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Delayed onset of renal disease in mice expressing a human C-reactive protein transgeneComment on the article by Szalai et al.

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Vol. 50, No. 2, February 2004, pp 674–680
© 2004, American College of Rheumatology
DOI 10.1002/art.20030
Dynamic gadolinium-enhanced magnetic resonance
imaging of the wrist in patients with rheumatoid
arthritis: comment on the article by Cimmino et al
To the Editor:
We read with interest the article by Cimmino et al (1)
on the ability of dynamic gadolinium-enhanced magnetic resonance imaging (MRI) of the wrist to discriminate between
active and inactive rheumatoid arthritis (RA). They described
this technique as “an excellent candidate for the ideal method
for the followup of patients with RA.”
We take issue with this conclusion, which was based on
results of a study of a small group of subjects who were not well
matched for age (the average age in the control group was 39
years, compared with 62 years in RA patients) or disease
duration. Importantly, no significant difference was found
between patients with active disease and those with “intermediately active disease,” which was defined as any level of
activity between active disease and complete clinical remission.
Significance was reached only when the entire group of RA
patients with any disease activity was compared with those with
full disease remission combined with normal controls. These
results suggest that the method used is unlikely to be sensitive
enough for use in clinical trials, in which perhaps a 30%
reduction in joint inflammation over time might be expected.
The appeal of dynamic enhanced MRI as a means to
measure synovitis lies in its apparent objectivity, providing, as
it does, a numeric result upon which clinical and research
decisions can confidently be based. Such confidence might be
misplaced. Our own study of dynamic enhanced MRI of the
wrist in 42 patients with early RA (2) revealed a number of
points pertinent to the current study. We found that placement
of the cursor at the region of highest signal intensity was
critical to the results obtained. Although aiming for the
brightest region on the slice showing most enhancement might
seem straightforward, deviation by as little as 1–2 mm could
greatly affect the rate of early enhancement (REE). This is
because the region of interest (ROI) covers many highintensity pixels, all of which may change in brightness differently over time. Thus, the REE is an average of multiple pieces
of information, obtained both spatially and temporally during
the examination.
In our study, blinded repositioning of the ROI cursor
was performed in 10 patients and revealed 10% variability in
the initial rate of enhancement (2). Figure 1 depicts cursor
placement at 3 different regions of the wrist where there was
bright enhancement of synovial membrane in a patient with
early active RA. The rate of increase in signal intensity over a
42-second period varied by 18% according to cursor placement, from 26.2 to 28.3 to 32.1 pixels/second for points shown
in Figures 1A, B, and C, respectively. Which of these points
should be used for a followup study? The one with highest
maximum signal intensity (Figure 1B), the one with the highest
rate of increase in signal intensity (Figure 1A), or a different
point altogether that happens to be very bright at followup?
Cimmino et al have not provided data on reliability or reproducibility of their measurements, and we are not convinced of
the suitability of this method for longitudinal followup of RA
Figure 1. A, Dynamic enhanced T1-weighted fat-suppressed spoiled
gradient-recalled acquisition in the steady state coronal magnetic
resonance image of the wrist with cursor placement at the radiocarpal
joint, showing initial rate of enhancement as 32.1 pixels/second B,
Cursor placement more distally within the midcarpal joint shows a rate
of 28.3 pixels/second C, Placement within the midcarpal joint on a
more dorsal slice produces a rate of 26.2 pixels/second.
Cimmino and colleagues also reported a high degree of
correlation between dynamic MRI and clinical measures of
synovitis. Interestingly, these results were achieved in patients
with widely disparate disease duration. Our data, from a more
homogeneous group, revealed similar correlations at 1 year
from disease onset (2), but in early disease only the pain score
correlated with the initial rate of enhancement on dynamic
MRI. This may be because MRI is capable of detecting the
increased synovial vascularity of early synovitis before it becomes clinically apparent. For this reason, we would suggest
that disease duration is of crucial importance in any comparison between MRI and clinical synovitis.
We believe that MRI synovitis is more reliably measured by a global score quantifying synovial membrane thickness as well as postcontrast enhancement (3). This score is
derived visually from the whole joint scanned and is likely to
reflect not only synovial angiogenesis (which best correlates
with dynamic MRI results) but also hypertrophy and cellular
infiltration, which correlate with synovial volume (4). Our
global MRI synovitis score was a better predictor of erosions
after 1 year than was synovitis scored using dynamic MRI (␹2
(1df) ⫽ 9.2, P ⫽ 0.003 versus ␹2 (1df) ⫽ 4.7, P ⫽ 0.03) (2) and
closely resembles the score recommended by the Outcome
Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) MRI working party (5). Along with that group, we favor
incorporating MRI measures of synovitis into clinical trials of
new therapeutics for RA to more accurately determine the role
of MRI in clinical and research practice.
