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The implications of biologic therapy in ankylosing spondylitisComment on the articles by Brandt et al and Braun et al.

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ARTHRITIS & RHEUMATISM
Vol. 50, No. 7, July 2004, pp 2373–2380
© 2004, American College of Rheumatology
LETTERS
Kawashima and Miossec suggested the absence of
IL-18R ␤-chain expression by RA FLS in culture as the reason
for their IL-18 resistance (1) and postulated that cellular
contamination might have been the explanation for apparent
IL-18R ␤-chain expression by FLS in our study (8). We
therefore searched for additional evidence for the cellular
purity of our FLS cultures. Reverse transcribed complementary DNA was still available from 26 of the 27 previously
studied cultures (8). Only 1 sample was degraded. Because
IL-18R expression is characteristic of Th1 lymphocytes (2), I
searched for evidence of contamination by Th1 lymphocytes in
these cell extracts by probing them for evidence of interferon-␥
(IFN␥) by reverse transcription–polymerase chain reaction
(Figure 1). All of the FLS specimens were free from IFN␥
messenger RNA (mRNA), although IFN␥ mRNA was detectable in positive controls. These additional data suggest that
leukocyte contamination was not the reason for IL-18R expression in FLS in our experiments (8).
Nevertheless, it remains true that direct addition of
IL-18 to FLS can be associated with mild, variable, and even
absent expression of adhesion molecules and other mediators
of inflammation (3,4,8). As before, my experiments lead me to
conclude that this IL-18 resistance is likely to be attributable to
as yet unexplained postreceptor mechanisms (8).
DOI 10.1002/art.20346
Interleukin-18 receptor expression in synovial
fluid–derived fibroblast-like synoviocytes: comment
on the article by Kawashima and Miossec
To the Editor:
I read with interest the article by Kawashima and Miossec, which showed differential expression of interleukin-18
receptor (IL-18R) by fibroblast-like synoviocytes (FLS) from
patients with rheumatoid arthritis (RA) (1). IL-18 is a potent
activator of T cells and macrophages and an important mediator
of arthritis in animal models (2). IL-18 is mainly produced by
macrophages but also by FLS (2). The possibility of autocrine
activation of FLS by IL-18 (3,4) is of particular interest in view of
the unusual characteristics of FLS in RA (5,6).
FLS can be identified in cell cultures by their characteristic morphology, by the absence of macrophage (CD14,
CD68) or dendritic cell markers (CD80, CD86), and by the
presence of positive staining for fibroblast markers such as
CD90/Thy-1. Well-defined FLS are obtained by prolonged
culture of primary synovial cells through several passages, and
the cell culture medium has some influence on the number of
passages required to obtain pure FLS cultures (7).
Figure 1. A–C, Representative flow cytometry profiles of fibroblast-like synoviocytes (FLS) from long-term
cultures. All cultures showed positive staining for CD90/Thy-1, and all were negative for CD14 and CD86. D,
Reverse transcription–polymerase chain reaction for interferon-␥ (IFN␥) in long-term FLS cultures. FITC ⫽
fluorescein isothiocyanate; PE ⫽ phycoerythrin. M ⫽ molecular mass marker; ␾ ⫽ negative control without cDNA
specimen, positive controls with cDNA from 106 peripheral blood mononuclear cells (PBMCs) from healthy donors
stimulated with 10 ␮g/ml phytohemagglutinin for 24 hours (PB⫹) or from unstimulated PBMCs (PB⫺).
2373
2374
LETTERS
Although expression of both IL-18R chains was predominantly seen in synovial fluid–derived adherent cells with
fibroblast-like morphology, it might be interesting to search for
colocalization of IL-18R ␤-chain expression and FLS markers in
synovial tissues. The peculiar biology of synovial fluid–derived
cells with fibroblast biology (9) warrants further attention.
Burkhard Möller, MD
Klinikum der J. W. Goethe-Universität
Frankfurt, Germany
1. Kawashima M, Miossec P. Heterogeneity of response of rheumatoid
synovium cell subsets to interleukin-18 in relation to differential
interleukin-18 receptor expression. Arthritis Rheum 2003;48:631–7.
2. Gracie JA, Robertson SE, Mclnnes IB. Interleukin-18. J Leukoc
Biol 2003;73:213–24.
3. Morel JC, Park CC, Zhu K, Kumar P, Ruth JH, Koch AE. Signal
transduction pathways involved in rheumatoid arthritis synovial
fibroblast interleukin-18-induced vascular cell adhesion molecule-1
expression. J Biol Chem 2002;277:34679–91.
4. Morel JC, Park CC, Woods JM, Koch AE. A novel role for
interleukin-18 in adhesion molecule induction through NF kappa B
and phosphatidylinositol (PI) 3-kinase-dependent signal transduction pathways. J Biol Chem 2001;276:37069–75.
