Ectopic lymphoid neogenesis in psoriatic arthritis
Juan D Can ˜ete, Begon ˜a Santiago, Tineke Cantaert, Raimon Sanmartı ´, Antonio Palacin, Raquel Celis,
Eduard Graell, Beatriz Gil-Torregrosa, Dominique Baeten, Jose ´ L Pablos
............................................................... ............................................................... .....
See end of article for
Dr J L Pablos, Servicio de
Reumatologı ´a, Hospital 12
de Octubre, 28041 Madrid,
Accepted 2 December 2006
Published Online First
11 January 2007
Ann Rheum Dis 2007;66:720–726. doi: 10.1136/ard.2006.062042
Background: Ectopic lymphoid neogenesis (LN) occurs in rheumatoid synovium, where it is thought to drive
local antigen-dependent B cell development and autoantibody production. This process involves the
expression of specific homing chemokines and the development of high endothelial venules (HEV).
Objective: To investigate whether these mechanisms occur in psoriatic arthritis (PsA) synovium, where
autoantibodies have not been described and the organisation and function of B cells is not clear, and to
analyse their clinical correlates.
Methods: Arthroscopic synovial biopsy specimens from patients with PsA before and after tumour necrosis
factor a blockade were characterised by immunohistochemical analysis for T/B cell segregation, peripheral
lymph node addressin (PNAd)-positive HEV, and the expression of CXCL13, CCL21 and CXCL12 chemokines
in relation to the size of lymphoid aggregates.
Results: Lymphoid aggregates of variable sizes were observed in 25 of 27 PsA synovial tissues. T/B cell
segregation was often observed, and was correlated with the size of lymphoid aggregates. A close
relationship between the presence of large and highly organised aggregates, the development of PNAd+
HEV, and the expression of CXCL13 and CCL21 was found. Large organised aggregates with all LN features
were found in 13 of 27 tissues. LN in PsA synovitis was not related to the duration, pattern or severity of the
disease. The synovial LN pattern remained stable over time in persistent synovitis, but a complete response to
treatment was associated with a regression of the LN features.
Conclusions: LN occurs frequently in inflamed PsA synovial tissues. Highly organised follicles display the
characteristic features of PNAd+ HEV and CXCL13 and CCL21 expression, demonstrating that the
microanatomical bases for germinal centre formation are present in PsA. The regression of LN on effective
treatment indicates that the pathogenic and clinical relevance of these structures in PsA merits further
diseases, with which it shares several phenotypic features.1
However, although the peripheral joint involvement often
displays a different distribution, the clinical and pathogenic
features of PsA partially overlap those of rheumatoid arthritis
(RA), and both diseases can lead to significant bone and
Histopathological analyses of RA and PsA synovial tissues
point to differential features that can be of potential value in
the diagnostic classification of patients with undifferentiated
arthritis, although the fundamental features are similar.3–5
Neovascularisation, infiltration by mononuclear cells (T and
B lymphocytes, plasma cells and macrophages) and synovial
lining hyperplasia are observed in both conditions. B cells and
plasma cells are important components of inflammatory
infiltrates in both diseases, and follicular aggregates of
lymphocytes resembling lymphoid follicles have been well
characterised in RA but only occasionally described in PsA.6–11
In RA, several studies have confirmed the presence of
competent germinal centres (GCs) both at the structural and
at the molecular level.6–9 12This process of organisation of T and
B cells is called ectopic LN, and it is associated with the
development of high endothelial venules (HEV) and the ectopic
expression of a restricted set of homing chemokines, physio-
logically involved in the traffic and tissue compartmentalisation
of T and B cells in secondary lymphoid organs.6 8The role of
these factors in ectopic LN has been shown in relevant murine
transgenic models. In such models, the process can be driven by
soriatic arthritis (PsA) is a chronic inflammatory joint
disease associated with skin psoriasis. It is usually included
within the spondyloarthritis group of inflammatory joint
enforced ectopic expression of lymphotoxin (LT)-ab or that of
the homing chemokines CXCL13, CCL21 or CXCL12.13–15
Tumour necrosis factor (TNF) a, and particularly, lymphotoxin
(LT)-ab play a potential role in the development of the HEV
phenotype and the expression of homing chemokines, and in
RA they seem to contribute to LN.6 16 17The expression of TNFa
and LTb has also been demonstrated in PsA, but LN and GC
formation has not been studied in PsA synovium.18 19
On the basis of structural and molecular similarities between
genuine GC in lymphoid tissues and LN in RA synovitis, it has
been suggested that these structures may play a role in local
antigen-driven B cell development and autoantibody responses.