Fiona M. McQueen, MBChB, MD, FRACP
Jeff Crabbe, MBChB, FRANZCR
Neal Stewart, MBChB, FRANZCR
University of Auckland
Auckland, New Zealand
1. Cimmino MA, Innocenti S, Livrone F, Magnaguagno F, Silvestri
E, Garlaschi G. Dynamic gadolinium-enhanced magnetic resonance imaging of the wrist in patients with rheumatoid arthritis
can discriminate active from inactive disease. Arthritis Rheum
2. Huang J, Stewart N, Crabbe J, Robinson E, McLean L, Yeoman S,
et al. A 1-year follow-up study of dynamic magnetic resonance
imaging in early rheumatoid arthritis reveals synovitis to be
increased in shared epitope-positive patients and predictive of
erosions at 1 year. Rheumatology (Oxford) 2000;39:407–16.
3. McQueen FM, Stewart N, Crabbe J, Robinson E, Yeoman S, Tan
P, et al. Magnetic resonance imaging of the wrist in early rheumatoid arthritis reveals a high prevalence of erosions at four months
after symptom onset. Ann Rheum Dis 1998;57:350–6.
4. Østergaard M, Hansen M, Stoltenberg M, Gideon P, Klarlund M,
Jensen KE, et al. Magnetic resonance imaging–determined synovial membrane volume as a marker of disease activity and a
predictor of progressive joint destruction in the wrists of patients
with rheumatoid arthritis. Arthritis Rheum 1999;42:918–29.
5. Conaghan P, Edmonds J, Emery P, Genant H, Gibbon W,
Klarlund M, et al. Magnetic resonance imaging in rheumatoid
arthritis: summary of OMERACT activities, current status, and
plans. J Rheumatol 2001;28:1158–62.
DOI 10.1002/art.20137
To the Editor:
We appreciate the interest shown by McQueen et al in
our recent article on dynamic MRI of the rheumatoid wrist.
Their comments deserve some further consideration. McQueen et al state that they do not share our opinion that this
technique could represent “an excellent candidate for the ideal
method” of followup of RA patients. This is in contrast with
their recent statement (1) that dynamic MRI “may have an
important role in monitoring responses to new anti-rheumatic
agents, including biologics. . . .” In their letter, McQueen et al
observe that in our study we could not find any significant
difference between RA patients with 2 different degrees of
disease activity. Furthermore, they claim that this difference
became significant only when the entire group of patients with
any disease activity was compared with another group comprising patients with disease in remission and normal controls.
As a matter of fact, our study showed that patients with high or
intermediate disease activity had a significantly higher relative
enhancement (RE) than did either patients in remission or
normal controls.
The fact that dynamic MRI could not differentiate
patients with active RA according to the definition often used
to enroll patients in clinical trials (ⱖ6 swollen joints and ⱖ9
tender joints plus at least 2 of the following features: morning
stiffness lasting at least 45 minutes, erythrocyte sedimentation
rate [ESR] ⱖ28 mm/hour, and C-reactive protein [CRP] value
more than 3-fold the upper limit of normal) from those who
had a milder disease but were not in remission as defined by
Pinals et al (2) has already been discussed. We believe that the
above-mentioned arbitrary definition of disease activity is too
rough to reflect real differences in joint inflammation. In fact,
dynamic MRI correlates well with several clinical and laboratory data of continuous distribution, such as number of swollen
joints, number of tender joints, the Ritchie index, score on the
Health Assessment Questionnaire (3), CRP value, and ␣2 globulins, as well as with the disease activity score (DAS) (4). The
impression that the DAS is a more sensitive indicator of disease
activity is confirmed by the fact that it is able to fully differentiate
the 3 groups of patients (P ⬍ 0.00001 by analysis of variance).
Therefore, our data support the view that dynamic
MRI is sensitive enough to follow up patients receiving
disease-controlling treatments or biologics. As an example, a
patient recently treated with infliximab had a 62.3% decrease
in RE (from 145 to 54.7) and a 68.5% decrease in the REE
(from 2 to 0.63) after the first month of therapy, corresponding
to 2 infusions. In the same period, the DAS diminished from
4.1 to 2.1 (49% decrease). Interestingly, among the components of the DAS, only the ESR, which is not correlated with
either RE or the REE, did not decrease as much as the other
components. We admit that this example is only anecdotal.
