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The cutting edge of spondylarthropathy research in the millennium.

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Vol. 46, No. 3, March 2002, pp 606–613
DOI 10.1002/art.10041
© 2002, American College of Rheumatology
The Cutting Edge of Spondylarthropathy Research
in the Millennium
Kaisa Granfors,1 Elisabeth Märker-Hermann,2 Filip de Keyser,3 Muhammad A. Khan,4
Eric M. Veys,3 and David T. Y. Yu5
tissues linking tendon and ligament to bone. They are
located at the metaphyses and diaphyses of long bones.
Fibrocartilage entheses have an additional transitional
zone of fibrocartilage at the bony interface (Figure 1)
(2). They are located at sites with a great deal of joint
movement, probably because fibrocartilage can dissipate
mechanical stress.
Fibrocartilage entheses have 4 consecutive zones
(Figure 1), as follows: 1) a tendon beginning with sparse,
longitudinally oriented fibroblasts which then merge into
dense fibrous connective tissue; 2) a zone of uncalcified
fibrocartilage where cells now assume the morphology of
chondrocytes; 3) a fairly abrupt transition to calcified
fibrocartilage; and 4) the bone. This tidemark is in
continuity with the tidemark of the neighboring articular
cartilage. The calcified fibrocartilage anchors the
ligament/tendon into the bone using tiny vanguards of
collagen fibers which penetrate into the bone trabeculae.
It is an important concept, when considering the
pathogenesis of SpA, that the above-described structure
is not a static one. The enthesis has a high capacity for
dynamic tissue turnover in continual response to
changes in mechanical factors. This would explain why
this is a target for inflammation. Because entheseal
insertions are quite ubiquitous, there is a corresponding
diversity of entheseal-associated pathologic and clinical
manifestations in SpA.
In addition to defining the gross anatomy, Benjamin and Ralphs (1,2) have also characterized the
biochemistry of the entheses using immunohistochemistry, Western blotting, and polymerase chain reaction
(PCR). Type II collagen and proteoglycan aggrecan
messenger RNA (mRNA) synthesized by fibrocartilage
cells are consistently found in the enthesis distal to the
mid-tendon. The ability of the entheseal fibrocartilage
to resist compression is the result of the presence of
these type II collagen and aggrecan messages in the
extracellular matrix. This distribution of proteoglycan
In the last few years, with advances in technology
and concept, research on the spondylarthropathies
(SpA) has moved from random harvesting of piecemeal
data to systematic evaluations of core puzzles. In the
Second International Congress of Spondylarthropathies,
held in Ghent, Belgium, on October 4–7, 2000, the most
recent data were presented and these core puzzles were
defined. The factors that are unique to SpA are 1) the
site of inflammation is not only the synovium, but also
the enthesis; 2) the essential predisposing gene is HLA–
B27; 3) a number of other genes are required for
development of ankylosing spondylitis (AS), a prototype
of SpA; and 4) certain facultative intracellular Gramnegative bacteria can induce reactive arthritis (ReA), a
form of SpA.
Inflammation in SpA
Enthesitis is the hallmark that distinguishes SpA
from all other arthritides (1). Because of its relative
inaccessibility, the enthesis has eluded scientists until
now. Dr. M. Benjamin (Wales, UK) defines the enthesis
as the area of insertion of tendon, ligament, joint
capsule, or fascia to bone. There are 2 types: fibrous
entheses and the more common fibrocartilage entheses.
Fibrous entheses are simply dense fibrous connective
Kaisa Granfors, PhD: National Public Health Institute,
Turku, Finland; 2Elisabeth Märker-Hermann, MD: Johannes Gutenberg University of Mainz, Mainz, Germany; 3Filip de Keyser, MD, Eric
M. Veys, MD: Ghent University Hospital, Ghent, Belgium; 4Muhammad A. Khan, MD: Case Western Reserve University, Cleveland,
Ohio; David T. Y. Yu, MD: UCLA School of Medicine, Los Angeles,
Address correspondence and reprint requests to Kaisa Granfors, PhD, National Public Health Institute, Department in Turku,
Kiinamyllynkatu 13, FIN-20520 Turku, Finland. E-mail: kaisa.