5. Pap T, Muller-Ladner U, Gay RE, Gay S. Fibroblast biology: role of
synovial fibroblasts in the pathogenesis of rheumatoid arthritis.
Arthritis Res 2000;2:361–7.
6. Firestein GS. Evolving concepts of rheumatoid arthritis. Nature
2003;423:356–61.
7. Burg S, Zschabitz A, Stofft E. Effect of different media on
long-term cultivation of human synovial macrophages. Z Rheumatol 1991;50:142–50.
8. Moller B, Kessler U, Rehart S, Ottmann OG, Kaltwasser JP,
Hoelzer D, et al. Interleukin-18 receptor expression in fibroblastlike synoviocytes. Arthritis Res 2002;4:139–44.
9. Neidhart M, Seemayer CA, Hummel KM, Michel BA, Gay RE, Gay
S. Functional characterization of adherent synovial fluid cells in
rheumatoid arthritis: destructive potential in vitro and in vivo.
Arthritis Rheum 2003;48:1873–80.
DOI 10.1002/art.20307
Matrix metalloproteinase 9 in the saliva of patients
with Sjögren’s syndrome: comment on the article by
Goicovich et al
To the Editor:
We read with great interest the article by Goicovich
and coworkers on protein degradation by matrix metalloproteinases (MMPs) from the salivary glands of patients with
Sjögren’s syndrome (SS) (1). The authors describe some
interesting observations on the ability of enzymes to degrade
various components of the basal lamina and extracellular
matrix (ECM). In addition, they report an intriguing finding of
ultrastructural changes in the glands. Although it is not
possible to directly relate these 2 separate sets of observations
to one another, they call attention to some interesting and
often neglected aspects of disease pathogenesis.
The report by Goicovich et al confirms the previously
described finding of high concentrations of MMP-9 in the
saliva of patients with SS: Hanemaaijer et al (2) reported
mean ⫾ SEM salivary MMP-9 levels of 53 ⫾ 10 units/mg in
patients versus 17 ⫾ 3 units/mg in controls (P ⫽ 0.01).
Furthermore, part of the salivary MMP-9 in patients had been
autoactivated, such that the in vivo level of active MMP-9 was
9 ⫾ 3 units/mg in patients versus 1.0 ⫾ 0.5 in controls (P ⫽
0.002). This seems to be related to activation of proMMP-9 by
human trypsin 2 (3), which is a relatively recently described
proMMP-9 activator (4) not related to bovine trypsin (5). The
latter is an unlikely activator of human proMMPs in vivo
although cited as such in the report by Goicovich et al (1).
This work further emphasizes the potential role of
inhibitors of MMP-9 in the treatment of tissue-destructive
diseases, as has been described by investigators at our institutions. In one group of studies, the suppressor form of inhibitor
of nuclear factor ␬B complementary DNA (6) and cepharantine (7) were used for this purpose, in another, cyclic peptides
containing the sequence HWGF were used to specifically
inhibit MMP-9 (8). Proteolytic processing of structurally supportive and signaling ECM may have important implications
for the function and remodeling of acinar and ductal epithelial
cells in healthy subjects and patients with SS.
Yrjö T. Konttinen, MD, PhD
University of Helsinki
Helsinki, Finland
M. Azuma, DDS, PhD
Tokushima University School of Dentistry
Tokushima, Japan
1. Goicovich E, Molina C, Perez P, Aguilera S, Fernandez J, Olea N,
et al. Enhanced degradation of proteins of the basal lamina and
stroma by matrix metalloproteinases from the salivary glands of
Sjögren’s syndrome patients: correlation with reduced structural
integrity of acini and ducts. Arthritis Rheum 2003;48:2573–84.
2. Hanemaaijer R, Visser H, Konttinen YT, Koolwijk P, Verheijen
JH. A novel and simple immunocapture assay for determination of
gelatinase-B (MMP-9) activities in biological fluids: saliva from
patients with Sjogren’s syndrome contains increased latent and
active gelatinase-B levels. Matrix Biol 1998;17:657–65.
3. Konttinen YT, Halinen S, Hanemaaijer R, Sorsa T, Hietanen J,
Ceponis A, et al. Matrix metalloproteinase (MMP)-9 type IV
collagenase/gelatinase implicated in the pathogenesis of Sjogren’s
syndrome. Matrix Biol 1998;17:335–47.
4. Sorsa T, Salo T, Koivunen E, Tyynela J, Konttinen YT, Bergmann
U, et al. Activation of type IV procollagenases by human tumorassociated trypsin-2. J Biol Chem 1997;272:21067–74.
