular reference to
changes in incidence with time, age and gender.
We prospectively studied all patients presenting with
SRV since 1988 to our hospital, which serves a stable
population of 413,500 (males 200,000). The population is
99% Caucasian.The Scott and Bacon (1984) classification
criteria were applied to all patients.To improve
completeness data from our register was compared with
hospital discharge data and histopathology records. 95%
confidence intervals (95% CI) were calculated using the
Poisson distribution for the observed number of cases.
During 1988-97 45 cases of SRV (21 men) were observed in
our population.The median age was 65 years (range 23-82,
disease duration 12 years (1-32 years). The overall
annual incidence of SRV was 10.9/million (95%CI
7.9-14.5). There was a decrease in overall incidence
between 1988-92 12.1/million (7.2-17.8) and 1993-97
(9.3/milion (5.6-14.3). SRV was similar in frequency in
women 11.2/million (7.2-16.7) and men 10.5/million
(6.5-16.0), however the age specific incidence was
highest in the 65-74 age group at 56.2/million
(37.6-80.7) with males 41.6/million and women 32.6 /million.
We conclude that SRV although uncommon is still a
significant problem, with an annual incidence similar to
that of Wegener's granulomatosis. There has over the ten
year period been a slight decrease in incidence which is
in contrast to primary systemic vasculitis where there
has been a slight increase over the same time period,
suggesting that different aetiological factors may be
important in determining susceptibility to development
of vasculitis. There is a marked age specific increase
in incidence similar to that seen in primary systemic
vasculitis.
Presentation Date: Sunday, November 14, 1999, Time:
4:00PM, Room: Auditorium
[846] LYMPHOCYTIC VASCULITIS IN X-LINKED
LYMPHOPROLIFERATIVE DISEASE.J P Dutz, X Wang, L
Benoit, H Hare, A Junker, D De Sa, R Tan. Vancouver, BC,
Canada, Vancouver, BC, Canada, Vancouver, BC, Canada.
Systemic vasculitis is an uncommon manifestation of
X-linked lymphoproliferative disease (XLP), a disorder
in which there is a selective deficit in immunity to
Epstein-Barr virus (EBV). The molecular basis for XLP
has recently been ascribed to mutations affecting
SLAM-associated protein (SAP), an SH2 domain containing
protein expressed primarily in T cells. We describe a
patient who presented with a chronic systemic vasculitis
and fulfilled clinical criteria for the diagnosis of XLP.
Sequencing of this patient's SAP gene revealed a novel
mutation affecting the SH2 domain. The patient presented
with virus-associated hemophagocytic syndrome (VAHS) and
later developed chorioretinitis, bronchiectasis,
hypogammaglobulinemia and a serologic response to EBV.
He further developed mononeuritis and fatal respiratory
failure. Evidence of widespread small vessel and medium
vessel vasculitis was noted at autopsy. There was
involvement of cerebral and coronary arteries and
involvement of the segmental vessels of the kidneys,
testes, pancreas as well as retinal scarring.
Immunohistochemical analysis using antibodies to CD45RO
and CD20 revealed that the vessel infiltrates consisted
primarily of T cells. Lymphoid vasculitis has rarely
been described in association with XLP. Patients with
features of pulmonary lymphomatoid granulomatosis,
pulmonary Wegener’s disease and necrotizing vasculitis
with aneurysmal dilatation have been reported. To our
knowledge, this is the first case to document
chorioretinitis as a manifestation of this vasculitic
syndrome in association with XLP. Large-vessel arteritis
and Kawasaki-like arteritis have been associated with
chronic EBV infection and murine gammaherpesvirus 68, a
virus related to EBV, has been shown to infect vascular
smooth muscle causing large-vessel arteritis in mice. We
propose that functional inactivation of SAP may impair
the immunological response to primary EBV infection
predisposing affected males to systemic vasculitis.
ACR Poster Session C: Vasculitis I (8:00 AM-9:30 AM)
[266] NON-VASCULITIC ANTI NEUTROPHIL CYTOPLASMIC ANTIBODIES
(ANCA).D Zauli, A Grassi, C Descovich, G Ballardini, M
Fusconi, F B Bianchi. Bologna, Italy, Bologna, Italy.
ANCA are currently considered specific serologic markers of
systemic small vessel vasculitides, although they have been
described in a variety of different diseases. Recently an
International Consensus Statement (1) on testing and reporting
of ANCA results has indicated that positive fluorescence alone
is not specific for the diagnosis of Wegener granulomatosis or
microscopic polyangiitis. Sera are referred to our laboratory
for ANCA testing mostly from Internal Medicine and
Gastroenterology Departments. Aim of this work was to evaluate
the prevalence of pANCA and cANCA in such sera unlikely to be
from vasculitic patients.
A total of 810 sera were received from 704 patients in the last
three years and were tested by immunofluorescence on
alcohol-fixed human neutrophils. A final diagnosis was available
in 355 cases. In such cases the prevalence of pANCA and cANCA
was 20% and 8%, respectively. The most frequent ANCA associated
diagnoses were autoimmune hepatitis type 1 (38), primary
sclerosing cholangitis (6), inflammatory bowel disease (7),
organspecific autoimmune diseases (7), erosive osteoarthritis
(6), Wegener granulomatosis (5), rheumatoid arthritis (4). cANCA
were generally of lower titer than pANCA. In most ANCA positive
sera other autoantibodies (antinuclear, anti smooth muscle,
rheumatoid factor, anti thyroid) were also detected, some of
which (antinuclear in particular) might have interfered with the
fluorescent ANCA pattern.
The present data indicate that: 1. most ANCA testing in Internal
Medicine and Gastroenterology appears to be unnecessary given
their rather low prevalence in patients referred to these
specialities and is essentially indicated in the suspect of
autoimmune liver diseases (both hepatitis and cholangitis) and
inflammatory bowel disease 2. but, due to their presence in
these non-vasculitic diseases, they are to be considered less
specific than currently believed for the diagnosis of
vasculitides 3. other concomitant autoantibodies may intefere
with the recognition of fluorescent ANCA patterns 4. as a
consequence, ELISA results are mandatory before making any
decision about treatment of ANCA associated vasculitides, as
suggested by the overmentioned Consensus Statement (1).
1. Savige J et al. Am J Clin Pathol 1999;111:507-13.
Presentation Date: Sunday, November 14, 1999, Time: 8:00AM,
Room: Hall D
[276] A VASCULITIS WEBPAGE: ROLE IN PATIENT EDUCATION AND
CLINICAL RESEARCH.M L Uhlfelder, W Tun, J H Stone, D B
Hellmann. Baltimore, MD.
Objective. To evaluate the use of the Internet as a tool
for patient education and research. Methods. The Johns Hopkins Vasculitis Center's website
was established to provide information about vasculitis to
patients in lay terms. We posted a questionnaire on the website
(3/16/99) to learn about the website visitors. Patients with
vasculitis were asked to provide clinico-epidemiologic
information about themselves, including demographic
characteristics, type of vasculitis, and age at diagnosis. On
4/20/99 we added the generic SF-12 quality of life questionnaire
to the website for visitors with vasculitis. Results. Since its first posting on 7/31/99, the
Vasculitis Center website has received 296,311 visitors, or
approximately 1,000 "hits" per day. Over a 9-month
period, interest in the website increased, from 12,000 visitors
in 8/98 to 39,000 visitors by 4/99. To date, 304 completed
questionnaires have been received, including 126 SF-12
questionnaires. Among the 304 visitors who completed
questionnaires, 205 (67.4%) have vasculitis and 77 (25.3%) were
family members of patients with vasculitis. Of the responders,
188 (64.6%) were female, 103 (35.4%) were male. The mean age was
44.8 years (range 16-83 years) and the mean age at time of
diagnosis was 43.3 years (range 4 months-85 years). Of the 304
responses, 250 visitors (82.2%) provided current address
information. Twenty-five (10.0%) were from Maryland or a
surrounding states (VA, PA, WV, DC, DE). Forty-two (16.8%) of
the responses were from 21 different countries outside of the
U.S., including Canada, India, Vietnam, Italy, Brazil, and
Australia, among others. The diagnoses of the 304 responders
include CNS vasculitis (13.5%), polyarteritis nodosa (10.5%),
leukocytoclastic vasculitis (8.2%), Wegener's granulomatosis
(7.6%), rheumatoid vasculitis (5.3%), Behcet's disease (3.6%),
Henoch-Schonlein purpura (3.6%), giant cell arteritis (3.0%),
and hypersensitivity vasculitis (3.0%). Seventy-eight responses
(25.6%) were uncertain of their specific vasculitis diagnosis. Conclusion. The internet is a valuable means for patients
to obtain information on vasculitis and for researchers to
obtain information from vasculitis patients. It can be a useful
tool for research utilizing self-administered surveys,
especially in rare disorders such as vasculitis.
Disclosure:
Keywords: Vasculitis; Patient Education
ACR Poster Session A: Education and Health Behavior (8:00
AM-9:30 AM)
Presentation Date: Sunday, November 14, 1999, Time: 8:00AM,
Room: Hall D
[627] PREVALENCE OF ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES
(ANCA) IN PATIENTS WITH VARIOUS PULMONARY DISEASES OR MULTIORGAN
DYSFUNCTION.D Vassilopoulos, J L Niles, A Villa-Forte, A
C Arroliga, E J Sullivan, P A Merkel, G S Hoffman. Cleveland,
OH, Boston, MA, Boston, MA.