Submitted for publication May 15, 2001; accepted in revised
form August 14, 2001.
the synovial lining layer and an increase in ␣v␤5 integrins in the sublining layer. Because engagement of ␣v
integrins regulates the proliferation, migration, and collagenase expression of a variety of cell types, this differential integrin expression may play an important role in
the aggressive growth of the synovial pannus in RA.
How does HLA–B27, the essential gene, mediate
Figure 1. The normal structure of fibrocartilage entheses, showing
the 3 fibrocartilage types that reduce wear and tear at the attachment
of the human Achilles tendon (T). In addition to enthesis fibrocartilage (EF), there is a sesamoid fibrocartilage (SF) on the deep surface
of the Achilles tendon and a periosteal fibrocartilage (PF) on the
calcaneus. These protect the bone and tendon, where they press
against each other during dorsiflexion of the foot. The free movement
of the tendon is promoted by the retrocalcaneal bursa (RB). (Toluidine blue stained sagittal section; original magnification ⫻ 4.) Reproduced, with permission, from ref. 2.
aggrecan and type II collagen is of interest to investigators of SpA. Autoimmune reactivities to these molecules
in mice can result in arthritis.
Although peripheral arthritis is not uncommon in
SpA, histologic studies of SpA synovial membranes were
infrequent until the mid-1990s. A crucial question is,
how does the histopathology of SpA synovitis differ from
that of rheumatoid arthritis (RA)? This was examined
quantitatively by Dr. D. Baeten (Ghent, Belgium) (3).
The discriminatory features are the following. 1) The
single interesting feature in SpA synovitis is the overexpression of CD163 by activated macrophages. Since
CD163⫹ macrophages secrete proinflammatory cytokines, these data underline the prominent role of macrophages in the pathogenesis of SpA. 2) Lymphoid aggregates are less frequent in SpA compared with RA, while
CD3⫹, CD4⫹, and CD20⫹ lymphocytes are also expressed at lower levels in SpA. 3) Vascularity is more
prominent and more tortuous in SpA. In psoriatic
arthritis (PsA), as described by Dr. D. Veale (Leeds,
UK), tortuosity is caused by abnormal angiogenesis
mediated by transforming growth factor ␤ (TGF␤) and
vascular endothelial growth factor. Distribution of integrins on synovial fibroblasts is a distinguishing feature.
RA is characterized by a decrease in ␣v␤3 integrins in
Initial hypotheses on the role of HLA–B27 in
disease pathogenesis followed the footsteps of crystallographers in assuming that HLA–B27 mediates arthritis
through its physiologic function as an antigen-presenting
molecule, consisting of a standard trimeric structure of
the heavy chain, the ␤2-microglobulin, and a peptide.
New data on this concept were presented in a roundtable
discussion. It is now obvious that the presentation of an
arthritogenic peptide to disease-inducing CD8⫹ T cells
can be influenced by the molecular structure of the
antigen-binding groove, and that this groove differs
between certain disease-associated and nonassociated
HLA–B27 subtypes.
Dr. J. Lopez de Castro (Madrid, Spain) analyzed
the peptide repertoires of 2 closely related pairs of
HLA–B27 subtypes, B*2705 versus B*2709 and B*2704
versus B*2706, using high-performance liquid chromatography and mass spectrometry (4). B*2709 and
B*2706 are less associated with AS compared with
B*2705 and B*2704. There is only a 30% difference in
the peptide repertoires of these subtype pairs. However,
identification of peptides common to AS-associated
HLA–B27 subtypes might not be the answer. Dr. Lopez
de Castro also showed that although the same peptide
can be immunogenic when presented by the ASassociated B*2705, B*2702, and B*2704, the cytotoxic T
cell responses elicited in the context of each subtype are
different; hence the “antigenic” properties of the peptide change upon binding to each subtype.
In addition to basic biochemistry studies, actual
testing with patient materials was carried out by Dr. E.
Märker-Hermann (Mainz, Germany). She found that
among several HLA–B27 binding peptides, the HLA–B27/
enterobacteriae cross-reactive peptide (LRRYLENGK),
previously reported by Scofield et al (5), was the only
peptide recognized more often by HLA–B27–restricted
CD8⫹ T cells from AS patients compared with healthy
controls (6). Identification of other disease-related immunodominant peptides is urgently needed.