5. Ogata Y, Itoh Y, Nagase H. Steps involved in activation of the
pro-matrix metalloproteinase 9 (progelatinase B)-tissue inhibitor of
metalloproteinases-1 complex by 4-aminophenylmercuric acetate
and proteinases. J Biol Chem 1995;270:18506–11.
6. Azuma M, Aota K, Tamatani T, Motegi K, Yamashita T, Harada K,
et al. Suppression of tumor necrosis factor ␣–induced matrix
metalloproteinase 9 production by the introduction of a superrepressor form of inhibitor of nuclear factor ␬B␣ complementary
DNA into immortalized human salivary gland acinar cells: prevention of the destruction of the acinar structure in Sjögren’s syndrome
salivary glands. Arthritis Rheum 2000;43:1756–67.
7. Azuma M, Aota K, Tamatani T, Motegi K, Yamashita T, Ashida Y,
et al. Suppression of tumor necrosis factor ␣–induced matrix
metalloproteinase 9 production in human salivary gland acinar cells
by cepharanthine occurs via down-regulation of nuclear factor ␬B:
a possible therapeutic agent for preventing the destruction of the
acinar structure in the salivary glands of Sjögren’s syndrome
patients. Arthritis Rheum 2002;46:1585–94.
8. Koivunen E, Arap W, Valtanen H, Rainisalo A, Medina OP,
Heikkila P, et al. Tumor targeting with a selective gelatinase
inhibitor. Nat Biotechnol 1999;17:768–74.
LETTERS
DOI 10.1002/art.20502
Reply
To The Editor:
We would like to thank Drs. Konttinen and Azuma for
their interesting comments concerning some of the observations in our recently published article. We will focus here on 3
specific issues raised, namely the correlational character of our
analysis, the confirmatory nature of our results with respect to
previous studies, and the potential relevance of our findings for
developing new therapeutic approaches.
The reasons for the demise of structural integrity of
acini in salivary glands from SS patients, a condition that leads
to xerostomia, are still not understood. In our study, a strong
correlation was observed between enhanced proteolytic activity toward basal lamina proteins in extracts from labial salivary
glands (LSGs) of SS patients and the loss of ultrastructure of
acinar basal lamina and the apical pole of acinar cells, where
the exocytotic machinery is found. Such loss of organization in
the apical region of acinar cells may be assumed to have
dramatic consequences for the secretory process.
It is important to emphasize that the same glands were
characterized by both biochemical and ultrastructural analysis
in our studies. Thus, although protease activity was analyzed in
vitro, we believe the results obtained provide a highly probable
mechanistic basis to understand the observed ultrastructural
changes as presented in our work. Unfortunately, studies to
address more directly the relevance of this mechanism cannot
be performed in patients. Thus, our carefully controlled study
documents for the first time that MMP protein and activity
levels are elevated in gland cells from SS patients. We suggest
that this change may trigger degradation of ECM proteins and
thereby provoke the damage to salivary gland architecture and
function characteristic of this disease. Accordingly, these observations provide new insights into the cellular and molecular
mechanisms associated with salivary tissue destruction in SS.
Until 1999, work related to this disease had been
carried out using cell lines derived from either nontransformed
or SV40-transformed salivary glands, which were stimulated
with cytokines (1). In this experimental setting, increased
expression of MMP-2 was observed. It is difficult to relate
results obtained in this manner to events occurring in a gland,
for at least 2 reasons. First, 3-dimensional (3-D) organization
of acini is of fundamental importance in determining the
physiologic response to signals. This has been widely studied
using mammary glands, and the results clearly underscore the
importance of 3-D organization (2). Second, SV40transformed cell lines often display karyotypic changes (3) that
are likely to alter the pattern of gene expression among other
things and, as a consequence, the behavioral repertoire.
In a different study, changes in MMP-2 and MMP-9
immunoreactivity were not detected in tissue sections obtained
from salivary glands of SS patients when compared with
control subjects; however, increased gelatinolytic activity of
MMP-9 was detected in whole saliva zymograms from SS
patients (4). Given that whole saliva extracts were used in
those experiments, the cellular origin of this activity remained
unclear. The question is particularly relevant since mucositis
occurs frequently in SS patients. Such chronic inflammation
may be expected to favor the appearance of enzymes secreted
from other sources, such as periodontal pockets.
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The question was raised as to whether MMPs could
also be activated by trypsin. This has been shown to be the case
in vitro, using APMA or bovine trypsin or MMP-3 (5). In this
context, it is important to note that we discussed the fact that
lower molecular weight MMPs were detected when extracts
from patients and controls were treated with APMA. A
possible explanation is that activation of some MMPs or
MMP–tissue inhibitor of metalloproteinases 1 (TIMP-1) complexes by some of the agents mentioned may generate lower
molecular weight MMPs with decreased activity. This explanation was provided based on studies performed in vitro (5) and
is suggestive of what may occur in vivo. However, further
studies will be needed to test this possibility more rigorously.