They may also contribute to other processes such as antigen
presentation and costimulation of T cells, and synthesis of
soluble mediators, which could collectively explain the ther-
apeutic efficacy of B cell depletion.20In PsA, clonal expansion of
synovial B and T cells supporting a local antigen-driven process
has also been suggested but, in contrast with RA, the lack of
detectable autoantibodies makes the role of B cells uncer-
We have searched for the presence of ectopic LN in PsA
synovial tissues and its relationship to the expression of
homing chemokines and the development of PNAd+ HEV.
Our data demonstrate that a significant proportion of patients
Abbreviations: CCP, cyclic citrullinated peptide; CRP, C reactive protein;
DAS, Disease Activity Score; ESR, erythrocyte sedimentation rate; GC,
germinal centres; HEV, high endothelial venule; LN, lymphoid neogenesis;
LT, lymphotoxin; PNAd, peripheral lymph node addressin; PsA, psoriatic
arthritis; RA, rheumatoid arthritis; RF, rheumatoid factor; TNF, tumour
with PsA contain large and well-organised T/B cell aggregates
and that this phenomenon is closely related to the development
of PNAd+ HEV and the expression of homing chemokines
CXCL13 and CCL21. These features do not seem to indicate a
particular clinical subset, but can disappear after full remission
of the disease.
PATIENTS AND METHODS
Patients and biopsies
Synovial biopsy specimens were obtained by needle arthroscopy
from 27 patients with PsA1selected by the presence of active
synovitis (pain and inflammatory synovial fluid) of the knee. In
eight patients, a second biopsy specimen of the same knee was
obtained after 12 weeks of treatment with a TNFa antagonist
(six etanercept and two infliximab). In three additional
patients, a second contralateral knee biopsy specimen was
obtained after a variable time while still taking the same
treatment. These second biopsy specimens are independently
described and analysed. Disease activity was measured by
Disease Activity Score (DAS) 28. The type and extent of
psoriasis were recorded before arthroscopy.23 24All patients gave
informed consent, and the study was approved by the ethics
committee of the Hospital Clinic of Barcelona, Barcelona, Spain.
Arthroscopy was performed with an arthroscope of diameter
2.7 mm (Storz, Tullingen, Germany) without lavage. For
technical reasons, only 150–250 ml of saline was injected,
without intra-articular steroids. In all, 8–12 samples were
obtained from each patient from the suprapatellar pouch
and the medial gutter. Biopsy specimens were fixed in
4% formaldehyde and embedded in paraffin wax.
Sequential sections of PsA synovial tissues were analysed for
the presence of lymphoid aggregates and the expression of the
following markers by peroxidase immunohistochemical analy-
sis. T cells were labelled with rabbit anti-human CD3 polyclonal
(A0452, DAKO, Cambridge, UK), B cells with mouse anti-
human CD20 (clone L26, DAKO), HEV with rat anti-human
PNAd (clone MECA-79, PharMingen, Oxford, UK), CXCL13
with goat anti-human CXCL13 polyclonal (AF801, R&D
Systems, Abingdon, UK), CCL21 with goat anti-human CCL21
polyclonal (AF366, R&D Systems) and CXCL12 with mouse
anti-human CXCL12 K15C monoclonal antibody.25Positive
controls included similarly processed human tonsil sections,
and negative controls included non-immune matched mouse,
rat or goat immunoglobulins instead of the primary antibodies.
Antigen retrieval was required for most antibodies, and it was
performed by microwave heating in 1 mM EDTA for 15 min.
Primary antibodies were developed with appropriate secondary
biotinylated antibodies, following a biotin peroxidase-based
method (ABC, Vector Laboratories, Burlingame, California,
USA), and using diaminobenzidine as chromogen. Sections
were finally counterstained in Gill’s haematoxylin.
Analysis of lymphoid aggregates
The highest grade of lymphoid aggregation within each
synovial tissue sample was determined according to a pre-
viously described scoring method,8based on the number of
radial cell counts such that grade 1 corresponded to 2–5 radial
cell counts, grade 2 corresponded to 6–10 radial cell counts and
grade 3 corresponded to .10 radial cell counts. The presence of
T/B cell segregation, PNAd+ HEV, and CXCL13, CCL21 or
CXCL12 within lymphoid aggregates was analysed. Fisher’s
exact test was used to evaluate associations of the presence or
absence of all qualitative variables in the different groups.