Dr. J. Sieper (Berlin, Germany) described a novel
approach to search for biologically significant antigenic
peptides by screening all chlamydial proteins and peptides derived from those for binding to HLA–B27, and
determined whether these peptides would be cut by
proteasomes using special computer programs. T cells
from patients with Chlamydia-induced ReA recognized
3 such peptides. The identification of these peptides
would be important if there is an oligoclonal T cell
response in SpA. Actually, this has been tested by Dr. E.
May (Mainz, Germany/Dallas, TX). He analyzed the
GenBank data of more than 100 T cell receptor (TCR)
CDR3 sequences derived from ReA patients from different groups. Closely related sequences were found in
all 7 patients examined. When T cells using this motif
were expanded in vivo and characterized functionally,
clones were found that are CD8⫹ and HLA–B27 autoreactive. This finding of a conserved TCR motif may
indicate that 1 or a few arthritogenic peptides are
recognized in the context of HLA–B27, and that autoreactive CD8 T cells may be involved in the disease
Dr. P. Bowness (Oxford, UK) pointed out that in
addition to the fact that HLA class I molecules, such as
HLA–B27, have a key role in initiating an immune
response by binding small antigenic peptides and presenting them to CD8⫹ T cells, HLA–B27 has a unique
structural feature that may contribute to the pathogenesis of SpA. HLA–B27 has an unpaired cysteine residue
(Cys67) in the extracellular ␣-1 domain, and free HLA–
B27 heavy chains can form a stable disulfide-bonded
heavy chain homodimer (termed HC-B27) on the cell
surface dependent on this Cys67 residue (7–9). This may
result in altered function that can be pathogenic. Incidentally, higher levels of cell surface HC-B27 have been
detected in 2 SpA patients, compared with healthy
individuals possessing HLA–B27.
The special characteristic of ReA-triggering bacteria, which is the ability to live intracellularly, has
stimulated several groups to conduct studies on the
interaction between the causative bacteria and HLA–
B27–positive and –negative host cells in vitro. In these
studies, a possible role of HLA–B27 cannot be the
classic one, i.e., antigen presentation, since usually only
cells of one type are in culture with the bacteria.
Considering the pathogenesis of the infections caused by
ReA-triggering bacteria and ReA itself, 2 steps have
been of special interest: invasion and intracellular survival of the bacteria. During the roundtable discussion
(Drs. R. Inman, Toronto, Canada, K. Granfors, Turku,
Finland, J. Kuipers, Hannover, Germany, and D. Elewaut, La Jolla, CA), no uniform conclusion about the
effect of HLA–B27 on invasion or uptake of these
bacteria into cells of different types was achieved. However, the level of invasion of ReA-triggering bacteria
into HLA–B27–positive and –negative cells might not be
the main issue in the pathogenesis of ReA. There is
evidence that HLA–B27 plays a modulatory role in the
early signal transduction events induced by Salmonella
invasion (Dr. D. Yu, Los Angeles, CA) (10). In several
studies (Dr. K. Granfors, Turku, Finland [11,12]; Dr. R.
Inman, Toronto, Canada), HLA–B27 seems to confer
the defect in intracellular elimination of ReA-triggering
bacteria both in transfected cell lines and in monocytes
from healthy persons. However, the molecular basis for
these phenomena is unclear.
The interesting recent observations in relation to
these findings were presented by Dr. R. Colbert (Cincinnati, OH). He showed evidence that the HLA–B27
heavy chain tends to misfold during assembly. This may
be relevant, since protein misfolding can influence intracellular signaling pathways (13–15) and thus could be
responsible for the non–antigen presentation effects.
HLA–B27 misfolding and accumulation might contribute an endoplasmic reticulum stress response, leading to
nuclear factor ␬B (NF-␬B) activation. Consequently,
this could stimulate synthesis of proinflammatory cytokines such as tumor necrosis factor ␣ (TNF␣) in monocytes and macrophages. It is of particular interest that
monocytes expressing HLA–B27 have enhanced NF-␬B
activation and TNF␣ production compared with control
monocytes upon Salmonella lipopolysaccharide (LPS)
stimulation (Dr. M. Penttinen, Turku, Finland) (16).
Misfolding offers a plausible explanation for the effects
of HLA–B27 that are independent of its antigenpresentation properties.