Objective: To evaluate the prevalence of ANCA in patients
who present with clinical manifestations that may mimic
“ANCA-associated” diseases. Methods: Serum specimens were prospectively collected
from: a) 29 outpatients in a pulmonary clinic with various
parenchymal disorders (Group I) and b) 99 patients (pts)
admitted to the medical intensive care with evidence of
multiorgan dysfunction (Group II). Sera from 18 pts with
biopsy-proven Wegener's granulomatosis (WG) served as positive
controls (Group III). Each specimen was tested in a blinded
manner for the presence of ANCA by a combination of standard
indirect immunofluorescence (IIF) and specific enzyme
immunoassays (EIA) for proteinase-3 (PR3) and myeloperoxidase (MPO). Results:
GROUP
Diagnosis
n
IIF (+)
%
PR3(+)
%
MPO (+)
%
I
Pulmonary diseases
29
8
27.6
0
0
0
0
II
Multi-organ dysfunction
99
37
37.4
2
2
1
1
III
Wegener's controls
18
13
72.2
12
66.6
1
5.5
Group I consisted of pts with various interstitial lung diseases
(n=14), lung cancer (n=8), sarcoidosis (n=5), actinomycosis
(n=1) and bronchiectasis (n=1). Group II pts were further
subgrouped to pts with evidence of pulmonary and renal failure
(n=44), pulmonary failure alone (n=37), renal failure alone
(n=7) or other organ dysfunction (n=11). Although a weakly (+)
IIF pattern was observed in 27.6% of group I and 37.4 % of group
II pts, only 3 sera contained ANCA by EIA and these cases were
known to have WG (2) and microscopic polyangiitis (1). Conclusions: We were unable to detect ANCA specific for
PR3 or MPO in a diverse group of pts who did not have WG or MPA,
but who presented with evidence of various pulmonary and/or
multiorgan diseases. This study emphasizes the excellent
specificity of ANCA when IIF and EIA are combined, even when pts
with uncertain diagnoses that may mimic vasculitides are
included in test performance analysis.
Presentation Date: Sunday, November 14, 1999, Time: 4:00PM,
Room: Ballroom C
[630] EXPRESSION OF RECOMBINANT PROTEINASE 3, THE
AUTOANTIGEN IN WEGENER'S GRANULOMATOSIS, IN INSECT CELLS.Y
M van der Geld, M Smook, P C Limburg, C GM Kallenberg. Groningen,
Netherlands.
Proteinase 3 (Pr3), a 29 kD serine protease from neutrophilic
granulocytes, is the major autoantigen for anti-neutrophil
cytoplasmic autoantibodies (ANCA) in patients with Wegener's
Granulomatosis. Little is known about the major antigenic sites
on Pr3. To facilitate epitope mapping, Pr3 was cloned in insect
cells by a baculovirus expression system.
Four different sequences of the Pr3 cDNA were amplified by PCR,
two clones containing the pro-peptide of Pr3 with or without a
His-tag (rproPr3-his and rproPr3, respectively) and two clones
without the pro-peptide and with or without a His-tag (rPr3-his
and rPr3, respectively). The His-tag was inserted to facilitate
isolation. The Pr3 sequences were cloned into a plasmid under
the control of the Polyhedrin promoter and insertion of the
honeybee melittin signal peptide enabling secretion of rPr3s.
The plasmid was transposed in the genome of baculovirus, and
wild type as well as Pr3- containing virus genome was
transfected into sf21 insect cells.
By PCR using internal Pr3 primers we could detect the Pr3
sequences in the plasmid, the rec. baculovirus genome, and after
infection in rec. baculovirus particles. After infection of sf21
cells with the rec. virus, all four rPr3 forms were secreted
into the medium. On SDS-PAGE the four rPr3 forms migrated at
approx. 32 kD, rproPr3-his being the largest protein and rPr3
the smallest protein. All products were recognized by rabbit
serum raised against Pr3 and by at least two different anti-Pr3
moabs as tested by immunoblot and by IIF on slides with
transfected cells. Indirect immunofluorescence on infected cells
with an anti-His moab confirmed the presence of the His-tag in
cells expressing rproPr3-his and rPr3-his. Furthermore, capture
ELISA with 10 Pr3-ANCA sera showed that all 10 sera recognized
rPr3 and rPr3-his similar as neutrophil Pr3 whereas rproPr3 and
rproPr3-His were less well recognized. Finally, purification of
rproPr3-His using a Ni-NTA column resulted in one clear band of
32 kD.
In conclusion, rPr3 and rPr3-his are well recognized by Pr3-ANCA
sera. Furthermore, the presence of a C-terminal His-tag does not
interfere with the antigenicity. His-tag containing rPr3 is easy
to purify. Thus, rPr3 expressed in insect cells can be used as
tool for diagnostic tests as well as epitope mapping studies.
Presentation Date: Sunday, November 14, 1999, Time: 4:00PM,
Room: Ballroom C
[827] HUMAN c-ANCA IgG INDUCES PULMONARY VASCULITIS IN RATS.W Weidebach, V S Viana, A S Leme, F M Arantes, M A Martins, P
H Saldiva, E Bonfa. Sao Paulo, SP, Brazil.
Autoantibodies to neutrophil cytoplasm (cANCA) are highly
specific for Wegener’s granulomatosis. The strong association
between ANCA titers and clinical disease activity or relapse
supports the involvement of this antibody in the pathogenesis of
the disease. Moreover, studies in vitro have demonstrated
that cANCA directly activates leukocytes by inducing oxidative
burst, enzyme release, or endothelial cytotoxicity. However, the
direct pathogenic role of cANCA is still unknown. The aim of the
present study is to reproduce in rats the pulmonary lesion of
Wegener granulomatosis with human cANCA enriched IgG fraction.
Groups of Wistar rats (n=18) were injected via internal
jugular vein with 20 mg of total IgG fraction cANCA and anti-PR3
positive isolated from serum of 3 different active WG patients
obtained before therapy. Control animals were injected with IgG
fraction from normal human serum (n=10) or saline (n=18).
Animals were sacrificed after 24 h of injection for lung
histological analysis. Vasculitis and inflammatory infiltrate
were absent in all animals injected with saline and in 9/10
animal injected with normal IgG. In contrast, all 18 animals
injected with IgG cANCA demonstrated an intense vasculitis and
pleomorphic leukocyte infiltrate particularly around small
venules, and 7 animals presented a granuloma like formation. The
inflammatory response was dose dependent, since lower
concentrations of this antibody induced mild pulmonary lesion.
Moreover, the administration of IgG fraction obtained from one
of the patients in remission, after therapy and with no
detectable cANCA, was not able to reproduce the same pulmonary
tissue alterations induced by its paired IgG positive for this
antibody taken before therapy. This experimental model further
supports the pathophysiological role of cANCA. Future studies
should be aimed in these animals to elucidate initial triggering
pathogenic factors that synergize with cANCA to cause disease.
ACR Poster Session C: Vasculitis I (8:00 AM-9:30 AM)
Presentation Date: Monday, November 15, 1999, Time: 8:00AM,
Room: Hall C
[888] ANTI-NEUTROPHIL CYTOPLASMIC ANTIBODY (ANCA) ORDERING
IN ACADEMIC CENTERS: PATTERNS OF USE AND TEST PERFORMANCE
CHARACTERISTICS.L A Mandl, E L Smith, R A Lew, D H
Solomon, R H Shmerling. Boston, MA, Boston, MA, Boston, MA.
Introduction:Although anti-pronteinase3 (PR3) and
anti-myeloperoxidase (MPO) ANCAs are strongly associated with
Wegener's Granulomatosis, Churg-Strauss Angiitis, polyarteritis
nodosa, and necrotizing glomerulonephritis, the diagnostic role
of these tests remains unclear. Patterns of use in clinical
practice, which will affect test operating characteristics, have
not been well described. Methods:This study evaluated patterns of ANCA
ordering at two academic teaching centers. Characteristics of
553 consecutive patients on whom ANCAs were ordered were
idenfied by retrospective chart review, blinded for ANCA results.
Included were signs and symptoms present at the time of ANCA
ordering, previous history of an ANCA associated disease, and
final diagnosis as determined by the treating physician. Results:The most common problems present at the
time of ANCA ordering were dyspnea (26%), renal failure
(23%),and cough (22%). There were 204 different final diagnoses,
and only 8.5% of patients had an ANCA-associated disease. When
used as a diagnostic test in patients with no previously
diagnosed ANCA-associated disease, sensitivity was 59.2%,
specificity 87.3%, and positive predictive value (PPV) 20.0%.
Excluding both borderline results and p-ancas without
significant antibody titers, sensitivity decreased to 42.9%,
while specificity and PPV increased to 97.1% and 39.1%,
respectively.
Exploratory cluster analysis failed to disclose any patterns of
symptoms associated with a positive ANCA.
ANCA-Associated Disease PRESENT
ANCA -Associated Disease ABSENT
Positive ANCA Result
9
14
Negative ANCA Result
12
460
Conclusions:Although specificity was high,sensitivity
and PPV of ANCA testing were low in this patient population. The
majority of tests did not positively identify an ANCA-associated
disease, and there were a significant number of false positives.