The MMP-9–TIMP-1 complex may also form a ternary complex with MMP-3. In the presence of large amounts of MMP-3,
the MMP-9–TIMP-1 interaction is weakened and strong gelatinolytic activity of MMP-9 is detected (5). Interestingly, we
have found increased amounts of MMP-3 in LSGs of patients
with SS compared with controls (6). Hence, elevated levels of
MMP-9 activity may also be the consequence of increased
MMP-3 in SS patients.
Finally, we share the enthusiasm of Drs. Konttinen and
Azuma with respect to the therapeutic relevance of these
findings. Both our observations in SS patients and their recent
studies in cultured human cell lines (NS-SV-AC) underscore
the potential of MMP-9 inhibitors (e.g., cepharantine) for the
treatment of tissue-destructive diseases (7,8). Certainly, rigorously controlled clinical trials should be developed to confirm
or dismiss such possibilities. In our studies, we have specifically
focused on identifying basic mechanisms associated with the
structural changes of the acinar and ductal labial salivary cells
observed in SS. Certainly, our data concerning MMP-9 provide
strong support for the opinions expressed by our colleagues.
However, additional, equally exciting, possibilities are likely to
emerge from future studies.
Marı́a-Julieta González Burgos, MSc
Universidad de Chile
Sergio Aguilera Covarrubias, MD
Clı́nica INDISA
Universidad Andrés Bello
Claudio Molina Castillo, DDS, MSc
Universidad Mayor
Lisette Leyton Campos, PhD
Universidad de Chile
Santiago, Chile
1. Azuma M, Motegi K, Aota K, Hayashi Y, Sato M. Role of cytokines
in the destruction of acinar structure in Sjögren’s syndrome salivary
glands. Lab Invest 1997;77:269–80.
2. Bissell MJ, Weaver VM, Lelievre SA, Wang F, Petersen OW,
Schmeichel KL. Tissue structure, nuclear organization, and gene
expression in normal and malignant breast. Cancer Res 1999;59
Suppl:1757–63.
3. Darimont C, Avanti O, Tromvoukis Y, Vautravers-Leone P, Kurihara N, Roodman GD, et al. SV40 T antigen and telomerase are
required to obtain immortalized human adult bone cells without
loss of the differentiated phenotype. Cell Growth Differ 2002;13:
59–67.
4. Konttinen YT, Halinen S, Hanemaaijer R, Sorsa T, Hietanen J,
Ceponis A, et al. Matrix metalloproteinase (MMP)-9 type IV
collagenase/gelatinase implicated in the pathogenesis of Sjögren’s
syndrome. Matrix Biol 1998;17:335–47.
2376
LETTERS
5. Ogata Y, Itoh Y, Nagase H. Steps involved in activation of the
pro-matrix metalloproteinase 9 (progelatinase B)-tissue inhibitor of
metalloproteinases-1 complex by 4-aminophenylmercuric acetate
and proteinases. J Biol Chem 1995;270:18506–11.
6. Perez P, Goicovich E, Alliende C, Aguilera S, Leyton C, Molina C,
et al. Differential expression of matrix metalloproteinases in labial
salivary glands of patients with primary Sjögren’s syndrome: mechanisms of exocrine parenchyma destruction. Arthritis Rheum 2000;
43:2807–17.
7. Azuma M, Aota K, Tamatani T, Motegi K, Yamashita T, Ashida Y,
et al. Suppression of tumor necrosis factor ␣–induced matrix
metalloproteinase 9 production in human salivary gland acinar cells
by cepharanthine occurs via down-regulation of nuclear factor ␬B:
a possible therapeutic agent for preventing the destruction of the
acinar structure in the salivary glands of Sjögren’s syndrome
patients. Arthritis Rheum 2002;46:1585–94.
8. Koivunen E, Arap W, Valtanen H, Rainisalo A, Medina OP,
Heikkila P, et al. Tumor targeting with a selective gelatinase
inhibitor. Nat Biotechnol 1999;17:768–74.
DOI 10.1002/art.20343
The implications of biologic therapy in ankylosing
spondylitis: comment on the articles by Brandt et al
and Braun et al
To the Editor:
We read with interest the reports by Brandt et al (1)
and Braun et al (2) regarding the use of biologic therapy for
active ankylosing spondylitis (AS). The definition of active
disease used in those studies, i.e., a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (3) of ⬎4 and a visual
analog scale (VAS) score for spinal pain of ⬎4, is arbitrary.
Over many years, we have assessed our AS patients annually in
a specialty clinic. Since 1996, one aspect of this assessment has
been measurement of the BASDAI, of which the VAS for
spinal pain is a component. Ours is the only AS clinic within
our geographic area, and as such, our patients would be
expected to be representative of the population of AS patients
who need to attend a specialty clinic.