Quantitative variables were analysed using the non-parametric
Mann–Whitney U test.
Clinical and histopathological features
A total of 27 patients with PsA with a clinically inflamed knee
joint were included, 66% of whom were men, and they had a
disease duration (mean (SD)) of 82.6 (107) months. Seven
(26%) patients had a disease duration of ,1 year (3.1
(2.2) months). Also, 17 (63%) patients had oligoarthritis and
10 (37%) had polyarthritis; 12 (48%) patients had erosive
disease; 16 (59%) patients had type I and 11 (41%) type II
Demographic and clinical data of patients with psoriatic arthritis
All patients (n=27) LN features + (n=13) LN features 2 (n=14)
Disease duration (months)
Early disease (,6 months)
DMARD use before biopsy
Anti-TNF treatment along follow-up
DAS, Disease Activity Score; DMARD, disease-modifying antirheumatic drug; LN, lymphoid neogenesis; TNF, tumour
Values are given as mean (SD) or (%). Patients with LN features include those with grade 3 infiltrates, T/B cell
segregation, peripheral lymph node addressin-positive high endothelial venule, and CXCL13 and CCL21 expression.
There were no significant differences between LN+ and LN2 groups.
Lymphogenesis in PsA 721
psoriasis. The extent of psoriasis as measured by Physician’s
Global Assessment (n=24) was severe in one, moderate in
eight, mild in seven, minimal in eight and clear in three
patients. In all, 9 (33%) patients were taking disease-modifying
antirheumatic drug treatment (eight taking methotrexate and
one taking chloroquine) at the time of arthroscopy. DAS28 was
4.1+1.2, and none of the patients was rheumatoid factor (RF) or
anti-cyclic citrullinated peptide (CCP) positive. Table 1 sum-
marises the clinical and demographic features.
All tissue samples contained synovial lining and inflamma-
tory infiltration of the sublining. In 25 of 27 synovial tissues,
aggregation of mononuclear cell infiltrates (lymphoid aggrega-
tion) was detected.
Grading of aggregates and T/B cell segregation
The 27 PsA synovial tissues were classified according to the
highest grade of lymphoid aggregation present (table 2, fig 1): 2
tissues contained no aggregates, 10 had only grade 1 or 2
aggregates and 15 had large grade 3 aggregates (range 1–27
aggregates, mean (SD) 5.6 (7.8) per tissue section). The
number, proportion and grade of aggregates present in each
section is presented in an online supplementary table (available
T/B cell segregation was observed in all groups, but the
proportion of T/B cell segregated lymphoid infiltrates was
increased in parallel to the grade of lymphoid aggregation: half
of the grade 1 and 2 infiltrates displayed T/B cell segregation,
whereas all but one grade 3 infiltrates displayed these features
(table 2, fig 1 and online supplementary table; supplementary
table available at http://ard.bmj.com/supplemental).
Presence of HEV and chemokine expression
We first studied control tonsil sections to confirm the specificity
of antibodies. We observed a specific pattern of PNAd, CXCL13,
CCL21 and CXCL12 expression similar to that described
previously.8 26 27PNAd-associated MECA-79 epitope was speci-
fically detected on HEV (fig 2A). CXCL13 was predominantly
detected in stromal follicular dendritic cell-like networks of the
dark zone of GCs (fig 2B). Weak CXCL13 immunostaining was
present in some HEV. CCL21 expression was predominantly
present in stromal cells and HEV of the perifollicular areas
(fig 2C). CXCL12 was detected in stromal cells, and a strong
immunostaining was also observed on the endothelium of HEV
in the dark zone of GC and perifollicular areas (fig 2D). CXCL12
and CCL21 were also detected in the crypt epithelium (data not
shown). Matched non-immune immunoglobulin controls did
not produce a detectable immunostaining (figs 2E–F).
Vessels with HEV morphological features and the presence of
the HEV-associated PNAd (MECA-79) epitope were exclusively
observed within lymphoid aggregates of tissues containing
grade 3 aggregates with T/B cell segregation (table 2, fig 3C). In
these tissues, PNAd+ HEV were predominantly located within
or in the periphery of large grade 3 aggregates.