Furthermore, the efficacy of anti–tumor necrosis factor ␣
therapy, which overwhelms that of any traditional diseasecontrolling antirheumatic drug, should be easily demonstrated
clinically and with imaging systems. It is not clear to date
whether dynamic MRI could evaluate minor changes of disease activity due to either spontaneous fluctuations or the
effects of traditional disease-controlling therapy.
Another point raised by McQueen et al concerns the
choice of the area of the synovial membrane where the
enhancement curve should be calculated. Our study is not
concerned with the comparison of the different possibilities
listed in their letter, i.e., the area with the maximum initial
signal intensity or the one with the highest increase in signal
intensity. This point needs further research and standardization. What we can state on the basis of our results is that
identifying the slice with the highest visual enhancement after
gadolinium infusion and positioning the ROI in the area with
the highest rate of increase in signal intensity resulted in good
discrimination of patients with disease in remission from those
with active disease and yielded excellent correlations with
clinical and laboratory data. We agree that ROI repositioning
is crucial for comparison of results, especially in followup
studies. Reproducibility of results depends on precise repositioning of the hand in the gantry in order to yield comparable
slices for followup studies. Extremity-dedicated MRI is partic-
Marco A. Cimmino, MD
Enzo Silvestri, MD
Giacomo Garlaschi, MD
Università di Genoa
Genoa, Italy
Figure 1. Positioning of the patient’s wrist in the dedicated coil. The
lower limit of the anatomic snuff-box should correspond to the internal
border of the coil.
ularly suited for this scope, because the hand can be precisely
placed based on anatomic fiducials (5) (Figure 1). In this
respect, we are developing a positioning device that should
further improve the precision of the study by reducing the
possibility of movements of the wrist. In this way, higher
degrees of reproducibility should be ensured, unless major
anatomic changes due to rheumatoid synovitis occur between 2
Finally, McQueen et al highlight the importance of
disease duration in the evaluation of dynamic MRI in comparison with clinical data. Their finding that dynamic MRI correlates
with the same clinical data of our study after only 1 year of
followup, but not in the very early phase of RA (2), is difficult
to explain and raises some concerns. If their explanation that
MRI can detect synovitis in a preclinical phase is true, then
their patients, being without arthritis, cannot fulfill the American College of Rheumatology (ACR; formerly, the American
Rheumatism Association) criteria for RA (6). On the contrary,
our study was concerned with patients with RA and synovitis of
the wrist, who were identified according to the ACR criteria
and attended a rheumatology clinic. The common goal of
research in the area should be to develop a technique that is
useful in prospective cohorts of patients, regardless of disease
duration. In fact, in a series of 73 RA patients from our clinic,
no correlation between disease duration and dynamic MRI was
found (Cimmino MA: unpublished observations).
Dynamic MRI is an appealing method to quantify
synovial inflammation, because it is objective, easy to perform,
rapid (15 minutes) and requires no time-consuming postexamination calculations. Studies on the correlation of dynamic MRI
of the wrist with synovial membrane histology and with biologic markers of neoangiogensis and synovial cell density are
needed to demonstrate whether this technique is a comprehensive indicator of the different aspects of synovial damage.
Comparisons with more complex and time-consuming global
scores of joint involvement by RA should also be performed to
try to identify the best MRI approach to quantification of
synovitis in RA.
1. Huang J, Stewart N, Crabbe J, Robinson E, McLean L, Yeoman S,
et al. A 1-year follow-up study of dynamic magnetic resonance
imaging in early rheumatoid arthritis reveals synovitis to be increased in shared epitope-positive patients and predictive of erosions at 1 year. Rheumatology (Oxford) 2000;39:407–16.
2. Pinals RS, Masi AT, Larsen A. Preliminary criteria for clinical
remission in rheumatoid arthritis. Arthritis Rheum 1981;24:1308–15.
3. Fries JF, Spitz PW, Kraines RG, Holman HR. Measurement of
patient outcome in arthritis. Arthritis Rheum 1980;23:137–45.
4. Van der Heijde DM, van’t Hof M, van Riel PL, van de Putte LB.
Development of a disease activity score based on judgment in
clinical practice by rheumatologists. J Rheumatol 1993;20:579–81.
5. Garlaschi G, Silvestri E, Satragno L, Cimmino MA. The rheumatoid hand: diagnostic imaging. Springer-Verlag Milan: SpringerVerlag Italia; 2002.
6. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF,
Cooper NS, et al. The American Rheumatism Association 1987
revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315–24.
DOI 10.1002/art.20003
Diagnostic value of Doppler ultrasonography in
rheumatoid arthritis: comment on the article by
Weidekamm et al
To the Editor:
We read with interest the recent article by Weidekamm et al (1). The authors should be congratulated on a
solid contribution to the elucidation of the use of ultrasonography (US) in rheumatoid arthritis (RA). The article, however,
raises some important issues that require comment.