As currently ordered, the role of ANCA as a diagnostic test
should be viewed cautiously.
ACR Poster Session C: Health Services and Outcomes II (8:00
AM-9:30 AM)
Presentation Date: Monday, November 15, 1999, Time: 8:00AM,
Room: Hall D
[928] A MULTI-CENTRE RANDOMISED TRIAL OF CYCLOPHOSPHAMIDE
VERSUS AZATHIOPRINE DURING REMISSION IN ANCA-ASSOCIATED SYSTEMIC
VASCULITIS (CYCAZAREM).R Luqmani, D Jayne, EUVAS (European
Vasculitis Study Group). Edinburgh, United Kingdom, London,
United Kingdom.
Background: This study aimed to determine whether
azathioprine was as effective as cyclophosphamide for the
prevention of disease relapse in ANCA-associated systemic
vasculitis (Wegener's Granulomatosis and microscopic
polyangiitis). Methods: New patients with threatened vital organ
function and presenting serum creatinine under 500mmol/l
(5.7mg/dl) were included. Following remission induction with
prednisolone and daily, oral cyclophosphamide for three months,
patients were randomised to continue cyclophosphamide to 12
months or to switch to azathioprine. Both groups received the
same tapering prednisolone dose and after 12 months converted to
the same reducing azathioprine dose until the study end at 18
months. The primary end-point was relapse rate. Results: Preliminary results are now available: 155
patients were recruited from 40 centres in 11 European countries
over 24 months. 141 entered remission and were randomised to
cyclophosphamide (70) and azathioprine (71). There were 12
relapses (17%) in the cyclophosphamide group and 11 (16%) in the
azathioprine group (relative risk 0.93, 95% C.I. 0.39-2.24). One
death occurred in each group during the remission phase. 88
adverse-effect events occurred in the cyclophosphamide group and
80 in the azathioprine group. The frequency of severe and
life-threatening adverse-effects was 20 for each group. There
were no differences in serum creatinine at 18 months (median 108
mmol/l, 1.22 mg/dl in both groups),
Birmingham Vasculitis Activity Score (BVAS) or in cumulative
damage assessed by the Vasculitis Damage Index (VDI) between the
two groups. Conclusions: We conclude that following remission
induction with oral cyclophosphamide and prednisolone remission
maintenance therapy with azathioprine is as effective as
continued cyclophosphamide in the prevention of disease relapse
during the 15 month follow-up period of this trial.
Presentation Date: Monday, November 15, 1999, Time: 9:45AM,
Room: Auditorium
[1276] STAPHYLOCOCCAL SUPERANTIGENS: A RISK FACTOR FOR
DISEASE REACTIVATION IN WEGENER'S GRANULOMATOSIS.E R
Popa, C A Stegeman, N A Bos, W M Manson, J Arends, W M Johnson,
C GM Kallenberg, J W Cohen Tervaert. Groningen, The Netherlands,
Groningen, The Netherlands, Groningen, The Netherlands,
Groningen, The Netherlands, Ontario, Canada.
In Wegener's Granulomatosis (WG), chronic nasal carriage of
Staphylococcus aureus (S. aureus) is associated with an
increased frequency of disease relapses. We hypothesized that
staphylococcal superantigens (SAg) constitute a risk factor for
disease reactivation in WG. In an observational longitudinal
cohort study we performed nasal cultures every 4 to 6 weeks in
consecutive patients with WG and typed SAg-encoding genes in S.
aureus strains collected during the time period from 1990-1996.
Genes encoding for the staphylococcal SAg SEA, SEB, SEC, SED,
SEE, toxic-shock syndrome toxin 1 (TSST-1) and exfoliative toxin
A (ETA) were detected using a multiplex PCR technique. In
addition, the nuclease A (nuc-A) gene, which is specific for S.
aureus, was co-amplified as an internal control. SAg genes were
present in S. aureus strains from 31/47 (66.0 %) WG patients
(total 236 strains), whereas 16 patients (34.9 %) carried
SAg-negative S. aureus strains (total 354 strains). S. aureus
strains positive for SEA were present in 19/31 (61.3 %) WG
patients (116/236 strains, 49.1 %), for TSST-1 in 19/31 (61.3 %)
patients (93/236 strains, 39.4 %), for SEC in 11/31 (35.5 %)
patients (33/236 strains, 14.0 %), for ETA in 5/31 (16.1 %)
patients (50/236 strains, 21.2 %), for SED in 4/31 (12.9 %)
patients (11/236 strains, 4.6 %), for SEB in 2/31 (6.4 %)
patients (5/236 strains, 2.1 %). SEE genes were not detected.
Twenty-seven of the 31 patients (87.0 %) carrying a SAg-positive
S. aureus strain had one or more disease relapses between 1990
and 1998, whereas 6/16 patients (37.5 %) carrying a SAg-negative
S. aureus strain had one or more relapses during this follow-up
period (P=0.0008). In conclusion, WG patients carrying
SAg-positive S. aureus strains are more prone to relapses than
patients carrying SAg-negative strains. These findings support
our hypothesis that S. aureus SAg play a role in disease (re)activation
of WG.
Disclosure:
Keywords: Wegner's Granulomatosis; Staphylococcus
ACR Concurrent Session: Vasculitis: Pathogenesis and Treatment
(4:00 PM-5:30 PM)
[1280] A STAGED APPROACH IN THE TREATMENT OF WEGENER'S
GRANULOMATOSIS: INDUCTION WITH GLUCOCORTICOIDS AND DAILY
CYCLOPHSOPHAMIDE SWITCHING TO METHOTREXATE FOR REMISSION
MAINTENANCE.C A Langford, C Talar-Williams, K S Barron,
M C Sneller. Bethesda, MD.
Daily cyclophosphamide (CYC) and glucocorticoids (GC) is a
highly effective regimen for the treatment of WG but is
associated with serious side effects. In seeking less toxic
options, methotrexate (MTX) has been found to be an acceptable
alternative but it may have a higher relapse rate and is limited
to patients with non severe disease. As a means of circumventing
these limitations, we conducted an open-label prospective
standardized trial using CYC and GC for induction and MTX for
remission-maintenance in the treatment of WG.
Initial treatment consisted of prednisone 1 mg/kg/day given
together with CYC 2 mg/kg/day. At remission, CYC was stopped and
MTX was begun at 15 mg/week and increased to 20-25 mg/week. MTX
was maintained for 2 years after which time it was tapered and
discontinued.
Thirty-one patients entered into this study, of whom 17 (55%)
had glomerulonephritis and 16 (52%) had severe disease defined
by renal, pulmonary, or neurologic criteria. Remission was
achieved in all 31 patients (100%) at a median time of 3 months
(range 1-10 months). GC were discontinued at a median time of 8
months (range 5-19 months). No patients have died, 1 voluntarily
withdrew, 2 came off study for drug toxicity, and 5 (16%) have
relapsed. The median time from remission to relapse was 13
months. All 5 patients were on MTX alone and had been off GC a
minimum of 6 months. The likelihood of relapse was not
influenced by either severe disease or glomerulonephritis. The
median follow-up time since remission of the remaining 23
patients is 22 months (4-49 months). Of these, all patients have
discontinued GC, 6 have discontinued MTX, 4 are tapering MTX,
and 13 remain in the maintenance phase of treatment. Toxicities
were 2 MTX pneumonitis (6%), leukopenia (3-CYC, 4-MTX), 2
cystitis (6%), 3 non-infectious GC toxicities, 2 bacterial
pneumonia (6%), 4 herpes zoster (13%).
Use of GC and daily CYC for induction followed by MTX for
remission maintenance is an effective and less toxic alternative
to the standard CYC regimen. This approach can be used in all
patients eligible to receive MTX at remission, regardless of
initial disease severity.
[1403] ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES IN SYSTEMIC
LUPUS ERYTHEMATOSUS: THE PREVALENCE AND THE RELATION WITH
CLINICAL FINDINGS.Y Kabasakal, K Aksu, F Oksel, G Keser,
V Ynal, H Kocanaoeullary, A Sin, A Ityk, E Doeanavtargil. Izmir,
Turkey.
Objective: In this study, we tested serum antineutrophil
cytoplasmic antibodies (ANCA) in patients with systemic lupus
erythematosus (SLE), in respect to their relation with SLE
activity and clinical findings.
Methods: One hundred and seventeen consecutive patients were
enrolled in this study. (F/M:108/9; mean age 32±11years; mean
disease duration 36±35 months). Disease activity at the time of
assesment was evaluated using SLE Disease Activity Index (SLEDAI).
Presence of clinical activity in SLE was defined, if SLEDAI
score was greater than 10. The sera collected from patients were
examined for cytoplasmic (cANCA) and perinuclear patterns of
ANCA (pANCA) by indirect immunofluorescence (IIF). A titer of
>1/20 was regarded as positive. In order to differentiate
pANCA from ANA (antinuclear antibodies), pANCA positive sera on
ethanol fixed neutrophils were also tested on formalin fixed
neutrophils. Those positive for pANCA on formalin fixed
neutrophils were also tested for MPO antibodies by ELISA. As
control groups, 5 patients with Wegener granulomatosus (WG) and
18 healthy controls were also included.