Which other genes contribute to AS?
Recent studies of families and twins affected by
AS suggest a polygenic model of genetic susceptibility.
Considerable epidemiologic and transgenic animal
model data indicate a direct role for HLA–B27, but
additional non–HLA–B27 genes, both within the major
histocompatibility complex (MHC) region on chromosome 6 and on other chromosomes, are also necessary
for disease development. The results from the ongoing
European and North American genome-wide searches
for these susceptibility and severity genes in AS patients
were discussed in a roundtable discussion with presentations by Drs. M. Brown (Oxford, UK), M. Breban and
C. Miceli-Richard (Paris, France), J. Reveille (Houston,
TX), and M. Khan (Cleveland, OH). The task of all
these studies is to define regions on different chromo-
somes likely to contain AS-susceptibility genes and
finally to identify the actual genes lying within these
regions. In genome-wide screens, microsatellites are
used which are defined as highly polymorphic dinucleotide repeats, mostly noncoding sequences, that can be
used to establish linkage of a certain chromosome region
with a disease. Microsatellites are usually amplified
using PCR, and fragments are then separated on polyacrylamide gels and detected by autoradiography or by
using fluorescence-labeled primers in automatic sequencers.
Dr. M. Brown has observed markers of interest
on chromosome 2q, in the vicinity of the interleukin-1
(IL-1) and IL-1RA gene family; these are chromosomes
10, 16, and 19 (17). His group has collected informative
data from 230 families with AS; he hopes that the
number will exceed 300 by the end of 2001. The results
of French and North American studies support the
presence of additional susceptibility/severity genes in the
MHC region, but do not confirm British results regarding markers of interest on other chromosomes. French
investigators have studied somewhat similar numbers of
families with SpA, and the group in the United States
has analyzed 96 families with AS in the first year of their
study. Dr. C. Miceli-Richard found that the best linkage
outside the MHC lies on chromosome 14. Remarkably,
another region of interest was identified at the telomeric
site of the X chromosome. Dr. M. Khan pointed out that
the 3 studies have used different criteria for disease
classification, and maximization of resource utility by
international collaboration (pooled data) as well as
genetic studies of isolated, genetically more homogeneous populations for linkage disequilibrium mapping
will be very helpful. He presented HLA–B27 polymorphism data which showed the structural differences
between the 21 different alleles (subtypes) of HLA–B27,
and reported observing the second family known to date
with HLA–B*2708 and AS (18).
Dr. D. Yu (Los Angeles, CA) discussed the
differentially expressed genes in the joints and peripheral blood of patients with AS and related SpA, as
studied by DNA microarrays, which are glass microslides
or nylon membranes containing complementary DNA
(cDNA) samples in an ordered 2-dimensional matrix.
His laboratory is using this method to study whether the
genes expressed in SpA are different from those of other
chronic inflammatory arthritides, such as RA and PsA,
to identify potential mediators or signaling pathways of
inflammation, and to test if they are altered by specific
antiarthritic drug therapy.
Gene-expression profiles of such patients were
generated by measuring the hybridization of isotopelabeled mRNA to the microarrays of 588–1176 cDNA.
The microarrays showed that at least 30 genes of diverse
characters are activated in the peripheral blood mononuclear cells (PBMC) of RA patients; these include
genes for cytokines/chemokines, their receptors, and
adhesion/signaling molecules. In contrast, in SpA, only
⬃6 of such genes are activated, and include TNF␣, IL-8,
and intracellular adhesion molecule 1 genes. When
comparing both PBMC and synovial fluid mononuclear
cells (SFMC) in the same patients, both in RA and in
SpA, the SFMC repertoires appear to be very limited,
with TNF␣ and IL-1␤ being the dominant genes. But, in
spite of the diversity in the PBMC in RA, cells that
selectively migrate into the joints carry a smaller repertoire, and there is dominance of TNF␣ that extends to
the synovial tissues. Regarding signaling molecules, cjun/
cfos are activated in almost all SFMC samples. On global
activation (by anti-CD3) of synovial T lymphocyte
clones, both the proinflammatory gene TGF␤ and the
antiinflammatory gene IL-13 are expressed, indicating
that each clone is potentially arthritis-mediating or
suppressive, perhaps depending on the activating ligand.
