Nailfold capillaroscopy abnormalities are associated with the presence of anti-endothelial cell antibodies in Sjogren's syndrome.
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ABSTRACT: Nailfold capillaroscopy is widely used in autoimmune patients to determine capillary morphology. Laser Doppler imaging (LDI) is a relatively new method for measuring the microcirculation of cutaneous perfusion. The aim of this study was to investigate the capillary morphology and microcirculation among patients with Sjögren's syndrome (SS) and poly/dermatomyositis (PM/DM) with these two non-invasive methods and to detect secondary Raynaud's syndrome (SRS) in these autoimmune diseases. Thirty patients with primary SS, 30 patients with PM/DM, 30 patients with primary Raynaud's syndrome (PRS), and 30 healthy volunteers were included in the study. Nailfold capillaroscopy and LDI were performed on each patient. A comprehensive analysis was performed among the patients and healthy individuals. Among SS patients avascularity and among PM/DM patients avascularity and capillary morphology changes were most often detected by capillaroscopy. With LDI the mean steady-state cutaneous perfusion was 1.25 perfusion units (PU) in region of interest 1 (ROI1), 1.22 in ROI2, and 1.49 at the fingertips in PRS patients; the corresponding values were 1.2, 1.03, and 1.48 PU in SS, 0.91, 0.76, and 1.19 PU in PM/DM, and 1.79, 1.62, and 2.2 PU in the controls. The differences were significant between each autoimmune group compared to the control group (p<0.02, p<0.001, and p<0.001, respectively). By using nailfold capillaroscopy, abnormalities in capillary morphology can be detected, and by using LDI, the reduced blood flow in the capillaries can be detected. These investigations can be useful in the detection of SRS, or in distinguishing whether the reduced blood flow is due to primary/systemic autoimmune diseases.Scandinavian Journal of Rheumatology 01/2008; 37(1):23-9. · 2.22 Impact Factor
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ABSTRACT: Anti-endothelial cell antibodies (AECA) have been detected in 19 to 30% of patients with systemic sclerosis (SSc). The objective of this study was first to assess the role of a secondary Sjögren's syndrome (SS) in the occurrence of AECA in SSc. Secondly, we researched AECA in patients with primary SS, and investigated whether AECA were associated with vascular manifestations (Raynaud's phenomenon and vasculitis). IgG-AECA were tested by an ELISA method in serum samples from 50 patients with SSc (16 of them had also a secondary SS), 50 patients with primary SS, and 50 healthy controls. AECA levels were significantly higher in patients with SSc or primary SS than in healthy controls (p < 0.01 and p < 0.01, respectively). In patients with SSc, AECA values were significantly higher in patients with secondary SS (p < 10(-5)). In patients with primary SS, AECA levels were significantly higher in patients with Raynaud's phenomenon (p < 0.01), but not in patients with vasculitis. In patients with SSc, AECA are associated with a secondary SS. In patients with primary SS, AECA are associated with Raynaud's phenomenon, but not with vasculitis.Annals of the Rheumatic Diseases 05/1997; 56(4):230-4. · 9.11 Impact Factor
Article: Wide-field capillary microscopy.Arthritis & Rheumatology 10/1981; 24(9):1159-65. · 7.48 Impact Factor
Letters to the Editor
Advance Access publication 20 March 2009
Unifying abbreviations for biologics in rheumatology—does
the idea hold promise?
SIR, Since presenting the idea of a unifying abbreviation system
for biologics used in trials and in clinics some years ago , I have
repeatedly been asked to both expand the list according to the
three-letter system and to test whether all new substances can be
coded without being ambiguous. The continuous development
and licensing of additional biologics in all kinds of rheumatolo-
gical disorders has helped significantly to achieve these goals, as
has the persisting variety of abbreviations frequently observed
even in the same satellite symposium addressing a given biological.
In keeping with the original idea, in the updated list (Table 1) the
added drugs are coded by the first two letters of the generic, e.g.
IN for infliximab, ET for etanercept, AD for adalimumab, etc.,
and the third letter indicating the biological structure or class of
the drug, i.e. X for a chimeric monoclonal antibody, Z for a
humanized monoclonal antibody, M for a human monoclonal
antibody, C for a soluble receptor/receptor–antibody fusion
protein and R for a receptor antagonist.
Disclosure statement: The author has declared no conflicts of
1Department of Internal Medicine and Rheumatology, Justus-Liebig
University Giessen, Giessen and2Department of Rheumatology and
Clinical Immunology, Kerckhoff Clinic, Bad Nauheim, Germany
Accepted 4 February 2009
Correspondence to: Ulf Mu ¨ ller-Ladner, Department of
Rheumatology and Clinical Immunology, Kerckhoff Clinic,
Benekestrasse 2-8, D-61231 Bad Nauheim, Germany.