Results: While none of the SLE patients had cANCA, 65 out of 117
(56%) patients were found to have pANCA on ethanol-fixed
neutrophils. However, on formalin fixed neutrophils, pANCA
positivity persisted only in 16 patients(14%). Of these 16
patients, only 2 (12.5%) were found to have MPO antibodies by
ELISA. While all patients in WG group (100%) were cANCA
positive, none of the healthy controls were ANCA positive. Among
the clinical and laboratory findings cited in SLEDAI; arthritis,
vasculitis and anti-dsDNA positivity were found to have
significant association with pANCA positivity (on formalin fixed
neutrophils). We could show no significant association between
disease activity (>10) and pANCA positivity.
Conclusion: In SLE, pANCA positivity on formalin -fixed
neutrophils was 14% (16/117). Using SLEDAI, no significant
correlation was found between formalin-fixed pANCA positivity
and disease activity. On the other hand, pANCA positivity in SLE
was found to be significantly associated with arthritis,
vasculitis and anti-dsDNA positivity.
Presentation Date: Tuesday, November 16, 1999, Time: 8:00AM,
Room: Hall B
[1461] DRUGS-ASSOCIATED CUTANEOUS VASCULITIS IN ADULTHOOD.
CLINICAL AND EPIDEMIOLOGICAL ASSOCIATIONS IN A DEFINED
POPULATION OF NORTHWESTERN SPAIN.C Garcia-Porrua, M A
Gonzalez-Gay, A Sanchez-Andrade, L Lopez-Lazaro. Lugo, Lugo,
Spain.
OBJECTIVE: To examine the incidence and clinical features
of adults with biopsy-proved cutaneous vasculitis (CV)
associated with drugs. METHODS: Retrospective study of an unselected population
of adults (age > 20 years) with biopsy-proved
leukocytoclastic CV diagnosed at the Hospital Xeral-Calde (Lugo,
Spain) from 1988 through 1997. Drug-associated CV was considered
if CV was confirmed by a skin biopsy and a history of drug
intake was present within a week prior to the development of CV.
Drug-associated CV were classified according to the ACR criteria.
To differentiate Henoch-Schonlein purpura (HSP) from
hypersensitivity vasculitis (HV), the traditional format of the
criteria proposed by Michel et al was used (J Rheumatol 1992;
19: 721-8). RESULTS: Thirty-three (23 men) of 138 patients (23.9%)
presenting with biopsy-proved CV were diagnosed with
drug-associated CV. The annual incidence rate in adults was
17.49 cases/million. Most drug-associated CV were related to
antibiotics and analgesics or nonsteroidal anti-inflammatory
drugs. All adults with drug-associated CV met the ACR
classification criteria for HV or HSP. Based on Michel’s
criteria 26 patients (78.8%) were classified as having HV and 7
as HSP. None of them met ACR criteria for other systemic
vasculitides, such as polyarteritis nodosa or Wegener’s
granulomatosis. Complete recovery without any sequelae was
observed in most cases. CONCLUSION: Among patients with CV, drug-associated
disease is common. Usually, it behaves as a benign disease with
a good outcome.
Disclosure:
Keywords: Vasculitis; Biopsy
ACR Poster Session E: Vasculitis II (8:00 AM-9:30 AM)
Presentation Date: Tuesday, November 16, 1999, Time: 8:00AM,
Room: Hall C
[1462] TEMPORAL CONCURRENCE OF VASCULITIS AND CANCER: A
REPORT OF 12 CASES.T E Hutson, G S Hoffman. Cleveland,
OH.
Vasculitis has been associated with solid organ and hematologic
cancer (CA). The rarity of these associations, and in many
reports, lack of temporal relationships, has led to skepticism
about vasculitis being a paraneoplastic syndrome. Objective: To review cases of concurrent vasculitis and
CA and explore evidence that would support the notion of
vasculitis being a type of paraneoplastic disease. Methods: Retrospective study of patients with vasculitis
and CA within 12 months of each other. Exclusions: chronic
autoimmune disease, hepatitis B or C. Results: Twelve patients were identified in whom both
vasculitis and CA occurred within the same 12 months. Mean age=65
(45-79). No gender preference (M=F). In 8/12 cases, diagnoses
were made within 3 months of each other. In 6, the diagnoses of
both processes was within 1 month. Ten of 12 patients had
vasculitis prior to or concurrent with CA. Seven of 12 had solid
organ tumors, 3 lymphomas, 1 leukemia, 1 multiple myeloma. The
most common vasculitis was cutaneous, leukocytoclastic (LCV) (7
cases). Four cases of LCV were associated with solid organ
tumors. Other vasculitides included giant cell arteritis (2),
polyarteritis nodosa (2) and Wegener's granulomatosis (1). Response to glucocorticoid and cytotoxic therapy:
Complete remission 4, partial improvement 4, no improvement 4.
Complete remission occurred in 3 of 4 patients in whom
vasculitis and CA were treated concurrently. In 2 patients,
immunosuppressive therapy was unsuccessful until definitive
treatment of CA was initiated. Conclusion: The close temporal relationship of CA and
vasculitis in our patients adds to circumstantial evidence of
vasculitis at times being a paraneoplastic condition. Failure of
vasculitis to respond to conventional therapy should raise
questions about underlying malignancy. Effective treatment of CA
enhances the likelihood of improvement in vasculitis.
Disclosure: Cleveland Clinic Foundation
Keywords: Vasculitis
ACR Poster Session E: Vasculitis II (8:00 AM-9:30 AM)
Presentation Date: Tuesday, November 16, 1999, Time: 8:00AM,
Room: Hall C
[1465] USE OF METHOTREXATE AND GLUCOCORTICOIDS IN WEGENER'S
GRANULOMATOSIS: LONG TERM RENAL OUTCOME IN PATIENTS WITH
GLOMERULONEPHRITIS.C A Langford, C Talar-Williams, M C
Sneller. Bethesda, MD.
Methotrexate (MTX) has been previously shown to effectively
induce remission in selected patients with Wegener's
granulomatosis (WG). Despite this, there has been reluctance by
some physicians to use MTX in patients who have
glomerulonephritis (GN), out of concern that it may be
deleterious to renal function. This paper reports on the long
term renal outcome of 21 WG patients with GN who were treated
with MTX.
In this trial, 42 patients were studied, of whom 21 (50%) had GN
defined by an active urinary sediment with red blood cell casts
and new or increased proteinuria. The median serum creatinine at
entry was 1.3 mg/dl (range 0.8-2.5mg/dl). Patients were not
enrolled if their creatinine was > 2.5 mg/dl. Overall, 20/21
achieved renal remission, with 1 patient developing a fatal
opportunistic infection prior to remission. At 1 month and 6
months following study entry, the creatinine for all patients
remained either stable (defined as a change of no more than 0.2
mg/dl) or improved. Eleven patients have relapsed, of whom 7
were retreated with MTX and again achieved remission. The 20
patients have now been followed for a median time of 76 months (range
20-108 months). Only 2 patients have had a rise in creatinine of
> 0.2 mg/dl from the time of protocol enrollment to most
recent follow-up. One patient with concurrent diabetes and
hypertension had a rise in creatinine from 1.5 to 1.8mg/dl over
59 months. The second patient's creatinine began at 1.8 mg/dl
and remained stable for 36 months after which time it rose to
2.9mg/dl. This was not associated with abnormalities of the
urine sediment or other evidence of active disease. Of the
remaining 18 patients, 12 have had stable renal function and 6
have had improvement of their creatinine by > 0.2 mg/dl.
This data supports that the use of MTX in the treatment of
WG-related GN is not associated with long term decline in renal
function. MTX should, however, be avoided in patients who have
acute or chronic renal insufficiency resulting in a serum
creatinine value of > 2.5 mg/dl.
ACR Poster Session E: Vasculitis II (8:00 AM-9:30 AM)
Presentation Date: Tuesday, November 16, 1999, Time: 8:00AM,
Room: Hall C
[1466] MAINTENANCE OF REMISSION WITH LEFLUNOMIDE IN
WEGENERS GRANULOMATOSIS.C Metzler, I Loew-Friedrich, E
Reinhold-Keller, C Fink, W L Gross. Luebeck, S-H, Germany,
Frankfurt, Hessen, Germany.
INTRODUCTION: Despite the capacity of continuos oral
cyclophosphamide (CYC) plus prednisone (PRED)to induce remission
in patients with generalized WG, a cure remains uncertain. A
relapse rate of more than 50% has been observed. Hence, patients
with generalizied WG need long-term treatment for the prevention
of relapse with an effective, but less toxic medication.
Remission maintaining drugs are often limited by a residual
impaired renal function or leucopenia caused by an earlier CYC
therapy. Leflunomide (LEF), a new immunosuppressive and
immunomodulating agent, that is now admitted for the treatment
of rheumatoid arthritis has shown no serious side effects.