We examined a cohort of 74 consecutive patients
attending the AS clinic for whom we had BASDAI data from
at least 3 visits over a 5-year period. The male:female ratio was
3:1, the mean age at the time of study was 48.6 years, and the
mean age at diagnosis was 28 years. Applying the criteria for
active disease used by Brandt et al and Braun et al in the
research trials (1,2), we examined what proportion of patients
with AS would be eligible for treatment with biologic agents
over a 5-year time line. By doing this, we applied longitudinal
rather than cross-sectional patient data.
The cross sectional data (Table 1) showed that the
percentage of patients attending an annual assessment who
met the eligibility criteria for anti–tumor necrosis factor (antiTable 1.
TNF) trials ranged from 50% to 66%. These data do not tell us
which of the patients are eligible from one year to the next.
Assessment of the longitudinal data showed that over the
5-year time period, on the basis of at least 3 annual BASDAI
scores per patient, there was a group of patients (28 of 74
[38%]) who always fulfilled the criteria for active disease
(group A). However, there was a second group (29 of 74
[39%]) who fell in and out of the eligibility criteria over the
same time period (group B). The remainder of the patients (17
of 74 [23%]) never met the criteria (group C). This means that
with conventional treatment alone, disease activity varies
markedly above and below the set criteria, which confirms that
it is not always the same people who would be eligible for the
trials every year. Furthermore, if the criteria are adhered to, it
is feasible that 77% of the cohort (group A plus group B)
would be receiving biologic treatment by the end of the 5-year
period, despite the fact that some of the patients’ disease
activity may have fallen below the criteria for active disease
without anything more than conventional treatment alone.
This of course has huge economic implications for health care
provision: a disease that is currently relatively cheap to treat
becomes very expensive.
It is clear that anti-TNF has a role in the treatment of
patients with AS. Reaching a consensus regarding which patients
should be eligible for treatment is difficult. A recent publication
(4) suggests a solution, although published data to confirm it are
lacking. Longitudinal data measured over years are needed. Our
data on a small but well-documented and sequentially reviewed
cohort suggests great variation year to year in patients’ eligibility
for biologic treatment. Health care providers will need to consider
the data before making policy statements. Long-term evidence for
efficacy is also urgently needed.
Ravik Mascarenhas, MRCP
Martin Davis, MRCP
Royal Cornwall Hospital
Truro, UK
Lindsay Robertson, MSc, MRCP
United Bristol Healthcare Trust
Bristol, UK
1. Brandt J, Khariouzov A, Listing J, Haibel H, Sorenson H,
Grassnickel L, et al. Six-month results of a double-blind, placebocontrolled trial of etanercept treatment in patients with active
ankylosing spondylitis. Arthritis Rheum 2003;48:1667–75.
2. Braun J, Brandt J, Listing J, Zink A, Alten R, Burmester G, et al.
Long-term efficacy and safety of infliximab in the treatment of
ankylosing spondylitis: an open, observational, extension study of a
three-month, randomized, placebo-controlled trials. Arthritis
Rheum 2003;48:2224–33.
3. Garrett S, Jenkinson T, Kennedy LG, Whitelock H, Gaisford P,
Calin A. A new approach to defining disease status in ankylosing
Cross-sectional data*
1996
No. of patients with BASDAI data available
No. of patients meeting criteria for active disease
(BASDAI ⬎4 and spinal pain VAS ⬎4)
% of patients eligible for biologic treatment
1997
1998
1999
2000
2001
51
27
58
29
57
29
63
39
50
33
54
30
52.9
50
50.9
61.9
66
55.6
* BASDAI ⫽ Bath Ankylosing Spondylitis Disease Activity Index; VAS ⫽ visual analog scale.
LETTERS
spondylitis: the Bath Ankylosing Spondylitis Disease Activity Index.
J Rheumatol 1994;21:2286–91.
4. Braun J, Pham T, Sieper J, Davis J, van der Linden S, Dougados M,
et al, for the ASAS Working Group. International ASAS consensus
statement for the use of anti-tumour necrosis factor agents in
patients with ankylosing spondylitis. Ann Rheum Dis 2003;62:
817–24.
DOI 10.1002/art.20503
Reply
To the Editor:
We would like to thank Dr. Mascarenhas and colleagues for their comments and the data provided. It is always
useful to receive this kind of feedback from daily clinical
practice. The main point clearly is uncertainty about the
indication for anti-TNF therapy for AS, a disease in which, for
decades, the standard of therapy in daily care has been that
there is little to offer patients. This is one of the reasons it has
been more than sufficient for the specialist to see the patient
once a year, as Mascarenhas and colleagues did. The high
proportion of patients with active disease in their series from
the UK reminds us of the historical dearth of effective
treatments for AS. We find it remarkable that 38% of these
patients continuously had active disease despite therapy with
nonsteroidal antiinflammatory drugs, and another 39% fulfilled criteria for active disease some of the time. These data
are consistent with recent calculations of data on AS patients
from the German Rheumatologic Database (1).