1 Mu ¨ller-Ladner U. Unifying abbreviations for biologicals in trials and publications.
Advance Access publication 23 March 2009
Nailfold capillaroscopy abnormalities are associated with
the presence of anti-endothelial cell antibodies in Sjogren’s
SIR, Primary SS is often associated with vascular features such as
RP, in 10–30% of the cases and vasculitis . In SS microvascular
abnormalities, assessed by nailfold capillaroscopy (NC), range
from non-specific to more specific or scleroderma-type findings
[2–4]. Patients with RP seem to have a higher frequency of NC
abnormalities with respect to non-RP patients and a scleroderma-
type NC pattern is associated with the presence of ACAs .
A higher deletion score on NC microscopy has been described in
those SS patients with systemic manifestations and RP .
Avascularity has been recently confirmed to be associated with a
reduction of the blood flow . Until now no association has been
described in SS between NC findings and serological parameters
of endothelial damage, including anti-endothelial cell antibodies
(AECAs), although these autoantibodies, claimed for a possible
pathogenetic role in autoimmune diseases, have been detected in
25–30% of SS and seem to be more frequent in those patients
presenting RP .
We investigated the microvascular involvement in a group of
66 consecutive primary SS patients, diagnosed according to the
American–European Criteria  [65 females, 1 male; mean age
54.2 years (range 26–76 years); mean disease duration 108.8
months (range 6–372 months)], looking for any NC abnormalities
and for AECAs. Patients gave their informed consent and
underwent a careful clinical assessment. The study was approved
by the local ethics committee.
Each patient performed NC, according to the standard method
. The following morphological parameters were considered:
number of capillaries per square millimetre, alterations of the
capillary length, morphology (tortuous, ramified/bushy capil-
laries) and distribution; presence of ectasic loops, haemorrhages
and flux abnormalities . A semi-quantitative rating scale
was adopted to score these changes, according to previous
studies : score 0¼no changes; 1¼few¼less than 4 alterations;
2¼some¼ between 4 and 6 alterations; 3¼frequent¼more than
6 alterations per linear millimetre. The mean score for each subject
was obtained analysing all fingers.
A full laboratory investigation included ESR, CRP, full blood
count, ANA detection by indirect IF (Binding Site). Anti-SSA/Ro
and anti-SSB/La antibodies were measured using an ELISA
(DIAMEDIX, Miami, FL, USA). AECA serum levels were
also measured. Briefly, human umbilical-vein endothelial cells
were isolated by collagenase perfusion and were cultured in
M199 medium (Sigma Chemical Co., St Louis, MO, USA).
Rheumatology key message
? This proposed coding system can be used for all current and future
TABLE 1. Updated abbreviation list for currently used bio-
logics in clinics, trials and publications in rheumatology and
related medical specialities
? The Author 2009. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: firstname.lastname@example.org
at University of Portland on May 20, 2011
These cells were used to detect AECA of IgG isotype by means of
a cyto-ELISA as previously described . Optical density (OD)
was read at 405nm wavelength and AECAs were expressed as
a binding index (BI). AECAs were considered positive when
the BI was higher than the cut-off value (meanþ2
66 healthy controls) corresponding to 50% of a positive reference
serum from an SLE patient. Each serum sample was tested in
The statistical analysis was performed analysing categorical
variables by ?2-test or Fisher’s exact test and differences between
the means were determined using Mann–Whitney test for
unpaired samples. P-values<0.05 were considered statistically
significant. Twenty-six (39.4%) of the 66 SS patients presented
RP, whereas an NC score 51 was found in 33 cases (50%), ANAs
were found in 55 patients (83.3%), anti-SSA/Ro antibodies in 47
(71.2%) and anti-SSB/La in 35 (53%) subjects. Sixteen (24.2%)
patients had AECA. RP was present in 8 (50%) AECA-positive
patients and in 17 (34%) patients without these autoantibodies.
The presence of ANA inversely correlated with the presence of
AECA in our patients (56 vs 92%) (P<0.003). An NC score of
51 was found in 13 (81.2%) AECA-positive patients (Fig. 1),
with respect to 20 (40%) AECA-negative patients (P<0.008).
No association was found concerning the other clinical, capillaro-
scopic or laboratory features (Table 1).