Especially severe leucopenia or complications in patients with
reduced renal function were not observed. OBJECTIVE: To examine
the efficacy and safety of leflunomide as maintenance of
remission in patients with generalized WG. PATIENTS and METHODS:
20 patients with generalized WG according to the ACR criteria
were treated with LEF after an induction of (complete or partial)
remission by CYC or MTX. The starting dose of LEF was 20mg/d,
increased to 30mg/d after three months, and if necessary (patients
in partial remission) elevated to 40mg/d. A concomitant therapy
with low dose PRED (max. 10mg/d) was allowed. The disease extent
and activity were evaluated by an interdisciplinary clinical,
radiological and seroimmunological staging at regularly
intervals. RESULTS: After 12 months 19 patients finished the
study according to the protocol. 15 patients remained in
remission, four relapsed (one under 40 mg LEF, three under 30
mg. In all patients PRED <5 mg/d). However only one major
relapse lead to a change of treatment to CYC because of active
renal involvement, two minor relapses and one major with cardiac
involvement were treated with an elevation of LEF and temporary
increase of PRED (10 mg). On the contrary the median PRED dosage
could be tapered from 5 to 0 mg/d. During the whole observation
time one patient finished the treatment because of other reasons.CONCLUSION:
Leflunomide seems to be effective and safe for maintenance of
remission in 20 patients with generalized WG over a observation
time of 12 month. Leflunomide is an effective alternative
remission-maintaining therapy, e.g. in patients with residual
impaired renal function or in patients with leucopenia after an
earlier cytotoxic treatment.
ACR Poster Session E: Vasculitis II (8:00 AM-9:30 AM)
Presentation Date: Tuesday, November 16, 1999, Time: 8:00AM,
Room: Hall C
[1467] ETANERCEPT IN WEGENER'S GRANULOMATOSIS (WG): RESULTS
OF AN OPEN-LABEL TRIAL.J H Stone, D B Hellmann, M L
Uhlfelder, N M Bedocs, S L Crook, J Holbrook, G S Hoffman.
Baltimore, MD, Cleveland, OH.
Objective. To evaluate the safety of etanercept in the
treatment of WG. Methods. This open-label trial of etanercept (Enbrel®;
Immunex Corporation), 25 mg sq b.i.w., evaluated the safety and
clinical response in 20 patients with WG. All patients met
modified ACR Criteria for WG and had active disease within 1
month of entry, defined by Birmingham Vasculitis Activity Score
(BVAS) for WG. Etanercept was added to the patients' standard
therapeutic regimens. Treatment continued for at least 6 months,
with 1 year follow-up. Results. Since 3/3/99, 16 of the 20 patients have been
enrolled (7 males and 9 females; mean age 46.9 years; range
24-73). Ten of 16 patients (63%) had etanercept added to stable
therapeutic regimens that had been only partially effective in
controlling their disease, and thus had etanercept as the only
new therapeutic variable. The mean BVAS for WG score at entry
was 3.6 (range: 1-8), and the mean ESR 33 mm/hr. Disease at
entry included upper respiratory involvement (14), arthritis
(7), conductive hearing loss (4), glomerulonephritis (2),
pulmonary nodules or endobronchial disease (2), retro-orbital
mass (2), mesenteric vasculitis (2), meningeal involvement (2),
alveolar hemorrhage (1), cutaneous vasculitis (1), and fever
(1).
To date, the mean length of treatment is 8.7 weeks (range: 3.6
weeks - 13.3 weeks). Eleven of 11 patients with a minimum of 1
month follow-up have reported improvement in constitutional
symptoms and sense of well-being. The mean BVAS for these 11
patients was 1.1, a decrease of 2.5 points over entry (95% C.I.
1.5-3.6; P < 0.001). Improvement has been noted in 5/5
patients with etanercept as the only new treatment variable and
1 month follow-up. All patients remain on treatment. No disease
worsenings or flares have occurred. Adverse events have been few
and include only mild injection site reactions experienced by 1
patient and 1 case of pneumococcal pneumonia in a patient with
severe subglottic stenosis. There have been no laboratory
abnormalities associated with etanercept treatment. Conclusions. Etanercept has been well tolerated in WG in
this open label trial. Preliminary results with regard to
efficacy are encouraging. A randomized, double-blind,
placebo-controlled trial of etanercept in WG is planned.
Disclosure: Dr. Stone is a consultant to Immunex
Corporation.
Keywords: Wegner's Granulomatosis
ACR Poster Session E: Vasculitis II (8:00 AM-9:30 AM)
Presentation Date: Tuesday, November 16, 1999, Time: 8:00AM,
Room: Hall C
[1470] SEVEN YEAR ANALYSIS OF ANTI-NEUTROPHIL CYTOPLASMIC
ANTIBODY(ANCA) UTILIZATION IN AN ACADEMIC HOSPITAL.T
Suhail, R E Wolf, M Hearth-Holmes. Shreveport, LA.
PURPOSE:1-To determine the Sensitivity (Sn), specificity
(Sp) and positive (+ve) predictive value (PPV) of ANCA for
Wegener's Granulomatosis (WG) in an academic hospital.2-To
investigate the pattern of ordering ANCA, its yield and any
clinical predictors for a +ve test. METHOD: Clinical symptoms, lab parameters and ordering
MDs of patients (Pts) with ANCA were reviewed from 01/01/92 to
12/30/98. All tests were done at a reference lab outside the
hospital. Antibodies (Abs) and their pattern [cytoplasmic (c) or
Perinuclear (p) ] were determined using flow cytometry and
immunofluorescence respectively. RESULT:Of232 Pts on whom ANCA was ordered, 6 had
biopsy proven (Bx) WG, 7 had c-ANCA, 3 Pts with c-ANCA had
non-WG disease. c-ANCA had 98% Sp, 50% Sn and PPV of 42.8%. Of 6
WG Pts, 5 were Caucasian, 1 African American, 4 males and 2
females. ANCA was more likely to be +ve if ordered for; in-Pts
(11.7% vs 5.7% P=0.05), pulmonary-renal syndrome (27.2% vs 8.5%
P=0.0018), acute renal failure (22.7% vs 8.5% P=0.017) or if
accompanied by tissue Bx (68.1% vs 39.7% P=0.0027). No
significant difference was found in serum creatinine (P>0.4),
proteinuria (P>0.32), hematuria (P>0.43), hemoptysis
(P>0.52) and sinusitis (P>0.38) between +ve and negative (
-ve) ANCA Pts.
Service
GWG
LWG
+ANCA
c
p
I
WG by Bx
Rheumatology (RHM) n=50
7
8
5
3
1
1
3
Nephrology (NPH) n=63
11
4
7
2
4
1
1
Otolaryngology (ENT) n=14
1
8
2
0
1
1
1
Pulmonary (PLM) n=11
2
7
0
0
0
0
0
GWG=for generalized WG, LWG=for Limited WG, I=indeterminate
pattern. CONCLUSION:Our data showed high Sp of c-ANCA for
WG like prior studies and validates the fact that WG is a rare
disease, more common in Caucasian and males. Increased
prevalence of ANCA -ve WG in our community decreased the Sn and
PPV of c-ANCA. PLM and ENT used ANCA more frequently for
screening of LWG as compared to RHM and NPH (10% vs 60%
P=0.0005) but overall yield for +ve ANCA was similar ( 10.6% vs
8% P>0.69). Yield for +ANCA can be improved by considering
clinical predictors.
Disclosure:
Keywords: Wegner's Granulomatosis; ANCA
ACR Poster Session E: Vasculitis II (8:00 AM-9:30 AM)
Presentation Date: Tuesday, November 16, 1999, Time: 8:00AM,
Room: Hall C
[1472] EPITOPE MAPPING OF ANCA POSITIVE SERA OF WEGENER'S
PATIENTS USING OVERLAPPING PEPTIDES COVERING THE FULL PROTEINASE
3 SEQUENCE.Y M van der Geld, A Simpelaar, R van der Zee,
J W Cohen Terveart, C A Stegeman, P C Limburg, C GM Kallenberg.
Groningen, Netherlands, Utrecht, Netherlands.
Anti-neutrophil cytoplasmic autoantibodies (ANCA) directed to
proteinase 3 (Pr3) are strongly associated with Wegener's
Granulomatosis (WG). Levels of anti-Pr3 do, however, not always
correspond to disease activity if WG nor to functional in vitro
effects, suggesting that epitopes differ in the pathogenicity.
To investigate (linear) epitopes of Pr3 recognized by Pr3-ANCA
we tested WG sera for reacting to overlapping linear peptides of
Pr3.
Fifty overlapping peptides spanning the whole human Pr3 sequence
were synthesized. Each peptide was 15 amino acids (aa) in length
with an overlap of 10 aa. At the N-terminus of the peptides a
cysteine residue was inserted; this residue was either
supplementary or part of the normal Pr3 sequence. The
cys-peptides (15 mg/ml) were
covalently bound to NH groups of Covalink NH plates using of the
N-hydroxysuccinimide ester SPDP. Sera of 27 Wegener's patients
with active disease and of 27 age and sex matched healthy
controls were tested in a 1:50 dilution. Sera from two patient
were also tested during a subsequent relapse. Furthermore, eight
different anti-Pr3 moabs and a rabbit serum raised against Pr3
were tested as well.
The rabbit serum raised against Pr3 recognized 3 distinct groups
of peptides, whereas normal rabbit serum showed no reactivity.
Sera of Wegener's patients and healthy controls both recognized
the linear peptides in a similar pattern. However, 5 peptide
areas were significantly better recognized by WG sera than by
healthy control sera. Two of those peptide areas were located
near the active center of Pr3. Sera of subsequent relapses did
not differ in peptide recognition. The anti-Pr3 moabs did not
bind to linear Pr3 peptides.