Mascarenhas et al state that the definition of active
disease used in our trials (2–5) is arbitrary. Although this is
basically correct, this definition is widely accepted internationally (6–8), and it clearly served the two main purposes of 1)
setting a cutoff that indicates active rather than inactive disease
and 2) concentrating on axial rather than peripheral disease.
Criteria for active disease in AS that are similar to those we
have used in the trials have recently been published (9). Since
the mean BASDAI was ⬎6 in most studies, it might even be
conceivable to raise the cutoff from 4 to 5, but in recent years
specialists have been generally reluctant to make decisions
regarding institution of anti-TNF therapy based solely on
numerical data. That is why we would like to stress that it was
ultimately the local expert who referred patients for the trials,
and at the Berlin consensus meeting (9) it was recommended
that the expert be the one to make decisions regarding
institution and discontinuation of anti-TNF therapy. This is the
only way these decisions should be made until there are
established criteria for prognosis and a standardized, widely
available magnetic resonance imaging (MRI) scoring system
(10). Although radiographic findings and C-reactive protein
(CRP) levels are not closely correlated with disease activity in
AS (11,12) there is some evidence that MRI findings and CRP
concentrations can have a role in predicting response to
therapy (13).
The rather high proportion of patients with active
disease in Mascarenhas and colleagues’ cohort in the UK
(50–66%) is based on the BASDAI questions that are related
to the state of disease in the last week (14). This is different
from studies in which patients had to have active disease for 4
weeks, as is also part of the recently published definition (9).
Another difference is that the cohort reported by Mascarenhas
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and colleagues was older and, at ⬎20 years, had a longer
disease duration than the patients included in most trials. This
is especially relevant if the disease stage of the patient, which
is assessed mainly based on radiographic progression, is taken
into consideration (15); the latter may largely explain the
limited response to anti-TNF therapy in older patients (13).
Finally, we believe our recent studies have contributed
substantially to the long-term experience with anti-TNF therapy in AS (4,5). Currently, we are investigating whether
anti-TNF (infliximab) therapy in patients with this disease can
be discontinued after 3 years of ongoing treatment.
Juergen Braun, MD
Joachim Sieper, MD
Benjamin Franklin Hospital
Free University
Berlin, Germany
1. Zink A, Braun J, Listing J, Wollenhaupt J, German Collaborative
Arthritis Centers. Disability and handicap in rheumatoid arthritis
and ankylosing spondylitis: results from the German Rheumatological Database. J Rheumatol 2000;27:613–22.
2. Braun J, Brandt J, Listing J, Golder W, Alten R, Burmester GR,
et al. Treatment of active ankylosing spondylitis with infliximab: a
double-blind placebo controlled multicenter trial. Lancet 2002;
359:1187–93.
3. Brandt J, Khariouzov A, Listing J, Haibel H, Sorensen H,
Grassnickel L, et al. Six-month results of a German double-blind,
placebo-controlled trial of etanercept treatment in active ankylosing spondylitis. Arthritis Rheum 2003;48:1667–75.
4. Braun J, Brandt J, Listing J, Zink A, Alten R, Burmester G, et al.
Long-term efficacy and safety of infliximab in the treatment of
ankylosing spondylitis: an open, observational, extension study of a
three-month, randomized, placebo-controlled trial. Arthritis
Rheum 2003;48:2224–33.
5. Brandt J, Listing J, Alten R, Burmester G, Gromnica-Ihle E,
Kellner H, et al. Two year follow up results of a controlled trial of
the anti-TNF alpha antibody infliximab in active ankylosing spondylitis [abstract]. Arthritis Rheum 2003;48 Suppl 9:S172.
6. Van den Bosch F, Kruithof E, Baeten D, Hersseens A, De Keyser
F, Mielants H, et al. Randomized double-blind comparison of
chimeric monoclonal antibody to tumor necrosis factor ␣ (infliximab) versus placebo in active spondylarthropathy. Arthritis
Rheum 2002;46:755–65.
7. Davis JC Jr, van der Heijde D, Braun J, Dougados M, Cush J,
Clegg DO, et al, for the Enbrel Ankylosing Spondylitis Study
Group. Recombinant human tumor necrosis factor receptor
(etanercept) for treating ankylosing spondylitis: a randomized,
controlled trial. Arthritis Rheum 2003;48:3230–6.