The title “Diagnostic Value of High-Resolution
B-Mode and Doppler Sonography. . .” suggests that investigation of the diagnostic value of sonography in RA was the main
purpose of the study. However, because all patients enrolled in
the study had RA, the value of US for diagnosing RA could not
be investigated. If by diagnostic value the authors mean the
ability to correctly detect various joint pathologies (e.g., synovitis or erosions), this would require comparison with some
kind of gold standard reference to determine the accuracy,
sensitivity, and specificity of the applied method.
The authors introduce a scoring system to quantify the
severity of the joint involvement, using a 4-point scale (0 ⫽ no
changes, 1 ⫽ slight changes, 2 ⫽ moderate changes, and 3 ⫽
strong changes of the soft tissue and erosions of the joint). The
scoring system pools information on inflammation and destruction, and the rating of the different types of pathologies as
well as the limits for the different grades are not further
described, leaving some questions unanswered (e.g., does a
small erosion without inflammatory changes result in grade
3?). Clear definitions and criteria for different grades could
help testing and use by other groups. Furthermore, it may be
controversial to pool reversible disease activity parameters
such as synovitis with signs of cumulative joint damage such as
erosions. Such a system has an inherent inability to be sensitive
for detecting change, because therapy most often reduces signs
of inflammation, while some erosive progression still occurs.
We would suggest evaluating inflammatory and destructive
parameters separately, as was previously done by several
groups of investigators (2–6).
The authors also introduce a 4-point scoring system for
power Doppler signal, with no, small, moderate, and strong
vascularization scored as 0, 1, 2, and 3, respectively. Very
relevantly, they illustrate the different grades in a figure.
However, 2 of the examples are sagittal cuts, while the other 2
are transverse cuts, making them difficult to use as reference
images for scoring. Moreover, and very importantly, the majority of the signal in the illustration of grade 2 (Figure 1C)
originates from the dorsal metacarpal artery, leaving only very
little signal originating from the synovium. Probably, the
remaining signal is not different from the illustration of grade
1 (Figure 1B), but, as mentioned, the cuts are difficult to
compare. Similarly, the image illustrating grade 3 (Figure 1D)
includes a large portion of physiologic signal from the dorsal
metacarpal artery. Because these aspects are not mentioned in
the figure legend, the figure may be misinterpreted.
In conclusion, the fact that use of a certain method, in
this case US, shows more abnormalities than does clinical
examination does not directly translate into a higher diagnostic
value, because without a gold standard reference it is unknown
whether a finding is true or false positive. Furthermore, when
new scoring systems are introduced, the benefits of thoroughly
described methods, unambiguous, explicit definitions and illustrations of pathologies and grades, and biologically maximally
meaningful scores cannot be overestimated. Once this is done,
studies are needed to clarify the validity of the system (including construct, face, content, criterion, and discriminant validities) (7), as is currently being done for magnetic resonance
imaging in RA (8), before the use of the system can be
generally recommended. We acknowledge the quality of the
study by Weidekamm et al and hope that discussion will
further advance the process of clarifying the role and the
optimal methodologies of US in RA.
Marcin Szkudlarek, MD
The Copenhagen University Hospital at Hvidovre
Mikkel Østergaard, MD, PhD, DMSc
The Copenhagen University Hospitals
at Herlev and Hvidovre
Copenhagen, Denmark
1. Weidekamm C, Köller M, Weber M, Kainberger F. Diagnostic
value of high-resolution B-mode and Doppler sonography for
imaging of hand and finger joints in rheumatoid arthritis. Arthritis
Rheum 2003;48:325–33.
2. Backhaus M, Kamradt T, Sandrock D, Loreck D, Fritz J, Wolf KJ,
et al. Arthritis of the finger joints: a comprehensive approach
comparing conventional radiography, scintigraphy, ultrasound,
and contrast-enhanced magnetic resonance imaging. Arthritis
Rheum 1999;42:1232–45.
3. Wakefield RJ, Gibbon WW, Conaghan PG, O’Connor P, McGonagle D, Pease C, et al. The value of sonography in the detection of
bone erosions in patients with rheumatoid arthritis: a comparison
with conventional radiography. Arthritis Rheum 2000;43:2762–70.
4. Szkudlarek M, Court-Payen M, Strandberg C, Klarlund M,
Klausen T, Østergaard M. Power Doppler ultrasonography for
assessment of synovitis in the metacarpophalangeal joints of
patients with rheumatoid arthritis: a comparison with dynamic
magnetic resonance imaging. Arthritis Rheum 2001;44:2018–23.