All peptides recognized were surface accessible and showed
substantial homology with the sequence of mouse Pr3 and human
leukocyte elastase. The areas recognized by Pr3-ANCA sera were
in accordance with published data. However, epitope areas
recognized by sera did not differ between patients and controls,
nor between periods of different disease activity and expression
within the individual patient.
Disclosure:
Keywords: Wegner's Granulomatosis; Proteinase 3
ACR Poster Session E: Vasculitis II (8:00 AM-9:30 AM)
Presentation Date: Tuesday, November 16, 1999, Time: 8:00AM,
Room: Hall C
[1473] ANCA TESTING IN PATIENTS SUSPECTED OF
ANCA-ASSOCIATED CONDITIONS: IMMUNOFLUORESCENCE AND ELISA
TECHNIQUES IN 916 CONSECUTIVE PATIENTS.J H Stone, M
Talor, J Stebbing, N R Rose, D B Hellmann, C L Burek. Baltimore,
MD.
Objective. To compare the utility of immunofluorescence
(IF) and ELISA tests for ANCA in a population of patients
suspected of having ANCA-associated conditions. Methods. Between 1/1/95 and 4/1/98, we performed ANCA
testing by IF and ELISA for PR-3 and MPO (INOVA) in 916
consecutive patients tested for ANCA. Among patients with serial
tests, only the first test results were included in this
analysis. Investigators masked to the results of ANCA testing
reviewed patients' clinical histories, and classified their
disease status according to Chapel Hill Consensus definitions as:
a) Wegener's granulomatosis (WG); b) microscopic polyangiitis (MPA);
c) Churg-Strauss syndrome (CSS); d) idiopathic necrotizing,
crescentic glomerulonephritis; e) inflammatory bowel disease; f)
undifferentiated disease process, possibly ANCA associated; g)
other vasculitic or renal disorder; h) other disease process; i)
no identifiable disease. Results. 105/916 patients (11%) had positive IF tests (56
C-ANCA; 49 P-ANCA). 29 patients (3%) were positive for PR-3, and
16 (2%) for MPO. Correlations between IF and ELISA tests were as
follows:
Among IF+ patients (n = 105)
Among ELISA+ patients (n = 45)
Either PR-3+ or MPO+: 40 (38%)
Either C- or P-ANCA+: 40 (89%)
PR-3+ if C-ANCA+: 24/56 (43%)
C-ANCA+ if PR-3+: 24/29 (83%)
MPO+ if P-ANCA+: 11/49 (22%)
P-ANCA+ if MPO+: 11/16 (69%)
Among patients with WG, 32/45 (71%) were IF+. 22/45 (49%) were
PR-3+, and 4/45 (9%) MPO+. Among the 28 WG patients with active
disease, 23 (82%) were IF+, 16 (57%) were PR-3+; and 3 (11%)
were MPO+. Considering all 41 patients with WG, MPA, or CSS who
had active disease at the time of testing, IF was positive in 33
patients (80%), and ELISA in 27 (66%). ELISA testing was
positive in only 1 IF-negative patient whose disease was active. Conclusions. In a consecutive series of patients
suspected of having ANCA-associated conditions, 89% and 95% had
negative tests by IF and ELISA, respectively. Considering the
low number of positive tests as well as the greater expense and
laboratory effort required for ELISA testing, IF testing serves
as an excellent screen for patients in whom ELISA testing is
indicated. ELISA testing should be performed in all patients
with positive IF tests to confirm antigen specificity.
Disclosure:
Keywords: Antineutrophil Cytoplasmic Antibodies; ANCA
ACR Poster Session E: Vasculitis II (8:00 AM-9:30 AM)
Presentation Date: Tuesday, November 16, 1999, Time: 8:00AM,
Room: Hall C
[1475] TNFa-PRIMING AND
ANTI-PROTEINASE-3 ANTIBODY-INDUCED EXPRESSION OF NEUTROPHIL b2-INTEGRIN
AND L-SELECTIN (LS).Y Molad, K Bloch, E Csernok, A
Weinberger, W L Gross. Israel, Lubeck, Germany.
Anti-proteinase-3 (PR3) antibody (Ab), the Wegener’s
granulomatosis-specific C-ANCA, was shown to bind to TNFa-primed
neutrophils (PMN’s) and activate these cells via its binding
to the Fc-receptors (FcR) and PR3. The purpose of this study is
to evaluate the role of TNFa-priming
and anti-PR3 binding on the surface expression of CD11b/CD18 and
L-selectin (LS). The surface expression of neutrophil CD11b and
LS was analyzed in anticoagulated (EDTA or heparin) whole blood
in response to TNFa 20 U/ml and mouse
anti-human monoclonal IgG1 to PR3 (WGM2) by means of FACScan.
The mean fluorescence intensity (MFI) of the analyzed molecule
is expressed as percentage of the stimuli-induced change
compared to the basal expression. TNFa-priming
of PMN's induces upregulation of CD11b and shedding of LS
similar to the effect of the chemoattractant FMLP, however,
binding of anti-PR3 Ab neither induces any change nor does it
augment the effect of TNFa. A similar
effect was observed with respect to the expression of CD66b
which reflects neutrophil degranulation.
% Change of MFI induced by PMN priming and activation
TNF-a (20 U/ml)
anti-PR3
TNF+anti-PR3
FMLP (100 nM)
CD11b
279.96±36.55
11.05±8.18
313.72±42.17
197.83±24.35
LS
-59.38± 4.14
13.79±7.90
-57.44± 5.30
-41.60± 4.63
CD66b
150.40±49.70
2.60±6.40
153.80±64.60
-
Similar results were obtained when analysis was performed with
heparin instead of EDTA, suggesting that the expression of
CD11b/CD18 and LS are Ca++-independent. Our data suggest that
while TNFa priming of PMN's is
sufficient for the induction of PMN adhesiveness to the vascular
wall, PR3-ANCA binding does not enhance its effect on the
surface expression of neutrophil b2-integrin
and LS.
ACR Poster Session E: Vasculitis II (8:00 AM-9:30 AM)
Presentation Date: Tuesday, November 16, 1999, Time: 8:00AM,
Room: Hall C
[1476] SERUM LEVELS OF VASCULAR ENDOTHELIAL GROWTH FACTOR
ARE ELEVATED IN PATIENTS WITH WEGENER'S GRANULOMATOSIS.Z
Zhou, C Richard, K Ferguson, M H Desjardins, H A Menard.
Sherbrooke, Quebec, Canada.
Aims. Assessment of disease activity in Wegener's granulomatosis
(WG) is a difficult task because of frequent discordance between
laboratory and clinical events. The place of cANCA/anti-PR3
antibody titers is controversial. Serum levels of vascular
endothelial growth factor (VEGF) have been reported to be
markedly elevated in WG patients. We measured anti-PR3
antibodies and VEGF levels in a series of WG patients during
apparent disease activity or inactivity.
Methods. Anti-PR3 levels were measured by a well standardized
quantitative immunoprecipitation assay (QIP) using [3H]-DFP
labeled PMN extracts. The mean normal value + 5 SD is 300 cpm.
VEGF levels were quantified using a sensitive sandwich ELISA Kit
(R&D Systems). In normal people, VEGF is 188 ± 133 pg/ml (range
58-360 pg/ml). Twenty-three WG patients provided 79 sera at
different clinical stages. Eight normal people served as
controls (N).
Results. In this series, 20/23 patients had anti-PR3 at least
one time. Disease activity was defined by clinical criteria and
anti-PR3 values. In the 79 WG sera, VEGF levels were 402 ± 231
pg/ml (range 103-1188) (p< 0.001 Vs N). In active disease (13
sera), QIP was 4751 ± 2649 cpm (range 2316-11057) and VEGF was
425 ± 235 pg/ml (range 103-764) (p<0.001 Vs N). In inactive
disease, QIP was 411 ± 459 cpm (range 38-1979) and VEGF was 397
± 232 pg/ml (range 115-1188) (p<0.004 Vs N). Mean VEGF
levels were slightly higher during activity but not
significantly so (p=0.35). There was no correlation between
anti-PR3 and VEGF levels.
Conclusions. Increased VEGF serum levels were observed in
patients with WG, whether active or inactive. That suggests that
VEGF has a role in vasculitis but not as a useful disease
activity parameter in individual patients. That is in contrast
to anti-PR3 levels.
ACR Poster Session E: Vasculitis II (8:00 AM-9:30 AM)
Presentation Date: Tuesday, November 16, 1999, Time: 8:00AM,
Room: Hall C
[1477] CD26 EXPRESSION PREDOMINATES IN NASAL GRANULOMA OF
LOCALIZED WEGENER'S GRANULOMATOSIS (WG).A Trabandt, A
Mueller, K Gloeckner, U Seitzer, J Paulsen, W L Gross. Luebeck,
Germany, Borstel, Germany, Kiel, Germany.
Objective. We investigated the phenotype of inflammatory cells
in situ potentially involved in granuloma formation in WG and
whether there is a Th-1/Th-2 polarization of immune responses in
the spectrum of WG characterized by granulomatous inflammation
in the localized phase (l-WG) and necrotizing vasculitis in the
generalized form (g-WG).