8. Collantes-Estevez E, Munoz-Villanueva MC, Canete-Crespillo
JD, Sanmarti-Sala R, Gratacos-Masmitja J, Zarco-Montejo P, et
al. Infliximab in refractory spondyloarthropathies: a multicentre
38 week open study. Ann Rheum Dis 2003;62:1239–40.
9. Braun J, Pham T, Sieper J, Davis J, van der Linden S, Dougados
M, et al, for the ASAS working group. International ASAS
consensus statement for the use of anti-tumour necrosis factor
biologic agents in patients with ankylosing spondylitis. Ann Rheum
Dis 2003;62:817–24.
10. Braun J, Baraliakos X, Golder W, Brandt J, Rudwaleit M, Listing
J, et al. Magnetic resonance imaging examinations of the spine in
patients with ankylosing spondylitis, before and after successful
therapy with infliximab: evaluation of a new scoring system.
Arthritis Rheum 2003;48:1126–36.
11. Spoorenberg A, van der Heijde D, de Klerk E, Dougados M, de
Vlam K, Mielants H, et al. Relative value of erythrocyte sedimentation rate and C-reactive protein in assessment of disease activity
in ankylosing spondylitis. J Rheumatol 1999;26:980–4.
12. Spoorenberg A, de Vlam K, van der Linden S, Dougados M,
Mielants H, van de Tempel H, et al. Radiological scoring methods
2378
LETTERS
in ankylosing spondylitis. reliability and change over 1 and 2 years.
J Rheumatol 2004;31:125–32.
13. Rudwaleit M, Listing J, Brandt J, Braun J, Sieper J. Prediction of
a major clinical response (BASDAI 50) to tumour necrosis factor
␣ blockers in ankylosing spondylitis. Ann Rheum Dis. Published
online first: 22 March 2004.
14. Garrett S, Jenkinson T, Kennedy LG, Whitelock H, Gaisford P,
Calin A. A new approach to defining disease status in ankylosing
spondylitis: the Bath Ankylosing Spondylitis Disease Activity
Index. J Rheumatol 1994;21:2286–91.
15. Braun J, van der Heijde D, Dougados M, Emery P, Khan MA,
Sieper J, et al. Staging of patients with ankylosing spondylitis: a
preliminary proposal. Ann Rheum Dis 2002;61 Suppl 3:iii19–23.
DOI 10.1002/art.20504
Sensitivity of dual x-ray absorptiometry to stature and
reference data source in pediatric patients: comment
on the article by Stewart et al
To the Editor:
We read with interest the recent study by Stewart et al,
which assessed lumbar spine areal bone mineral density
(BMD) in 15 children with juvenile dermatomyositis (DM) (1).
The authors should be commended for recognizing the risk of
osteoporosis in this patient population. Indeed, 5 of the
patients described had already sustained symptomatic vertebral compression fractures. However, as outlined below, this
report illustrates the challenges of interpreting dual x-ray
absorptiometry (DXA) results in children, particularly the
impact of the reference data used.
The authors cite as their comparison group the reference
data for 666 healthy children reported by Faulkner et al (2).
These reference data have the advantage of providing age- and
sex-specific Z scores (standard deviation scores) for children ages
8–17 years. However, we noted that 6 of the 15 patients described
by Stewart et al were outside the age range of the Faulkner
reference data. Furthermore, we were interested in determining
whether the patients with juvenile DM had decreased height for
age, because short stature results in an underestimation of the
BMD by DXA (3). Therefore, we used the patient heights
reported by Stewart et al to calculate age- and sex-specific height
Z scores (4). In addition, we used the reported BMD results to
generate BMD Z scores using the Faulkner reference data and
reference data from the manufacturer of the Hologic DXA
instrument (Hologic, Bedford, MA) (5).
In patients with juvenile DM, the mean (⫾SD) Z score
for height at the baseline visit was ⫺0.45 ⫾ 0.55 and decreased
further over the followup interval to ⫺0.78 ⫾ 0.77. Therefore,
short stature may have contributed to the apparent reduction
in BMD for age at baseline and the progressively greater
deficits that occurred during the followup interval. Importantly, our calculations using the Faulkner reference data
yielded significantly greater BMD Z scores than those reported by Stewart et al (see Table 1). At baseline, the Faulkner
Z scores were 0.45 SD greater than the Z scores reported by
Stewart et al. This represents a clinically and statistically (P ⫽
0.03) significant difference. Some, but not all, of the Z scores
presented in the report were consistent with those calculated
from the Hologic reference data. The Hologic reference data
do encompass the full range of patient ages but are not
sex-specific. In a previous systematic comparison of pediatric
reference data, we demonstrated that the use of sexnonspecific reference data results in substantial misclassification of DXA results (6), particularly an underestimation of
BMD Z scores in male subjects.