How do bacteria induce SpA?
It is well established that ReA is a joint inflammation following infections caused by certain Gramnegative bacteria. The role of infection in the pathogenesis of other SpA is suggested as well, but these
associations are not as clear. The ReA-triggering bacteria share certain characteristics which may be important
in the pathogenesis of the disease, e.g., they are able to
live intracellularly, they have LPS as an important
component of the outer membrane, and they cause
original infections on mucosa. During the Congress,
interaction of the ReA-triggering bacteria and host cells
was discussed in several sessions, and from different
points of view. It is currently generally accepted that this
interaction is abnormal in HLA–B27–positive persons
developing ReA and the causative bacteria persist in
their bodies for long times. How these bacteria are able
to hide in the host is not clear.
The bacteriologic view was given by Dr. J. Galan
(New Haven, CT) in his introductory lecture. He described a remarkable biochemical cross-talk which happens when Salmonella modulates host cellular functions
(19,20). This interaction leads to the activation of a type
III protein secretion system that directs the export and
translocation of a battery of bacterial effector proteins
into the host cells. These effector proteins, such as SopE
and SipA, can stimulate and interfere with a variety of
functions of the host cell. They stimulate marked actin
cytoskeletal reorganization via a signaling process dependent on small GTP-binding proteins called CDC42
and Rac, leading to membrane ruffling and macropinocytosis that ultimately results in the internalization of the
bacteria. Internalization into nonphagocytic cells is essential for the pathogenicity of Salmonella. The cellular
responses induced by Salmonella are short lived, and
when inside the cell, Salmonella turns off host cellular
responses and the cells regain their normal morphology.
This phenomenon is mediated by SptP, which, upon
delivery into the host cell, down-modulates the bacteriainduced cellular responses by acting as a GTPaseactivating protein for CDC42 and Rac. By alternately
activating and down-modulating the function of
GTPases, Salmonella modulates actin cytoskeleton and
host cellular functions. How these functions may be
affected by HLA–B27 is not yet clear.
In another introductory lecture, Dr. H. R. Schumacher (Philadelphia, PA) also discussed the host and
environmental balance, focusing on Chlamydia. Dr.
Schumacher and Dr. A. Hudson (Detroit, MI) have
found that in ReA, Chlamydia often causes persistent
infection of the synovium (21). The organisms in the
synovium are metabolically active, although at a low
state. Chlamydial genes encoding products required for
DNA synthesis and partitioning (dnaA, polA, mutS,
parB, minD) are expressed, but genes encoding products
required for cytokinesis (ftsK, ftsW) are not. A similar
expression of genes was also seen in in vitro models of
chlamydial persistence. Interferon-␥ (IFN␥) was shown
to be an important factor for persistent infection. Removal of this proinflammatory molecule from the culture medium led to release from persistence. Obviously,
there are other important factors as well, and continuing
research on these factors and how they may be related to
the triggering, perpetuating, and healing of SpA would
be important.
Presence of causative microbes (Chlamydia) or
components of causative microbes (enterobacteriae) in
the joint is obviously important in triggering ReA. When
an antichlamydial vaccine reduced the synovial levels of
chlamydial DNA by 26–60% in mice, joint histopathology was also reduced (Dr. J. Whittum-Hudson, Detroit,
MI) (22).
Biologic therapy for SpA
Anti-TNF␣. Trials of anti-TNF␣ therapy. TNF␣ is
a key molecule mediating the inflammatory process in
RA. TNF␣ blockade can be achieved therapeutically
with several biologic agents, including anti-TNF␣ monoclonal antibodies such as infliximab (Remicade; Centocor, Malvern, PA) and soluble TNF␣ receptors (23).
Several successful clinical trials with infliximab in patients with Crohn’s disease and RA have been reported.