CXCL13 immunostaining was restricted to scattered cells of
stromal or large mononuclear shape within lymphoid aggre-
gates (fig 3D). CXCL13+ cells were not organised as follicular
dendritic cell-like networks as observed in tonsils. Similar to
what was observed in tonsils, CXCL13 immunostaining was
detectable on some HEV, although it was very weak compared
with CXCL13-positive stromal or mononuclear cells. CXCL13
was not detected in other synovial areas such as synovial lining
cells. With the exception of one single case, all tissues classified
as grade 3 displayed CXCL13 immunostaining (table 2).
CXCL13 was detected in only 3 of 10 tissues containing grade
1 or 2 aggregates, which in all 3 cases showed T/B cell
CCL21 immunostaining was detected in 14 of 15 grade 3
tissues, in cells of stromal shape located within lymphoid
aggregates in a HEV perivascular location with only occasional
and weak staining of HEV (table 2, fig 3E). In 4 of 10 grade 1 or
2 tissues, CCL21 immunostaining was also detectable in some
lymphoid aggregates that also displayed T/B cell segregation. In
some tissues, synovial lining CCL21 immunostaining was also
observed, but it was weaker than that observed within
lymphoid aggregates and did not correlate with either the
grade of lymphoid aggregation or with the presence of CCL21
within lymphoid aggregates (data not shown).
CXCL12 immunostaining was detected in all tissues studied
for PsA. The pattern was similar to that described previously in
RA, and included the synovial lining layer, sublining scattered
fibroblasts and blood vessels.28Within grade 3 lymphoid
aggregates containing HEV, a strong immunostaining was
observed on HEV endothelium and perivascular stromal cells
(fig 3F), in contrast with the weak or undetectable HEV
immunostaining for CXCL13 and CCL21. However, the presence
of CXCL12 in stromal cells was similar in all groups of tissues
and among differently graded or T/B cell-segregated aggregates.
Correlation with clinical features
Patients were stratified by the presence or absence of LN
features (PNAd+ HEV, CXCL13+, CCL21+ and large grade 3
organised aggregates) in biopsies. There were no statistically
significant differences between the LN+ (n=13) or LN2
(n=14) groups regarding gender, age, disease duration, erosive
disease, articular pattern (oligoarticular versus polyarticular),
psoriasis type and extent, disease-modifying antirheumatic
drugs taken before arthroscopy, disease activity score or
initiation of anti-TNFa therapy during follow-up (mean (SD)
time to initiation 2.8 (1.6) years; table 1).
Response to treatment
Eleven patients underwent two biopsies over time during
treatment. In three patients who were not treated with TNFa
Histomorphological grading and lymphoid neogenesis markers in psoriatic arthritis synovial tissues
Number of tissues*
T/B segregationPNAd+ HEVCXCL13 CCL21CXCL12
HEV, high endothelial venule; PNAd, peripheral lymph node addressin.
*Grades correspond to the highest grade of lymphoid aggregation present in a synovial tissue, and percentages in this column are taken from the total number of
patients (n=25). Tissues from two patients did not contain detectable lymphoid aggregates and were not included here. All other data are presented as the number and
percentage of tissues positive for each particular feature within the subgroup of tissues with the indicated grade.
?p,0.03 grade 3 vs grade 1 and 2 groups (Fisher’s exact test).
722Can ˜ete, Santiago, Cantaert, et al
blockade and were therefore considered as a negative control
group, a second biopsy specimen of the contralateral knee was
obtained after a mean (SD) of 25 (18) months in the presence
of persistent active synovitis. Two patients had no LN features
at the first biopsy (lack of follicles with T/B cell segregation and
no expression of MECA, CXCL13 or CCL21), and these features
remained unchanged in the second biopsy (except for CCL21
positivity in one of them). One of them had moderate
improvement in the DAS28, whereas the other did not have
any change in disease activity. The third patient exhibited LN
features in both biopsies without changes in DAS 28 (table 3).
One patient treated with anti-TNFa with good improvement
(DAS28 at first biopsy 6.49 and after treatment 3.07) lacked LN
features in both biopsies (table 4).
Four patients with LN features in the first biopsy were
treated with anti-TNFa: two had moderate improvement and
the other two had no improvement as evaluated by DAS28
response criteria. All of them had, at least, active synovitis in
aggregates. Grade 1 (arrows) and 2
(arrowhead) (A, B), grade 2 (C, D) and
grade 3 (E, F) aggregates showing the
distribution of T cells (A, C, E), and B cells (B,
D, F), in serial consecutive sections
representative of 25 patients with psoriatic
arthritis are shown. Grade 2 and 3
aggregates shown in C, D and E, F were
classified as T/B cell segregated, whereas
grade 1 and 2 shown in A, B were not.
