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interest to learn how many synovial tissue samples obtained
from these patients were Chlamydia-positive, because chronic
reactive arthritis may develop in patients with AS.
Furthermore, psoriatic arthritis (PsA) constitutes another candidate for investigations on the etiologic role of
chlamydial infections. Silveira et al (11) performed a prospective study determining the prevalence of C trachomatis infection in patients with SpA, which demonstrated a significant
frequency of positive urogenital C trachomatis culture (22%) as
well as elevated levels of IgG antibodies (36%) or IgM
antibodies (14%) against C trachomatis in patients with PsA.
Using optimized PCR testing, we recently detected C trachomatis in synovial fluid samples from patients with PsA (12).
Moreover, using the same PCR technique, we identified C
trachomatis in the sacroiliac joint of a patient with PsA and
human immunodeficiency virus infection who was HLA–B27–
positive and had bilateral grade 2 sacroiliitis; this patient
presented with acute posturethritis reactive arthritis and acute
unilateral sacroiliitis, as determined by magnetic resonance
imaging (13). Taken together, these findings indicate the
possibility that C trachomatis is involved in the etiology of PsA
in at least some patients.
In conclusion, it is time to determine definite proof of
an infective, especially a chlamydial, etiology of AS and related
SpA. Technologies are now available to enlarge the prevalent
body of clinical, immunologic, and genetic studies. A concerted
program of investigation by rheumatologists, microbiologists,
and other researchers in the field is urgently needed. The
chances to prove an infective etiology are higher than ever
Supported by the German Competence Network in Rheumatology, Berlin.
Henning Zeidler, MD
Markus Rihl, MD
Hannover Medical School
Hannover, Germany
1. Carter JD, Gerard HC, Espinoza LR, Ricca LR, Valeriano J,
Snelgrove J, et al. Chlamydiae as etiologic agents in chronic undifferentiated spondylarthritis. Arthritis Rheum 2009;60:1311–6.
2. Ankylosing spondylitis and urogenital infection. Br Med J 1960;1:
3. Ford DK. One syndrome: many infectious agents. J Rheumatol
4. Lange U, Teichmann J. Ankylosing spondylitis and genitourinary
infection. Eur J Med Res 1999;4:1–7.
5. Csango PA, Upsahl MT, Romberg O, Kornstad L, Sarov I.
Chlamydia trachomatis serology in ankylosing spondylitis. Clin
Rheumatol 1987;6:384–90.
6. Kihlstrom E, Gronberg A, Bengtsson A. Immunoblot analysis of
antibody response to Chlamydia trachomatis in patients with
reactive arthritis and ankylosing spondylitis. Scand J Rheumatol
7. Van der Paardt M, van Denderen JC, van den Brule AJ, Morre
SA, van der Horst-Bruinsma IE, Bezemer PD, et al. Prevalence of
Chlamydia trachomatis in urine of male patients with ankylosing
spondylitis is not increased. Ann Rheum Dis 2000;59:300–2.
8. Mau W, Zeidler H, Mau R, Majewski A, Freyschmidt J, Stangel
W, et al. Clinical features and prognosis of patients with possible
ankylosing spondylitis: results of a 10-year followup. J Rheumatol
9. Rudwaleit M, Haibel H, Baraliakos X, Listing J, Marker-Hermann
E, Zeidler H, et al. The early disease stage in axial spondylarthritis:
results from the German Spondyloarthritis Inception Cohort.
Arthritis Rheum 2009;60:717–27.
Van der Linden S, Valkenburg HA, Cats A. Evaluation of
diagnostic criteria for ankylosing spondylitis: a proposal for
modification of the New York criteria. Arthritis Rheum 1984;
Silveira LH, Gutierrez F, Scopelitis E, Cuellar ML, Citera G,
Espinoza LR. Chlamydia-induced arthritis. Rheum Dis Clin North
Am 1993;19:351–63.
Freise J, Bernau I, Meier S, Zeidler H, Kuipers JG. Optimized
molecular biology testing for C. trachomatis in synovial fluid
samples in clinical practice [submitted for publication].