Even though a peculiar NC pattern has not been characterized
to date in SS patients (2–4), our findings show that an NC score
51 is detectable in 50% of the cases and is more frequent in
AECA-positive patients with respect to those without these
autoantibodies (P<0.008). Although not significant, this group
of patients also had a more frequent RP with respect to those
without AECAs (50 vs 34%), as shown in previous studies,
meaning that they may act with a mediated mechanism resulting
in an increased vascular reactivity . They also seemed to lack
ANA with respect to AECA-negative patients, thus confirming a
non-specific B-cell polyclonal activation in SS, where different
antigenic targets may differently stimulate the autoantibody
production. The detection of AECAs seems to be independent
of the presence of antibodies with unrelated specificities, such as
A high prevalence of AECAs has been frequently associated
with the presence of vascular lesions and with disease activity in
autoimmune diseases. However, it is difficult to define the role of
SS in the occurrence of AECAs, whose endothelial antigenic
targets are still unknown. The pathogenetic role of AECAs in the
development of vascular injury remains controversial.
We know that NC is a useful tool for the assessment of
microvascular involvement in many autoimmune diseases and it
seems to be able to show early abnormalities . The interesting
association of these NC findings with the presence of AECAs
suggests that these autoantibodies are involved in the determinism
of the endothelial damage in SS. The contemporary presence of
AECAs and more frequent NC abnormalities led us to sustain the
hypothesis that these two parameters may help in evaluating the
expression of vasculopathy in SS.
Disclosure statement: The authors have declared no conflicts of
VALERIA RICCIERI1, ILIANA SCIARRA1, FULVIA CECCARELLI1,
CRISTIANO ALESSANDRI1, CRISTINA CROIA1, MASSIMILIANO VASILE1,
MARIA GRAZIA MODESTI1, ROBERTA PRIORI1, GUIDO VALESINI1
1Division of Rheumatology, Department of Clinical Medicine and
Therapy, University of Rome ‘Sapienza’, Rome, Italy
Accepted 9 February 2009
Correspondence to: Valeria Riccieri, Division of
Rheumatology, Department of Clinical Medicine and Therapy,
University of Rome ‘Sapienza’, Viale del Policlinico 155,
00161 Roma, Italy. E-mail: email@example.com
1 Garcia-Carrasco M, Siso A, Ramos-Casals M et al. Raynaud’s phenomenon in
primary Sjogren’s syndrome. Prevalence and clinical characteristics in a series of
320 patients. J Rheumatol 2002;29:726–30.
2 Tektonidou M, Kaskani E, Skopouli FN, Moutsopoulos HM. Microvascular abnorm-
alities in Sjogren’s syndrome: nailfold capillaroscopy. Rheumatology 1999;38:
3 Capobianco KG, Xavier RM, Bredemeier M, Restelli VG, Brenol JCT. Nailfold
capillaroscopic findings in primary Sjogren’s syndrome: clinical and serological
correlations. Clin Exp Rheumatol 2005;23:789–94.
4 Szabo N, Csiki Z, Szanto A, Danko K, Szodoray P, Zeher M. Functional and
morphological evaluation of hand microcirculation with nailfold capillaroscopy and
laser Doppler imaging in Raynaud’s phenomenon and Sjogren’s syndrome and poly/
dermatomyositis. Scand J Rheumatol 2008;37:23–9.
5 Hebbar M, Lassalle P, Delneste Y et al. Assessment of anti-endothelial cell
antibodies in systemic sclerosis and Sjogren’s syndrome. Ann Rheum Dis 1997;56:
6 Vitali C, Bombardieri S, Jonsson R et al. European Study Group on Classification
Criteria for Sjogren’s syndrome: a revised version of the European criteria
proposed by the American–European Consensus Group. Ann Rheum Dis 2003;
Rheumatology key message
? A more severe NC score is significantly associated with the
presence of AECAs in SS.
FIG. 1. NC of an SS patient with AECAs (score >1).
parameters in SS patients with and without AECA
1. Comparisonof themainclinical–demographical and laboratory
Age, mean (range), years
Disease duration, mean (range), months
RP, n (%)
Xeropthalmia/xerostomia, n (%)
Articular involvement, n (%)
NC score 51, n (%)?
ANAþ, n (%)??
Anti-SSA/Ro antibodiesþ, n (%)
Anti-SSB/La antibodiesþ, n (%)
Letters to the Editor705
at University of Portland on May 20, 2011
7 Maricq HR. Widefield capillary microscopy: technique and rating scale for
abnormalities seen in scleroderma and related disorders. Arthritis Rheum
8 Cutolo M, Sulli A, Pizzorni C, Accardo S. Nailfold videocapillaroscopy assessment of
microvascular damage in systemic sclerosis. J Rheumatol 2000;27:155–60.