Original magnification 6400.
Histological grading of lymphoid
node addressin (PNAd) and homing
chemokine immunostaining in human tonsil
sections. Human tonsil sections were
immunostained for PNAd (MECA-79; A),
CXCL13 (B), CCL21 (C) and CXCL12 (D).
Note the variable staining of high endothelial
venule (arrows) for the different chemokines.
Lower panels (E–H) show non-immune
immunoglobulin controls matched to the
corresponding upper panel. Original
Specificity of peripheral lymph
Lymphogenesis in PsA723
the knee at week 12 when the second biopsy was performed; in
these four patients, LN features were unchanged in the post-
In the other three patients, LN features present at first biopsy
disappeared in the second biopsy, after all of them achieved full
remission of the disease (DAS after treatment (1.6; table 4).
These three patients are still in remission after 18, 24 and
68 months of follow-up.
The formation of ectopic LN is a well-recognised feature of
several chronic inflammatory diseases such as Sjo ¨gren’s
syndrome, autoimmune thyroid disease, and RA and chronic
infections.9 29 30In lymphoid tissues, these anatomical micro-
structures permit the functional interaction of antigen-present-
ing cells, T cells and B cells. GC are critical in the development
of B cell immune responses because they provide an infra-
structure to capture and store antigen, which drives B cell
development and differentiation into affinity-selected memory
B cells and plasma cells. The structural and molecular
similarities between genuine GC and ectopic lymphoid follicles
may suggest the immunological competence of these structures
as GC.9 31 32The contribution of these structures to autoantibody
responses against local autoantigens has been suggested, but
grade 3 lymphoid aggregates in psoriatic
arthritis synovial tissues. All sections
correspond to grade 3 aggregates from the
same individual immunostained for CD3 (T
cells; A), CD20 (B cells; B), peripheral lymph
node addressin (MECA-79) (C), CXCL13 (D),
CCL21 (E) and CXCL12 (F). (A) and (B) are
parallel sections of the same tissue and show
the same lymphoid aggregate. Note the
variable staining of high endothelial venule
(arrows) for the different chemokines.
Original magnification 6400.
Lymphoid neogenesis features in
Clinical and synovial immunohistological data of 11 rebiopsied patients*
Patient numberBiopsy Treatment Knee synovitisDAS28
Grade 3 follicles
(%) PNAd+ HEV CXCL13CCL21
DAS, Disease Activity Score; ETN, etanercept; HEV, high endothelial venules; IFX, infliximab; MTX, methotrexate; NSAID, non-steroidal anti-inflammatory drug; PNAd,
peripheral lymph node addressin.
*Patients 1–3 were rebiopsied at the contralateral knee with active synovitis after a mean (SD) of 25 (18) months from the first contralateral biopsy; they were receiving
stable treatment. Patients 4–11 were rebiopsied at the same knee after 3 months of anti-TNFa treatment.
724Can ˜ete, Santiago, Cantaert, et al
they may also play a role in the pathogenesis of chronic
inflammatory conditions by driving T cell responses and
producing proinflammatory cytokines.13 33
The expression of CXCL13 and CCL21 homing chemokines
and the development of HEV have been identified as necessary
components for cell recruitment and compartmentalisation into
functional zones during the development of lymphoid organs
and ectopic LN.8 14 15 34We show for the first time evidence that
in PsA these chemokines are locally expressed and significantly
correlate with cell cluster enlargement and organisation in a
secondary lymphoid organ-like fashion. The close relationship
between expression of CXCL13 and CCL21 chemokines, HEV
development and ectopic LN development is consistent with
previous observations in RA, reinforcing the concept of some
common physiopathological processes in both conditions.6 8The
proportion of patients showing LN features in our PsA series is
similar to that described previously in RA. However, the relative
extension of this process in PsA cannot be compared with the
previous RA series that includes larger surgically obtained
synovial tissue samples.6 8
The presence of T/B cell segregation and homing chemokine
expression in some small aggregates in the absence of HEV
suggest a sequential process, the last step of which is HEV
development and may specifically contribute to the enlarge-
ment of lymphoid aggregates, consistently with their well-
known role in L-selectin-initiated B and T cell recruitment from
the bloodstream.35By contrast, CXCL12 expression did not
correlate with the grade of cell aggregation, T/B cell segregation
or the presence of PNAd+ HEV. Interestingly, CXCL12 has been
associated to ectopic B cell recruitment and compartmentalisa-
tion,14 27and our present data show that it is the most abundant
chemokine in the HEVs of tonsils or PsA tissues. Therefore, we
cannot discard a specific role for CXCL12 in PsA LN, although
its expression by stromal cells does not seem sufficient to drive
this process. We have previously shown that in RA, CXCL12
mRNA is only expressed by stromal cells, whereas the protein is
displayed on surface heparan sulphate proteoglycans of
endothelial cells.28 29The development of the HEV phenotype
might specifically be associated to enhanced endothelial dock-
ing of CXCL12, as suggested by its abundant presence in RA
and PsA HEV.29
The clinical implications of ectopic LN, as well as the
potential effects of treatment on this process, have not been
elucidated in RA. Our data on PsA suggest that synovial LN is
not related to disease duration or severity, and rather seems to
be an individual feature, as hypothesised in RA.9A non-
significant trend towards longer disease duration and more
erosive disease in LN2 patients also argues against LN as a
factor of severity, but should be taken with caution due to the
small sample size.