Methods. The phenotype of inflammatory cells (CD3, CD4, CD8,
CD20, CD26, CD30, CD56, and anti-IFN-g) was analyzed in nasal
mucosal frozen biopsies derived from well characterized patients
with active l-WG (n=4) and g-WG (n=5). Cytokine production (IFN-g,
IL-4, and IL-10) by PBMC isolated from l-WG (n=13) and g-WG
(n=8) were measured by ELISA and RT-PCR.
Results. A high number of CD3+ T cells was visualized within
granulomatous formations (60% of inflammatory cells) - most of
them CD4+ compared to CD8+ T cells. Within the granulomas, the
palisading macrophage-appearing cells surrounding the central
necrosis were confirmed to be CD14+. In early granuloma
formation 45% of CD3+T cells were positively stained for CD26 -
a marker for a Th1-like immune response -, whereas 20% of T
cells were positive for CD26 in specimens from g-WG ; CD30+
cells were rarely detected in all cases. PBMC from l-WG
exhibited a higher spontaneous IFN-g production in contrast to
g-WG (207 vs 3 pg/ml, p< 0.05). IL-4 production was
negligible in both phases, however, IL-4 mRNA was detectable in
higher amounts in g-WG rather than in l-WG. IL-10 production of
anti-CD3 activated PBMC from l-WG was elevated compared to g-WG
(574 vs 154 pg/ml, p<0.05) or controls (574 vs 246 pg/ml,
p< 0.05).
Conclusion. Our findings demonstrate the presence of CD3+/CD26+
T cells within granulomatous nasal mucosal tissues and suggest
that this in situ Th1-like immune response is accompanied by an
increased peripheral IFN-g and IL-10 production in localized WG
(supported by SFB 367-A8).
Disclosure:
Keywords: Wegner's Granulomatosis; T Cells;
Interferon-gamma
ACR Poster Session E: Vasculitis II (8:00 AM-9:30 AM)
Presentation Date: Tuesday, November 16, 1999, Time: 8:00AM,
Room: Hall C
[1478] ANTI-ENDOTHELIAL CELL ANTIBODIES IN WEGENER'S
GRANULOMATOSIS (WG).G Rotiroti, T Godfrey, L LF Mendonca,
M Khamashta, G RV Hughes. London, United Kingdom.
Previous studies in WG showed controversial results concerning
the direct involvement of antibodies against antigens
constitutively displayed by endothelial cells. This study was
set up to verify the frequency and isotype of anti-endothelial
cell antibodies (AECA) in WG and to investigate whether the
presence of AECA was associated with clinical features. Patients and Methods: Seventy four sera from 31 long-term
followed-up WG patients were used for this study. AECA were
tested by ELISA and for this purpose we used human umbilical
vascular endothelial cells (HUVEC) as the antigenic source,
prepared in 2 different ways, i.e., fixed with 0.1%
glutaraldehyde and unfixed. Thirty sera from age-matched healthy
individuals served as control. The cut-off value of ELISA was 3
standard deviations above control group. Results: There was no difference in the binding of IgG or
IgM to endothelial cells when using fixed or unfixed cells, in
patients or controls. There was no significant difference
between the binding of IgM or IgG-AECA between controls and WG
(22% vs .25% and 9% vs. 13% resp). AECA levels above the cut off
was detected in 16% of WG (3 IgG-AECA and 2 IgM-AECA), a
frequency not different from matched controls. Although 4/5
patients with positive AECA presented signs of active disease,
there was no association between positive AECA and disease
activity. Only 2/9 patients with renal involvement had positive
AECA. There was no association between the presence of AECA and
ANCA (2/14), though there was a significant correlation between
the binding of IgG-AECA and titters of ANCA (r=0,52; p=0.02). Conclusion: In our series, the prevalence of AECA in WG
is low and not different from age-matched controls. Our data
suggests the autoantibodies against antigens present on
endothelial cell surface are a minor antibody system in WG.
ACR Poster Session E: Vasculitis II (8:00 AM-9:30 AM)
Presentation Date: Tuesday, November 16, 1999, Time: 8:00AM,
Room: Hall C
[1480] VASCULITIS ACTIVITY SCORE FOR WEGENER'S
GRANULOMATOSIS. A REPORT FROM THE INTERNATIONAL NETWORK FOR THE
STUDY OF SYSTEMIC VASCULITIDES (INSSYS).INSSYS.
Edinburgh, United Kingdom, Baltimore, Boston.
Purpose: Assessment of vasculitis activity has been
increasingly important with the improvement in survival as a
result of the use of immunosuppressive agents. We have sought to
refine a currently validated clinical assessment tool
(Birmingham Vasculitis Assessment Score) for use in therapeutic
trials of Wegener's Granulomatosis. Methods: A consensus meeting of experts in vasculitis
critically appraised and revised the BVAS instrument, produced a
new glossary and set of instructions, and added a 10 cm
physician's global assessment (PGA) to the form. The new
instrument was used to derive definitions of disease activity in
vasculitis. Each item was defined as either "major" or
"minor", and also defined as either "persistent"
or "new/worse". Following a training session using
paper cases with discussion, 14 participants independently
scored 10 simulated cases using the modified BVAS form. Results: The new BVAS for WG is a one-page form with
separate sections for specific items, PGA, scoring, and disease
status summary. The instrument is simple to complete. The new
glossary and instructions are highly detailed. The paper case
results were as follows: In 5 cases, there were major new items
constituting either a flare or new presentation of active
disease; 5 cases had minor new items; major or minor persistent
items were present in 1 case each. With the exception of minor
new items, the 14 observers showed consistent scoring (see table).
Type of Item
Percent Agreement: Median (Range)
Major New
96 (71-100)
Minor New
75 (21-100)
Major Persistent
100 (93-100)
Minor Persistent
89 (86-100)
The correlation between PGA and BVAS was high (r=0.88,
p<0.01). Analysis of variance confirmed that there were no
significant differences among observers for either BVAS scores
or PGA values. Conclusion: A modified BVAS form has been produced by
consensus and tested in 10 simulated cases. The results show
good agreement among observers. Minor discrepancies were
resolved by consensus. We propose to use this new instrument for
multi-center trials in Wegener's granulomatosis to define study
eligibility, measure disease activity, and assess response to
treatment.
Disclosure:
Keywords: Wegner's Granulomatosis
ACR Poster Session E: Vasculitis II (8:00 AM-9:30 AM)
Presentation Date: Tuesday, November 16, 1999, Time: 8:00AM,
Room: Hall C
[1481] INCREASING INCIDENCE OF WEGENER'S GRANULOMATOSIS IN
NORTHERN NORWAY.W Koldingsnes, J C Nossent. Tromsoe,
Norway.
Aim. To calculate annual incidence, prevalence and
survival rate of Wegener's granulomatosis (WG) in a stable
Caucasian population, during the 15-years period from 1984 to
1998. Methods. Hospital records with the diagnosis of WG,
Polyarteritis nodosa (PAN) and PAN-like diseases (ICD 9 and ICD
8 codes) from all the hospitals in the region, were reviewed to
find patients fulfilling the ACR criteria for WG. In addition
clinical records of patients with a histological diagnosis of
WG, PAN or granulomatous inflammation in upper airways, were
reviewed. Information of the denominator population in the
period, ca 464 000, was provided by the National Statistic
Office. Chi-squared, ANOVA, Kruskal-Wallis test and Kaplan-Meier
methods were used in the statistical analysis. Results. Fifty-three patients, 33 men and 20 females,
were diagnosed as WG in this 15-years period. The mean age at
diagnosis was 49.0 years ± 18.6 (range 10-84), and the disease
activity at time of diagnosis, measured by BVAS, was 21.8 ±
10.0, disease extent, measured by DEI score, was 8.5 ± 3,9. The
incidence, prevalence and survival of WG, for the three periods,
are shown below.
Group
Period
No. of patients
Annual incidence/million (95%CI)
Annual incidence/million (95%CI)
Prevalence/100 000 at the end of each period (95% CI)
5-years survival
Total
Adult
I
1984-88
11
4.7 (2.4-8.5)
6.0 (3.0-9.1)
3.0 (1.7-5.1)
82%
II
1989-93
13
5.6 (3.0-9.6)
6.5 (3.3-11.3)
4.3 (2.6-6.4)
69%
III
1994-98
29
12.4 (8.3-17.8)
15.0 (9.9-21.6)
8.9 (6.4-12.0)
90%
There were no statistical difference in age, delay of diagnosis,
treatment given, disease activity or disease extent between the
three groups, except for kidney and eye involvement. The median
creatinine value at debut was lower in group I, compared with
group II and III (87, 283 and 183 mmol/L
respectively), and more eye involvement was seen in group II. Conclusion. The incidence and prevalence of WG are
increasing in Northern Norway, and incidence in the last 5 years
is the highest reported. Data for the first and second period
are comparable to other studies. The increased incidence does
not seem to be due to an increased diagnostic awareness, as the
clinical characteristics in the three groups are comparable.
Disclosure:
Keywords: Wegner's Granulomatosis
ACR Poster Session E: Vasculitis II (8:00 AM-9:30 AM)
Presentation Date: Tuesday, November 16, 1999, Time: 8:00AM,
Room: Hall C
(
1281] COMPARISON OF 2 TREATMENT REGIMENS: CORTICOSTEROIDS
(CS) WITH AND WITHOUT CYCLOPHOSPHAMIDE (CYC) IN 215 PATIENTS
WITH CHURG-STRAUSS SYNDROME (CSS), MICROSCOPIC POLYANGIITIS (MPA)
OR POLYARTERITIS NODOSA (PAN).M Gayraud, P Letoumelin, B
Jarrousse, P Cohen, L Guillevin. Bobigny, Paris, France.