Rihl M, Wagner AD, Bakhsh KA, Rosenthal H, Bernateck M,
Kohler L, et al. Detection of chlamydial DNA in the inflamed
sacroiliac joint of a patient with multiple infections. J Clin
Rheumatol 2009;15:195–7.
DOI 10.1002/art.24967
To the Editor:
We thank Drs. Zeidler and Rihl for their comments
regarding our recent study (1). As they correctly point out in
their letter, uSpA shares many clinical features with AS, and
uSpA can evolve into AS. These observations may indicate that
the 2 conditions share a common etiology, or, equally interestingly, that they may reside within a spectrum of the same
disease. The data presented in our report suggest that chlamydiae are a common cause of uSpA; Zeidler and Rihl remind us of previously published data demonstrating that
patients with AS frequently test positive for Chlamydia trachomatis by investigation of the urogenital tract or by serology
In our cohort of 26 patients with uSpA who underwent
synovial biopsy, PCR analysis revealed that 16 of these patients
were positive for chlamydiae in synovial tissue. The results of
blood tests for chlamydia were available for 15 of the 16
patients who had positive results by PCR analysis. All 15 blood
samples were analyzed for C trachomatis, Chlamydia pneumoniae TWAR, and Chlamydia psittaci antibodies (IgM, IgG,
and IgA). Twelve of these 15 patients had positive results of
serologic testing for the presence of chlamydia. Interestingly,
all 12 patients were positive for C pneumoniae TWAR IgG,
and one patient was positive C pneumoniae TWAR IgA (i.e.,
positive for both IgG and IgA). We were surprised to observe,
however, that none of these study subjects were positive for
anti–C trachomatis antibodies. Unfortunately, blood tests for
chlamydia were not available for those patients with uSpA
whose synovial tissue was negative for chlamydia by PCR
analysis or for any of the control subjects with osteoarthritis.
None of the subjects in our study underwent an investigation of
the urogenital tract. Although the number of subjects in our
study was small and we had no control subjects, our data do
suggest that cross-reactivity may exist between anti–C pneumoniae IgG and synovially based chlamydial organisms in the
setting of a persistent infectious state. Data exist substantiating
this possible explanation (1). However, the precise explanation
for the universal absence of C trachomatis antibodies in these
patients is unclear.
Drs. Zeidler and Rihl further suggest that some cases
of PsA, which is another SpA, might also be caused by
chlamydial infection. We find it interesting indeed that they
recently detected C trachomatis in synovial fluid from patients
with PsA. Not only are the clinical features of PsA and reactive
arthritis indistinct, but palmoplantar pustular psoriasis and
keratoderma blenorrhagicum cannot be differentiated grossly
or histologically (2). Finally, we stress the fact that 14 (88%) of
the 16 subjects in our study whose synovial tissue was positive
for chlamydiae by PCR analysis had an asymptomatic initial
infection. This can and certainly does make classification of the
specific type of SpA less clinically apparent.
Taken together, data from our study and the important
observations cited by Zeidler and Rihl help to support the
hypothesis initially proposed by Dr. Denys Ford that one agent
may cause different clinical syndromes, and that one syndrome
may be attributable to many infectious agents (3). Indeed, we
discuss precisely those ideas in terms of recent data in a
manuscript that is now in preparation (4). We agree entirely
that a concerted effort needs to be undertaken to precisely
define the role of infectious agents in all types of SpA.
John D. Carter, MD
University of South Florida College of Medicine
Tampa, FL
Alan P. Hudson, PhD
Wayne State University School of Medicine
Detroit, MI
1. Stern DG, Neill MA, Schachter J. A seroepidemiologic study of
Chlamydia pneumoniae in Rhode Island: evidence of serologic
cross-reactivity. Chest 1993;104:208–13.
2. Schneider JM, Matthews JH, Graham BS. Reiter’s syndrome.
Cutis 2003;71:198–200.