Data on its use in SpA have become available only over
the last 2 years. The very recent experience with infliximab in SpA was presented at the meeting by the groups
from Ghent (Belgium), Berlin (Germany), and Erlangen
The Ghent group treated 4 patients who had
refractory Crohn’s disease associated with SpA with
infliximab (24). The duration of articular symptoms
ranged from 2 months to 25 years. One patient had AS
with severe inflammatory axial symptoms, a second
patient had AS with peripheral arthritis, and the 2 other
patients had peripheral arthritis. In all 4 patients, infliximab induced not only remission of their gastrointestinal
symptoms, but also remission of articular symptoms. The
onset of this effect occurred shortly after the infliximab
This preliminary experience with TNF␣ blockade
in patients with SpA associated with inflammatory bowel
disease led to a further open-label trial with infliximab in
21 patients with SpA (25). Patients received 3 infusions
of 5 mg/kg of infliximab at weeks 0, 2, and 6. Eleven of
the 21 included patients had AS, and all had active
disease. Spinal pain improved significantly in 7 of the 11
patients, shortly after the first infusion. Almost all
patients responded well after the induction therapy, with
an infusion every 14 weeks (Figure 2). Nine patients
included in the study had PsA. This subgroup responded
to the treatment in a similar way as did the total SpA
cohort. A similar favorable response was observed in the
2 patients with undifferentiated SpA.
The Berlin group treated 11 patients with active
AS, by administering 3 infusions of 5 mg/kg of infliximab
on weeks 0, 2, and 6 (26). One patient was withdrawn
because of urticarial xanthoma. Significant improvement
was documented in 9 of the 10 patients and lasted for 6
weeks after the third infusion in 8 of the 10 patients.
Magnetic resonance imaging (MRI) of the spine was
performed in 5 patients. At study enrollment, 3 of the 5
patients had evidence of spinal inflammation as detected
by MRI. The followup MRI performed 2–6 weeks after
the third infusion revealed improvement in 2 patients.
Dr. C. Antoni (Erlangen, Germany) reported on
the use of infliximab to treat 10 patients with severe PsA.
Seven of the 10 exhibited an American College of
Rheumatology 70% (ACR70) improvement response.
Figure 2. Efficacy of infliximab in 21 patients with spondylarthropathies. Patient global assessment on a 100-mm visual analog scale (VAS) (A) and
swollen joint count (B) were assessed over time during 36 weeks’ followup. The box and whisker plots show the median value (horizontal line) and
range (first to third quartiles in boxes, 98% of values between enclosed bars, outliers indicated by open circles) of the chosen parameter over time.
Significant differences were calculated by Wilcoxon signed rank test. ⴱ ⫽ P ⱕ 0.01 and ⴱⴱ ⫽ P ⱕ 0.001 versus baseline.
The Psoriasis Area and Severity Index (PASI) of the
psoriatic lesions showed improvement of 71%. Examination of the skin biopsy samples showed a remarkable
reduction in inflammation. Patients were re-treated every 8 weeks and showed a continuous response over 1
Published data on the clinical efficacy of other
anti-TNF␣ preparations are very limited. Mease et al
(27) reported the findings from their study with etanercept in patients with psoriasis and PsA. They treated 60
patients in a randomized, double-blind, placebocontrolled 12-week study. Eighty-seven percent of the
etanercept-treated patients met the PsA response criteria, compared with 23% of the placebo-controlled patients. The ACR20 preliminary criteria for improvement
were achieved by 73% of the etanercept-treated patients
compared with 13% of the placebo-controlled patients.
Of the 19 patients in each treatment group who could be
assessed for psoriasis, 26% of the etanercept-treated
patients achieved a 75% improvement in the PASI,
compared with none of the placebo-treated patients.
Biologic effects of anti-TNF␣ therapy. Data on the
effect of infliximab therapy on T cell cytokines and on
the immunopathology of the synovial membrane were
reported at the meeting. Treatment with 3 infusions of
infliximab in SpA patients (Ghent cohort) resulted in a
rapid and sustained increase in Th1 cytokines (IFN␥ and
IL-2) to levels comparable with those in healthy con-
trols. A reduction in IL-10–positive T cells was observed
in the first 4 weeks in those patients with high baseline
values. No effect was seen on IL-4 production. In the
Berlin cohort of AS patients, lymphocyte counts were
decreased after infliximab therapy. The TNF␣ secretion
capacity of peripheral blood T cells was found to be
enhanced. Together, these data support the view that
TNF␣ blockade essentially reverses the state of anergy
of Th1 cells, while no significant effect is observed on
Th2 cells.