In PsA, our previously published data showed a decrease in
the vascularity but not in lymphoid infiltration after anti-TNFa
treatment.36Our present data obtained from 11 patients who
underwent two biopsies point to the stability of the LN pattern
in persistent synovitis, but regression of lymphoid neogenesis
features in association with complete remission induced by
anti-TNFa treatment. The potential role of TNFa and particu-
larly LTab in driving HEV development and homing chemokine
expression has been shown in animal and human cellular
models.13 17Further studies with larger samples are needed to
search for the clinical correlates of this process and to extend
our observation of the regression of these lymphoid structures
and HEV in association to favourable therapeutic outcomes.
The demonstration of LN is particularly intriguing in PsA
because the contribution of B cells to its pathogenesis and,
particularly, the development of local B cell autoantibody
responses have not been explored. In cutaneous psoriasis, LN
has not been described and B cells are not an abundant
component, suggesting tissue-specific differences. Specific auto-
antibodies in PsA have not been described, and RF or anti-CCP
antibodies have been detected only in a small proportion of
patients.37In the present series, all patients were RF and anti-
CCP negative, excluding an association between these auto-
antibodies and LN. This contrasts with one study in RA, where
the presence of RF has been associated to higher aggregation of
infiltrates.16B cells could also drive antibody-independent
synovial inflammation through the development of T cell
responses or by enhancing cytokine production.33Further studies
of the molecular phenotype of synovial B cells and the effects of
specific B cell depletion therapy in PsA may be of help to address
the potential pathogenetic role of B cells in this disease.
In conclusion, LN occurs in the synovium of a significant
proportion of patients with PsA. Analysis of clinical data and
changes in rebiopsied patients suggest that LN is a stable and
individual feature that is reverted only by full remission after
described in PsA, these findings encourage further studies to
determine the role of synovial B cells in PsA.
JDC was supported by research grants from Fondo de investigacio ´n
sanitaria (FIS 04/1023 and 1027, and FIS 05/0913), by a research award
from the IDIBAPS and by a grant from Wyeth. JLP was supported by
FIS 05/0060 and by a grant from Schering Plough, SA, TC and DB were
supported by the European Community’s FP6 funding. This publication
reflects only the author’s views. The European Community is not liable
for any use that may be made of the information herein. We thank Dr
Arenzana-Seisdedos for kindly providing K15C the anti-CXCL12 mAb.
Supplementary table is available online at http://
Juan D Can ˜ete, Raimon Sanmartı ´, Raquel Celis, Eduard Graell, Beatriz
Gil-Torregrosa, Unitat d’Artritis, Servei de Reumatologı ´a, Hospital Clı ´nic
de Barcelona and IDIBAPS, Barcelona, Spain
Begon ˜a Santiago, Jose ´ L Pablos, Servicio de Reumatologı ´a, Unidad de
Investigacio ´n, Hospital 12 de Octubre, Madrid, Spain
Tineke Cantaert, Dominique Baeten, Division of Clinical Immunology and
Rheumatology, Academic Medical Center/University of Amsterdam,
Amsterdam, The Netherlands
Antonio Palacin, Servei de Anatomı ´a Patolo ´gica, CDB, Hospital Clı ´nic de
Barcelona, Barcelona, Spain
Competing interests: None.
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