5. Backhaus M, Burmester GR, Sandrock D, Loreck D, Hess D,
Scholz A, et al. Prospective two year follow up study comparing
novel and conventional imaging procedures in patients with arthritic finger joints. Ann Rheum Dis 2002;61:895–904.
6. Szkudlarek M, Court-Payen M, Jacobsen S, Klarlund M, Thomsen
HS, Østergaard M. Interobserver agreement in ultrasonography of
the finger and toe joints in rheumatoid arthritis. Arthritis Rheum
7. Felson DT, Anderson JJ, Boers M, Bombardier C, Chernoff M,
Fried B, et al. The American College of Rheumatology preliminary core set of disease activity measures for rheumatoid arthritis
clinical trials. Arthritis Rheum 1993;36:729–40.
8. McQueen F, Lassere M, Edmonds J, Conaghan P, Peterfy C, Bird
P, et al. OMERACT Rheumatoid Arthritis Magnetic Resonance
Imaging Studies: summary of OMERACT 6 MR Imaging Module.
J Rheumatol 2003;30:1387–92.
DOI 10.1002/art.20138
To the Editor:
We thank Drs. Szkudlarek and Østergaard for their
comments on our recent article, and appreciate their valuable
The purpose of our study was to point out the useful
application of B-mode and power Doppler sonography in
patients with RA. The predominant clinical issue was not to
diagnose RA, but to determine the grade of severity of soft
tissue lesions and hypervascularization. We noted that the
severity of joint lesions, including inflammation and soft tissue
abnormalities, should be ranked according to a standard score.
The proposed new scoring system helps to determine individual therapy and the efficacy of therapy during followup. One of
the limitations of our study is the lack of histologic data as a
standard of reference, but our aim was to avoid invasive
interventions in our patients.
Therefore, we used the results of the final clinical
outcome as a reference for our sonographic findings. We
demonstrated a significant correlation between clinical examinations and sonography, and we found that sonography did
not reveal any abnormalities over and above the clinical
results. In our opinion, B-mode sonography should be used to
score destruction of the joints, whereas power Doppler sonography should be used to score inflammation of the joints.
However, we agree with Drs. Szkudlarek and Østergaard that
some parameters of the high-resolution B-mode sonography
score should include signs of inflammatory changes such as
effusion or synovial thickening of the joint (Newman JS, Laing
TJ, McCarthy CJ, Adler RS. Power Doppler sonography of
synovitis: assessment of therapeutic response—preliminary
observations. Radiology 1996;198:582–4).
For a precise evaluation of the complete status of the
joint, we recommend the additional use of power Doppler
sonography with conventional B-mode sonography. We agree
with the authors that inflammatory and destructive parameters
should be evaluated separately, as proposed in a previous
report (Backhaus M, Kamradt T, Sandrock D, Loreck D, Fritz
J, Wolf KJ, et al. Arthritis of the finger joints: a comprehensive
approach comparing conventional radiography, scintigraphy,
ultrasound, and contrast-enhanced magnetic resonance imaging. Arthritis Rheum 1999;42:1232–45).
The new 4-point scoring system is useful in daily
clinical routine for the grading of lesions and hypervascularization. In our study, we combined each parameter in a 4-point
scale, according to the criteria of the Larsen score (e.g., slight
changes include periarticular tissue swelling and slight joint
space narrowing without erosions). This summary of the
individual parameters enabled us to make a better comparison
of high-resolution B-mode sonography with conventional radiography and clinical examinations, and also simplified statistical analyses.
The new power Doppler scoring system concentrates
on the inflammatory changes of the joint, expressed as hypervascularization. Therefore, we recommend using power Doppler sonography for the evaluation of inflammatory changes in
the followup period after therapy. Because sonography is an
investigator-dependent examination mode, and motion artifacts can be misinterpreted as hypervascularization of the
rheumatoid joints, inexperienced investigators should request
a second opinion, and in case of controversy, scoring should be
based on a consensus reading.
We hope that results of further studies with power
Doppler and B-mode sonography will support the usefulness of
the new recommended scoring system and help standardize the
investigation of inflammatory and destructive changes in RA.
Claudia Weidekamm, MD
University of Vienna
Vienna, Austria
DOI 10.1002/art.20017
Correlations of hip joint space among asymptomatic
subjects: comment on the article by Lanyon et al
To the Editor:
We were interested in the findings of Lanyon et al
regarding radiographic hip joint space width (JSW) among
asymptomatic subjects without hip osteoarthritis (OA) in the
UK (1), because their findings were in many ways similar to
ours using a different demographic population (2). However,
although our findings were consistent with those reported by
Lanyon et al, that women have significantly smaller JSW than
men, we found that these sex differences were no longer
significant when normalized for height. Lanyon et al similarly
observed that JSW and height were significantly related in both
sexes, and we speculate that in the population described by
them, the sex differences in JSW may be lost when similarly
normalized. This issue is not trivial, because these authors and
other investigators have used hip JSW as an epidemiologic
index of OA prevalence, and at least some of the female
preponderance that is often reported for JSW narrowing may
well be an artifact of stature rather than truly related to sex
differences. This is, in fact, implied by the authors’ findings
after they reduced their threshold definition for JSW narrowing in women.