In the Ghent patient cohort, synovial biopsy
samples were obtained from 8 patients with active knee
synovitis at baseline (28). A followup biopsy in these
patients was obtained at weeks 2 and 12. In all 8 patients,
there was a clear clinical improvement after anti-TNF␣
therapy. Histologic analysis showed no significant
changes in the overall degree of inflammatory infiltration, since the number of CD20⫹ lymphocytes and
plasma cells increased. When examined in detail, the
thickness of the synovial layer tended to decrease, with a
significant reduction in CD55⫹ synoviocytes at week 12.
Vascularity in the sublining layer was reduced, with
decreased endothelial expression of vascular cell adhesion molecule 1. The numbers of neutrophils, CD68⫹
macrophages, and CD163⫹ macrophages were all decreased.
IL-10. IL-10 is required to maintain immune
homeostasis. It inhibits TNF␣ and IL-1 and may also
up-regulate endogenous cytokine inhibitors. Dysregulation is involved in the development of inflammatory
bowel disease and arthritis. IL-10–deficient mice develop enteritis (29). IL-10 supplementation in these mice
is an effective treatment. Of interest in this regard are
certainly the data presented at the meeting by Dr. L.
Steidler (Ghent, Belgium), who reported that intragastric administration of IL-10–secreting Lactococcus lactis
caused a 50% reduction in colitis in mice treated with
dextran sulfate sodium and prevented the onset of colitis
in IL-10(⫺/⫺) mice (30).
Subreum. Subreum (OM 8980) is a fractionated
lyophilized extract from several forms of Escherichia coli
containing immunoreactive peptide fragments, including
heat-shock proteins (hsp70 and hsp60) (31). Subreum
has been shown to be effective in RA and it was
suggested that the efficacy could be a result of induction
of oral tolerance. In a double-blind, placebo-controlled,
single-center study, the results of which were presented
at the meeting by Dr. H. Mielants (Ghent, Belgium),
subreum was given to treat different forms of SpA for 48
weeks and compared against the effects of placebo.
Fifty-nine patients (23 with AS, 18 with PsA, 3 with
ReA, and 15 with undifferentiated SpA) were evaluated
in intention-to-treat analyses. In the subgroup of patients with undifferentiated SpA, a statistically significant improvement was found for all clinical parameters
in the subreum group versus placebo; 6 of the 8 patients
came into clinical remission versus 1 of the 7 placebo
patients after 24–36 weeks of treatment. Since 20% of
these patients will develop AS during disease evolution,
subreum administration could potentially influence this
Summary and conclusions
The recent International Congress on Spondylarthropathies yielded new insights that challenged some
accepted paradigms. In addition to synovium, the enthesis seems to be a site of inflammation. In considering the
pathogenesis of SpA, the role of the most important
predisposing gene, HLA–B27, may be more complex
than earlier thought. Current data suggest that in addition to antigen presentation, HLA–B27 may also act in
another way. Misfolding of HLA–B27 and accumulation
in the endoplasmic reticulum could explain the strong
activation of HLA–B27–positive cells, e.g., during stimulation with LPS. It is obvious that other genes, in
addition to HLA–B27, are involved in the pathogenesis
of SpA. At least some of them will be determined in the
near future with the aid of new, powerful techniques that
are being used in ongoing European and North American genome-wide searches for susceptibility and severity
genes in AS. The role of infection in the pathogenesis of
a form of SpA, ReA, is inevitable. Currently, the rapid
growth in knowledge about cross-talk between ReAtriggering bacteria and host cells will help us to understand how these bacteria modulate host cellular functions in order to be able to live and replicate
intracellularly. The results of the initial studies with
biologic treatments (especially with anti-TNF␣) give a
lot of hope for successful treatment of SpA in the near
future. In this most recent Congress, essential new
information was presented that will prove to be important in the ongoing investigations in this field.
The International Congress of Spondylarthropathies
was organized under the auspices of the International League
of Associations for Rheumatology, and additionally sponsored
by several pharmaceutical companies (major sponsors: Boehringer Ingelheim, Centocor—Schering Plough, Merck Sharp &
Dohme, OM Pharma, Pharmacia & Upjohn, and Pfizer; other
sponsors: AHP Pharma, Wyeth Lederle, Aventis Pharma,
AstraZeneca, Becton Dickinson, Searle, and UCB Pharma).
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