9 Conti F, Alessandri C, Bompane D et al. Autoantibody profile in systemic lupus
erythematosus with psychiatric manifestations: a role for anti-endothelial-cell
antibodies. Arthritis Res Ther 2004;6:R366–72.
10 Drouet C, Nissou MF, Ponard D et al. Detection of anti-endothelial cell antibodies by
an enzyme-linked immunosorbent assay using antigens from cell lysate: minimal
interference of antinuclear antibodies and rheumatoid factors. Clin Diagn Lab
Advance Access publication 9 April 2009
Cardiac infiltration in early-onset sarcoidosis associated with
a novel heterozygous mutation, G481D, in CARD15
SIR, Early-onset sarcoidosis (EOS) and Blau syndrome (BS) are
rare multi-organ granulomatous inflammatory disorders clinic-
ally characterized by the distinct triad of skin, joint and eye
lesions without any apparent cardio-pulmonary involvement .
Gain-of-function mutations in CARD15 (NM_022162) cause EOS
and/or BS (EOS/BS) [2–4], but not the development of adult-type
sarcoidosis [5, 6]. We identified a novel heterozygous gain-
of-function mutation, G481D, in CARD15 from a patient with
EOS, who was suffering from recurrent episodes of congestive
heart failure. Cardiac infiltration is a common clinical manifesta-
tion in adult-type sarcoidosis, but is rare and atypical in EOS/BS.
Notably, the cardiac manifestations of this patient are quite
similar to those in adult sarcoidosis. This is the first report
demonstrating the precise manifestations of cardiac infiltration of
sarcoidosis in a patient with a CARD15 mutation.
The patient was an 18-year-old female. At 3 months of age
she developed a miliaria-like skin rash. Thereafter, she presented
various manifestations, such as uveitis, joint involvement,
hepatosplenomegaly, arterial hypertension and congestive heart
failure. A lymph node biopsy showed fresh-looking multiple
granulomas, indicating a diagnosis of EOS. The administration of
glucocorticoids improved her symptoms. However, extended
treatments were required because of recurrent episodes of
congestive heart failure accompanied with the activation of an
autoinflammatory reaction. Echocardiography showed intra-
ventricular septum thickness [Fig. 1A (a, b)]. A histopathological
examinationofthe right ventricle
inflammatory cell infiltration, ballooning of myocardium and
mild fibrosis (Fig. 1B). The histopathological findings were similar
to those of cardiac sarcoidosis in adults. Other immunosuppres-
sive treatments, e.g. NSAIDs, MTX, AZA and/or CSA, did not
sufficiently improve her symptoms. The administration of TNF-?
inhibitor, infliximab, in combination with MTX effectively
inhibited the autoinflammation, thus resulting in an improvement
of the intraventricular septum thickness [Fig. 1A (c, d)].
Under approval by the Ethics Committee/Internal Review
Board of Hiroshima University and informed patient consent, we
analysed the nucleotide sequence of CARD15, and found a novel
heterozygous single base-pair substitution, 1442G>A (G481D), in
exon 4. This mutation was located within the nucleotide-binding
domain. NF-?B reporter assay revealed that MDP-independent
NF-?B transactivation in the G481D, C495Y and H496L mutants
in CARD15 showed significantly higher levels than that in wild-
type (WT) (Fig. 1C), thus suggesting the G481D mutation to be a
gain-of-function mutation .
Cardiac infiltration is a rare and atypical manifestation among
the patients with EOS/BS. Only one report has shown cardiac
infiltration among the patients with CARD15 mutations . The
patient suffered from severe multi-organ involvement, arterial
hypertension and myocardial hypertrophy, and was identified
as being a heterozygous C495Y mutation. The C495Y mutation
displayed the highest level of MDP-independent NF-?B activation
(Fig. 1C), and notably the G481D mutation also demonstrated
a relatively higher level of activity. Although no genotype–
phenotype correlation in EOS/BS could be proven in the previous
study, cardiac infiltration may therefore be associated with higher
levels of MDP-independent NF-?B activation .
FIG. 1. (A) Echocardiography findings (parasternal long-axis view) before (a, b) and after (c, d) sufficient anti-inflammatory treatments. The systolic (a, c) and diastolic (b, d)
image. (B) Histopathological findings of endocardium [(a) HE ?200, (b) Azan ?100]. (C) The MDP-independent (open columns) and MDP-dependent (filled columns) NF-
?B transactivation. Values represent the mean of the normalized data (mock without MDP¼1) of triplicate cultures, and error bars indicate the S.D. Both C495Y and H496L
are previously reported mutations in patients with EOS [3, 4].
706 Letters to the Editor
at University of Portland on May 20, 2011