In addition, whereas in the UK population there
appeared to be an age-related decline of JSW among women
but not men, no such decline was observed in the Turkish
population that we studied. This discrepancy might be attributable to several reasons. First, geographic variation in the
prevalence of radiographic hip OA has long been recognized.
Because hip OA is less common in Turkey than in the UK
(3,4), the progressive narrowing of JSW observed in the UK
may be reflecting early OA (as Lanyon et al stated in the
Discussion). Second, the higher mean age and narrower age
range in the UK study may have resulted in a larger group of
subjects with early OA, which could bias results toward a
narrower measured JSW. Finally, patients who have knee
deformity may slightly rotate and abduct their hips while lying
supine, and if this occurs during positioning for the intravenous
urography (IVP) it can result in an artifactual decrease in the
measured radiographic JSW of clinically normal hips (5). In a
population with a relatively high background prevalence of
knee OA, the effect may be significant if there is subtle
malpositioning by radiology technologists who are focusing on
the abdomen to achieve the proper IVP views.
Berna Goker, MD
Gazi University School of Medicine
Ankara, Turkey
Joel A. Block, MD
Rush Medical College
Chicago, IL
1. Lanyon P, Muir K, Doherty S, Doherty M. Age and sex differences
in hip joint space among asymptomatic subjects without structural
change: implications for epidemiologic studies. Arthritis Rheum
2. Goker B, Sancak A, Arac M, Shott S, Block JA. The radiographic
joint space width in clinically normal hips: effects of age, gender
and physical parameters. Osteoarthritis Cartilage 2003;11:328–34.
3. Goker B. Radiographic osteoarthritis of the hip joint in Turkey.
Rheumatol Int 2001;21:94–6.
4. Lawrence JS, Sebo M. The geography of arthritis. In: Nuki G,
editor. The etiopathogenesis of osteoarthrosis. Baltimore: University Park Press; 1980. p. 155–83.
5. Goker B, Sancak A, Haznedaroglu S, Arac M. The effects of minor
flexion, abduction or adduction on the radiographic joint space
width of the hip [abstract]. Arthritis Rheum 2002;46 Suppl 9:S149.
DOI 10.1002/art.20139
To the Editor:
We thank Drs. Goker and Block for their interest in
our study and for their speculations as to why the results of our
study differ from theirs (Goker B, Sancak A, Arac M, Shott S,
Block JA. The radiographic joint space width in clinically
normal hips: effects of age, gender and physical parameters.
Osteoarthritis Cartilage 2003;11:328–34). There are, of course,
important differences in design between the 2 studies. The
study by Goker at al included 118 Turkish subjects, of whom
only 67 were over age 40 years, and just 25 were over age 60
years. Although none had hip pain, the definition of normal
hips permitted inclusion of subjects with Kellgren/Lawrence
grades of 0, 1, or 2. Therefore, some of their subjects had
definite or possible osteophyte formation and possible joint
space narrowing (unfortunately, the exact number in each
grade was unspecified). In contrast, our starting study population included 689 UK subjects without hip pain, all of whom
were over age 45 years. We then focused on 533 subjects whose
radiographic definition of normal excluded subjects with any
evidence of OA in either hip—that is, no subject had any
evidence of osteophyte formation or narrowing in either hip,
and all were Kellgren/Lawrence grade 0. These important
differences in sample size and definition of normal are likely to
be the major reason for differences between the 2 studies.
It is likely that any sex differences in pelvic morphometry are multifactorial and are influenced by genetic, environmental, and hormonal factors. These same factors are likely to
influence general body morphology, including height. In our
UK study population, the influence of sex on joint space
remained significant (P ⫽ 0.022), even with the inclusion of
height as an independent variable. We have undertaken further regression analysis, and even when height is taken into
account there is still a significant decline in JSW in women
(P ⫽ 0.001), but not in men (P ⫽ 0.5). Thus, although height
and sex are very closely associated, there does appear to be a
difference that relates to sex, and not solely to height, with
respect to diminution of JSW with age.