Objective: To evaluate the impact of the adding of CYC to
CS as first-line therapy for patients with CSS, MPA and PAN not
related to HBV markers on survival, side effects and relapses. Methods: Between 1980 and 1993, 215 patients were
enrolled in prospective therapeutic trials of the French
Vasculitis Study Group and their long-term survival, side
effects and relapses rates were analyzed as a function of CYC
treatment at diagnosis. Long-term survival was stratified
according to disease severity using 2 prognostic scores: the
five-factor score (FFS) and the Birmingham Vasculitis Activity
Score (BVAS). Clinical data were as follows: 64 CSS, 58 MPA, 93
PAN; sex ratio: 108 F/ 107 M; mean age: 54.3±14.4; mean FFS: 1±1.2,
mean BVAS: 19.4±7.9, mean follow-up: 87.6±51 mo. Results: 64 patients died (30%) of: progressive
vasculitis (17), sepsis (10), cancer (10), heart disease (6),
sudden deaths (5), pulmonary embolism (3), miscellaneous (13).
51 patients relapsed (73 relapses).
Survival was comparable for patients receiving CS or CS+CYC.
When calculated after FFS stratification, we observed that CYC
prolonged survival in patients with FFS2
(p=0.041). Stratification according to BVAS detected no
difference in survival. However, patients whose BVAS was >30
tended to fare better under CYC. 15/22 patients who died of
severe vasculitis received CS alone. Among the 7 patients
receiving CYC who died of non controlled vasculitis, 5 died
during the first flare (2 died within the first 2 d of
treatment), 2 after relapses. The 10 patients who died of sepsis
had received CS+CYC. No relationship was found between the
occurrence of relapses and the initial disease severity or use
of CYC. Among the 86 patients (40%) who experienced 167 side
effects, 74 had received CYC (86%) (p<0.0001). Conclusions: Because adding CYC to CS prolongs survival
of the patients with severe vasculitis assessed as FFS but had
no such impact on less severely ill patients and did not
influence the occurrence or numbers of relapses, in light of its
potential side effects, it should only be considered as
first-line therapy for severe disease.
[1482] COMPARISON OF 2 DISEASE SEVERITY SCORES IN 278
PATIENTS TREATED FOR CHURG-STRAUSS SYNDROME (CSS), MICROSCOPIC
POLYANGIITIS (MPA) AND POLYARTERITIS NODOSA (PAN).M
Gayraud, P Letoumelin, P Cohen, L Guillevin. Bobigny, Paris,
France.
Objective: To retrospectively compare 2 scores in
vasculitis patients and test their abilities to predict
mortality, when applied at the time of diagnosis. Methods: The five factors score (FFS) and the Birmingham
Vasculitis Activity Score (BVAS) were applied at disease onset
to 278 patients treated for CSS, MPA or PAN related or not to
HBV markers. The FFS comprises the following items: serum
creatinine (
and > 1.58 mg/dl) and proteinuria (
and > 1g/d), presence of severe GI tract involvement,
cardiomyopathy and central nervous system (CNS) involvement,
with each factor present being accorded 1 point BVAS is an index
of disease activity based on systemic signs, skin, mucous
membranes and eyes, ear-nose-throat (ENT), chest, heart and
vessels, GI, kidney, nervous system. Our patients were evaluated
according to 4 arbitrarily designed BVAS categories: BVAS10,
10<BVAS20,
20<BVAS30,
BVAS>30. Results: Clinical data and scores are detailed in the
table. Mean FFS was 1±1.13, mean BVAS was 19±7.7
Parameter
CSS (64)
MPA (58)
PAN (93)
PAN HBV (63)
Sex (F/M)
35/29
28/30
46/47
22/41
Mean age
51.1
59.5
53.4
51.9
FFS
0.75±0.9
1.86±1.3
0.72±1
0.95±1
BVAS
22.1±6.3
23.4±8.4
15.1±6.4
18.6±7.3
Deaths
20 (31%)
22 (38%)
22 (23%)
21 (33%)
Mortality was correlated to the severity scores, FFS
(p<0.004) and BVAS (p<0.0002). FFS and BVAS were
correlated, r= 0.61. However, for CSS, BVAS overestimated
disease severity because of points attributed to ENT involvement
(3.5±1.6) and chest signs (2.6±1.1 excluding hemorrhagic
alveolitis) which is not present in the other vasculitides.
Maxillary sinusitis and asthma have not been demonstrated to be
factors of poor prognosis in CSS. Conclusion: The 2 scores were predictive of survival and
significantly correlated. FFS is easier to use and seems to be
more informative in CSS.
ACR Poster Session E: Vasculitis II (8:00 AM-9:30 AM)
Presentation Date: Tuesday, November 16, 1999, Time: 8:00AM,
Room: Hall C
[1459] TREATMENT OF MICROSCOPIC POLYANGIITIS (MPA) AND
POLYARTERITIS NODOSA (PAN) WITH POOR PROGNOSTIC FACTORS: PRELIMINARY
RESULTS AT 3 YEARS OF A PROSPECTIVE TRIAL COMPARING CORTICOSTEROIDS AND
6 OR 12 INTRAVENOUS CYCLOPHOSPHAMIDE (CYC) PULSES.P Cohen, J P
Arene, F Lhote, B Jarrousse, O Lortholary, L Mouthon, M Gayraud, J F
Cordier, L Guillevin, the French Polyarteritis Nodosa Study Group.
Bobigny, France.
Background A recent meta-analysis of 347 patients with PAN or MPA
significantly associated 5 factors (FFS) with a poor outcome:
creatininemia >140 mmol/l, proteinuria
>1 g/d, myocardial, Gl or CNS involvement. One aim of the study was
to compare the efficacy of 6 vs 12 CYC pulses in PAN or MPA patients
with at least 1 poor-prognostic factor at baseline. Patients and Methods PAN and MPA were defined using the Chapell
Hill classification. All patients received 3 methylprednisolone pulses
then oral prednisone, and were randomized for either 6 or 12 CYC pulses
(1/mo). They all gave written consent. Remission was defined as the
absence of clinical manifestations of vasculitis for >6 months;
relapse was defined as recurrence of baseline symptom(s) or new
manifestation(s). Results 73 patients have been enrolled so far, 9 were excluded
for misdiagnosis. Only 51 patients (16 females, 35 males, mean age±SD:
55.4 ± 17 yr) who have been followed for 6
months are analyzed. The mean follow-up duration was 18.2 ± 16.1 mo. 24
patients were diagnosed as MPA, 18 as PAN, and 9 remain unclassified.
35/51 patients (68.6%) obtained clinical remission (CR); 10 of them
(28.6%) relapsed. 15/51 (29.4%) failed to obtain CR; 1/51 was lost to
follow-up. At their last visit, 39/51 (76.5%) were alive, 33/51 (64.7%)
were in CR with or without maintainance therapy. CR, relapse, initial
failure and death rates were comparable for MPA and PAN patients. Twelve
(23.5%) patients died: uncontrolled vasculitis (n=6), infection (n=2),
lymphoma (n=1) or unknown cause (n=3). Mortality was significantly lower
in patients with FFS=1 vs FFS2
(p<0.04). Although the relapse rate was higher in the 6-pulse group,
no statistical difference was found. Comments In this preliminary report, although the 6-pulse group
tended to have more relapses, the difference in CR, relapses and
survival between arms was not significant. More patients and a longer
follow-up are necessary to obtain statistical power, and compare the
final remission rate and survival between the 2 regimens.
Disclosure: Supported by the Association pour la Recherche sur
les Angeites Necrosantes - Sponsored by the Hospices Civils de Lyon
2
(p=0.041). Stratification according to BVAS detected no
difference in survival. However, patients whose BVAS was >30
tended to fare better under CYC. 15/22 patients who died of
severe vasculitis received CS alone. Among the 7 patients
receiving CYC who died of non controlled vasculitis, 5 died
during the first flare (2 died within the first 2 d of
treatment), 2 after relapses. The 10 patients who died of sepsis
had received CS+CYC. No relationship was found between the
occurrence of relapses and the initial disease severity or use
of CYC. Among the 86 patients (40%) who experienced 167 side
effects, 74 had received CYC (86%) (p<0.0001).
6
months are analyzed. The mean follow-up duration was 18.2 ± 16.1 mo. 24
patients were diagnosed as MPA, 18 as PAN, and 9 remain unclassified.
35/51 patients (68.6%) obtained clinical remission (CR); 10 of them
(28.6%) relapsed. 15/51 (29.4%) failed to obtain CR; 1/51 was lost to
follow-up. At their last visit, 39/51 (76.5%) were alive, 33/51 (64.7%)
were in CR with or without maintainance therapy. CR, relapse, initial
failure and death rates were comparable for MPA and PAN patients. Twelve
(23.5%) patients died: uncontrolled vasculitis (n=6), infection (n=2),
lymphoma (n=1) or unknown cause (n=3). Mortality was significantly lower
in patients with FFS=1 vs FFS