3. Ford DH. One syndrome: many infectious agents. J Rheumatol
4. Stanich JA, Carter JD, Whittum-Hudson, Hudson AP. Rheumatoid arthritis: disease or syndrome? Submitted for publication.
DOI 10.1002/art.27209
Autoantibodies against the platelet-derived growth
factor receptor in scleroderma: comment on the
articles by Classen et al and Loizos et al
To the Editor:
We read with interest 2 recent articles in Arthritis &
Rheumatism reporting the lack of evidence of stimulatory
anti–platelet-derived growth factor receptor (PDGFR) autoantibodies in the sera of patients affected by systemic sclerosis
(SSc) (1,2). The 2 groups of investigators reached the same
conclusion by using different experimental settings, and their
results directly contradict our original observation of the
presence of agonistic antibodies to PDGFR in patients with
scleroderma (SSc) (3).
Before and after our 2006 report, we conducted an
extensive search for possible sources of artifacts, contaminants,
or flaws in the specific assays we have used. We observed that
the anti-PDGFR stimulatory fractions of total IgG purified
from serum were unstable and very sensitive to manipulation
during purification procedures (Gabrielli A, et al: unpublished
Contamination of our IgG preparations by PDGF or
transforming growth factor ␤ (TGF␤) has been checked. We
usually purify IgG from serum by a 2-step process. The first
step is based on binding of IgG to sepharose A/G. The second
step involves size-exclusion chromatography, which removes
molecules smaller than 5–10 kd. This step is critical and
essential to remove trace amounts of contaminating cytokines.
Our preparations are PDGF- and TGF␤-free, as demonstrated
by immunoblotting with several specific antibodies (we are
able to detect up to 0.1 ng of cytokine/200 ␮g IgG) (Gabrielli
A, et al: unpublished observations). Unfortunately, the studies
mentioned above did not follow this procedure.
The binding of PDGFR to both normal and SSc IgG is
of interest. Indeed, we did observe (by immunoprecipitation)
binding of normal IgG to the PDGFR in several circumstances.
By extensive testing of many sepharose A/G batches, we
eliminated the binding observed in normal IgG preparations
(n ⫽ 50). We do not yet know the relevance of this observation.
We believe that the analysis of a larger number of samples will
clarify the issue. Our recent data indicate that tagged
PDGFR␣/␤ can be used for a simple and selective IgG-binding
assay with serum.
We also noted important differences in the experimental settings that grossly affect the experimental results and may
explain the discrepancies between our work and that of the
other investigators. First, Classen et al used the F␣ fibroblast
cell line to test the levels of phosphorylated ERK and PDGFR
(3), but not the levels of reactive oxygen species (ROS), which
was the assay used by Baroni et al. Conversely, Classen et al
used a myeloid cell line for this purpose. Loizos et al (2) did
not use this cell line and did not test ROS levels; instead, those
investigators used an endothelial cell line to reveal PDGFR
Second, the presence of the Fc receptor on 32D
myeloid cells (4) and porcine aortic endothelial (PAE) cells (5)
may be sufficient to explain the absence of biologic effects of
SSc IgG on PDGFR-expressing 32D and PAE cells. In contrast, these cell lines are perfectly suitable for the detection of
PDGF biologic activity, because the low levels of cell surface
PDGFR (6) are sufficient to bind PDGF, whereas they may be
not able to respond to low-affinity IgG due to competition by
the Fc receptor. Finally, it would be interesting to see the
immunoprecipitation data with these different IgG samples.
In conclusion, we agree that the presence of agonistic
antibodies to PDGFR must be validated in a larger number of
patients affected by scleroderma and by different laboratories
before any conclusion can be drawn on their specificity and
impact on the disease. To achieve this goal, we must use a
common protocol for the isolation and the functional assay of
these IgG fractions, as suggested in the accompanying editorial
by Dragun et al (7). To settle the issue, we wish to continue
along these lines by providing positive and negative controls
for all groups. As in the case of thyroid-stimulating hormone
receptor–stimulating antibodies in Graves’ disease, this will
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