Goker and Block interestingly speculate as to whether
knee OA or deformity might have altered our results. The
prevalence of knee pain in our subjects without hip pain and
with normal hip radiographs was 26%. Not only is this prevalence identical to that in other unselected UK population
studies (Peat G, McCarney R, Croft P. Knee pain and osteoarthritis in older adults: a review of community burden and
current use of primary health care. Ann Rheum Dis 2001;60:
91–7), but we also observed no sex differences in knee pain
prevalence. This negates the suggestion that a high prevalence
of knee OA might have influenced these results.
Goker and Block also suggest that there may be basic
morphologic/racial differences between UK and Turkish individuals. This hypothesis would be interesting to test but could
be examined only if a similar, rigorous definition of normal
were to be used. We concur with Goker and Block that
differences in JSW between sexes, which may in part be
explained by differences in morphology, merit further study.
Peter Lanyon, MD
Kenneth Muir, PhD
Sally Doherty
Michael Doherty, MD
Queen’s Medical Center,
and Nottingham City Hospital
Nottingham, UK
DOI 10.1002/art.20041
Delayed onset of renal disease in mice expressing a
human C-reactive protein transgene: comment on the
article by Szalai et al
To the Editor:
In a recent study, Szalai et al showed that (NZB ⫻
NZW)F1 hybrid mice expressing a human C-reactive protein
(CRP) transgene survived ⬃8 weeks longer and developed
proteinuria ⬃5 weeks later than control (NZB ⫻ NZW)F1
mice without the transgene (1). In the mice with the human
CRP gene, serum levels of human CRP were stable at ⬃1
␮g/ml, no CRP was detected in the urine, and human CRP
accumulated in cells of renal tubules with increasing age of the
mice. The level of messenger RNA for human CRP was also
increased in the same cells.
Of note is that human CRP was not present in renal
glomeruli (Figure 7 of the article by Szalai et al and cover
picture of the June 2003 issue of Arthritis & Rheumatism); the
cover picture was mislabeled in that the red staining in cells of
renal tubules was for CRP as in Figure 7 and not for mouse
IgG). The authors discuss several possible mechanisms for the
observed findings and favor a hypothesis that somehow the
accumulation of human CRP in cells of renal tubules altered
the deposition of immune complexes in glomeruli and/or the
ensuing inflammation in glomeruli. There is no support for this
Szalai et al point out, and illustrate with electron
micrographs, that at 35 weeks the control (NZB ⫻ NZW)F1
mice had extensive subepithelial immune deposits and some
subendothelial and mesangial immune deposits. In contrast,
the mice with the human CRP transgene had sparse subepithelial and marked mesangial immune deposits. The authors
do not discuss what mechanisms may have caused the differences observed by electron microscopy. A likely explanation is
the effect of circulating CRP on deposition of histones or
nucleosomes in glomeruli. Subepithelial immune deposits are
formed locally, by first depositing the antigen mainly by
charge–charge interaction, followed by binding of other molecules and subsequently antibodies. In (NZB ⫻ NZW)F1 mice
as well as in kidney biopsy specimens from patients with
systemic lupus erythematous, histones are present at the
glomerular basement membrane (2,3). Furthermore, once
histones are present at the glomerular basement membrane,
these molecules can then bind DNA, nucleosomes, or other
anionic antigens, followed by antibodies (4,5). Therefore, the
human CRP present in the circulation of the transgenic mice
would bind histones, an interaction noted by the authors. The
histone–CRP complex would not penetrate the glomerular
basement membrane owing to size, and thereby would decrease the formation of subepithelial immune deposits and
delay proteinuria and loss of renal function. It would have been
useful if Szalai and colleagues had stained the glomeruli of the
control and transgenic mice for the presence of histones.
A concern is that the authors should have examined
the ultrastructural lesions of the transgenic mice beyond 35
weeks, at a time when these mice had proteinuria comparable
with that in the control mice at 35 weeks. This comparison
would have ruled out the possibility that the renal lesions were
at different stages of development and were delayed in the
mice with the CRP transgene.
Mart Mannik, MD
University of Washington
Seattle, WA
1. Szalai AJ, Weaver CT, McCrory MA, van Ginkel FW, Reiman
RM, Kearney JF, et al. Delayed lupus onset in (NZB ⫻ NZW)F1
mice expressing a human C-reactive protein transgene. Arthritis
Rheum 2003;48:1602–11.
2. Schmiedeke T, Stoeckl F, Muller S, Sugisaki Y, Batsford S, Woitas
R, et al. Glomerular immune deposits in murine lupus models may
contain histones. Clin Exp Immunol 1992;90:453–8.
3. Stökl F, Muller S, Batsford S, Schmiedeke T, Waldherr R,
Andrassy K, et al. A role for histones and ubiquitin in lupus
nephritis? Clin Nephrol 1994;41:10–7.
4. Schmiedeke TM, Stökl FW, Weber R, Sugisaki Y, Batsford SR,
Vogt A. Histones have high affinity for the glomerular basement
membrane: relevance for immune complex formation in lupus
nephritis. J Exp Med 1989;169:1879–94.
5. Gauthier VJ, Tyler LN, Mannik M. Blood clearance kinetics and
liver uptake of mononucleosomes in mice. J Immunol 1996;156:
Finally, Dr. Mannik points out that the cover picture
on the June issue of Arthritis & Rheumatism is mislabeled.
Although we were already aware of this mistake we take no
credit for it—this unfortunate error was introduced by the editors.
Alexander J. Szalai, PhD
The University of Alabama at Birmingham
DOI 10.1002/art.20141
To The Editor:
My colleagues and I are pleased by the attention Dr.
Mannik paid to our recent article and appreciate his thoughtful
As Dr. Mannik reiterates, in our report we entertained
several possible mechanisms for the observed findings and we
favored a hypothesis that somehow (admittedly, we don’t yet
know exactly how) the accumulation of CRP in cells of renal
tubules altered the deposition of immune complexes in glomeruli and/or the ensuing inflammation there. We also
pointed out that in human CRP–transgenic mice, subepithelial
deposition of immune complexes was sparser than in nontransgenic animals, whereas mesangial immune deposition was
more intense. Despite the entirely plausible nature of this
model, Dr. Mannik expresses two concerns: first, that there is
no support for our hypothesis that CRP altered the pattern of
immune complex deposition, and second, that we did not
discuss what mechanisms may have caused the differences
revealed by electron microscopy. He then offers his own
equally well-informed but no better supported hypothesis, i.e.,
that circulating CRP alters glomerular deposition of histones
or nucleosomes.
Our more mechanistic studies of these mice are ongoing, and we are considering many possible scenarios. We will
certainly heed Dr. Mannik’s advice and stain the glomeruli of
control and transgenic mice for the presence of histones. With
regard to examining lesion morphology beyond 35 weeks of
age, we did so and did see the same pattern of CRP and
immune deposits as was seen at 35 weeks. For logistical
reasons we chose to show only the images from the 35-weekold mice.
DOI 10.1002/art.20031
Self-arthrocentesis in a man with joint pain
To the Editor:
With the help of his spouse, a patient underwent
periodic home arthrocentesis. A 75-year-old man was seen for
evaluation of joint pain. He had bilateral knee crepitus, large
joint effusions, and radiographs characteristic of degenerative
joint disease with chondrocalcinosis. His wife requested that an
arthrocentesis be done to relieve his joint pain, and volunteered that she herself periodically “pinched” his knee joints to
drain fluid. She explained that she would repeatedly pinch the
skin overlying the medial compartment of the knee with her
fingernails until the skin was broken, and would further abrade
the underlying tissue until a path had been cleared into the
joint and fluid liberated. She would apply pressure to facilitate
drainage of synovial fluid. There was no apparent history of
past episodes of joint infection.
The couple was strongly discouraged from continuing
this practice. Conventionally performed sterile diagnostic arthrocentesis yielded a bland joint fluid with occasional calcium
pyrophosphate dihydrate crystals.
Under some circumstances, it may be prudent to
inquire about self-arthrocentesis when physical findings suggest self-induced trauma to the joint. The extent of this
practice is unknown.
Philip L. Cohen, MD
University of Pennsylvania and
Philadelphia Veterans Administration
Medical Center
Philadelphia, PA
Applications Invited for Editor of Arthritis & Rheumatism, 2005–2010
and Editor of Arthritis Care & Research, 2005–2009
During the summer and fall of 2004, the American College of Rheumatology Committee on Journal
Publications will review applications for the position of Editor, Arthritis & Rheumatism, 2005–2010 term and
the position of Editor, Arthritis Care & Research, 2005–2009 term. The official term of the next Arthritis &
Rheumatism editorship is July 1, 2005–June 30, 2010; however, some of the duties of the new Editor will
begin during a transition period starting April 1, 2005. The official term of the next Arthritis Care & Research
editorship is July 1, 2005–June 30, 2009; however, some of the duties of the new Editor will begin during a
transition period starting April 1, 2005. Applications will be available beginning February 4, 2004. The
deadline for completed applications is June 1, 2004, and the final selection will be announced by November
2004. It is requested, but not required, that those who plan to apply for either position submit a nonbinding
letter of intent by April 15, 2004. For additional information or to request an application or submit a letter of
intent, contact Jane Diamond, Managing Editor, at the ACR office.
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