It is also important to note that in 3 of 5 patients with
vertebral compression fractures, the fractures were located in
the scanned region (L1–L4). Because the compression fractures likely caused the affected vertebrae to appear smaller,
the measured lumbar vertebral BMD in these patients may
have been falsely high.
Because greater attention is being paid to the threat of
osteoporosis in the pediatric rheumatic diseases, it is vital to
recognize the limitations of DXA as a surrogate outcome
measure in children. A first step is to understand the nature of
the reference data we are using to compare our patients with
Table 1. Comparison of lumbar spine Z scores in patients with juvenile DM using reference data from Faulkner et al (2), Hologic (5), and Stewart
et al (1)*
Age, years
Baseline DXA Z score
Followup DXA Z score
Patient/
sex
Baseline
Followup
Faulkner
Hologic
Stewart
Faulkner
Hologic
Stewart
1/F
2/M
3/F
4/F
5/F
6/M
7/M
8/F
9/F
10/F
11/F
12/M
13/F
14/M
15/M
22.9
13
16.5
14.8
18.5
7.9
4.8
10.5
6.7
11.4
10.6
19.3
9.8
5.9
10.5
24.6
15
18.7
17.8
19.7
9.3
7.1
13.8
8.4
14.8
12.7
–
13.8
8.5
12.5
NA
⫺0.34
⫺0.55
⫺1.25
NA
0.05
NA
⫺1.31
NA
⫺0.70
⫺1.44
NA
⫺1.04
NA
⫺4.55
⫺0.96
⫺1.42
⫺0.84
⫺1.21
⫺1.05
⫺0.88
⫺0.32
⫺1.77
0.24
⫺1.55
⫺1.97
⫺1.14
⫺1.62
⫺2.84
⫺3.96
⫺1.24
⫺1.43
⫺0.84
⫺1.25
⫺1.35
⫺0.88
⫺0.35
⫺1.76
0.23
⫺1.55
⫺1.84
⫺0.76
⫺1.62
⫺2.86
⫺4.01
NA
0.23
NA
NA
NA
⫺0.73
NA
⫺3.39
⫺0.60
⫺1.68
0.26
–
⫺0.49
⫺2.63
⫺1.08
⫺0.92
⫺0.54
⫺1.04
⫺1.48
⫺1.02
⫺1.53
⫺0.99
⫺2.82
⫺1.32
⫺1.66
0.34
–
⫺0.27
⫺2.84
⫺1.95
⫺0.94
⫺0.52
⫺1.04
⫺1.48
⫺1.02
⫺1.53
⫺0.98
⫺2.8
⫺1.34
⫺1.65
⫺1.32
–
⫺0.28
⫺0.16
⫺2.03
* Data from patients who were outside the age range of the Faulkner reference data were considered not applicable (NA). DM ⫽ dermatomyositis;
DXA ⫽ dual x-ray absorptiometry.
LETTERS
2379
healthy controls. Future studies are needed to determine
optimal strategies for addressing the contribution of short
stature to DXA-derived 2-dimensional measures of BMD.
Until then, we need to be cautious when interpreting decreased BMD Z scores as evidence of osteoporosis.
Jon M. Burnham, MD
Babette S. Zemel, PhD
Mary B. Leonard, MD, MSCE
The Children’s Hospital of Philadelphia,
University of Pennsylvania School of Medicine
Philadelphia, PA
1. Stewart WA, Acott PD, Salisbury SR, Lang BA. Bone mineral
density in juvenile dermatomyositis: assessment using dual x-ray
absorptiometry. Arthritis Rheum 2003;48:2294–8.
2. Faulkner RA, Bailey DA, Drinkwater DT, McKay HA, Arnold C,
Wilkinson AA. Bone densitometry in Canadian children 8–17 years
of age. Calcif Tissue Int 1996;59:344–51.
3. Prentice A, Parsons TJ, Cole TJ. Uncritical use of bone mineral
density in absorptiometry may lead to size-related artifacts in the
identification of bone mineral determinants. Am J Clin Nutr
1994;60:837–42.
4. Ogden CL, Kuczmarski RJ, Flegal KM, Mei Z, Guo S, Wei R, et al.
Centers for Disease Control and Prevention 2000 growth charts for
the United States: improvements to the 1977 National Center for
Health Statistics version. Pediatrics 2002;109:45–60.
5. Southard RN, Morris JD, Mahan JD, Hayes JR, Torch MA,
Sommer A, et al. Bone mass in healthy children: measurement with
quantitative DXA. Radiology 1991;179:735–8.
6. Leonard MB, Propert KJ, Zemel BS, Stallings VA, Feldman HI.
Discrepancies in pediatric bone mineral density reference data:
potential for misdiagnosis of osteopenia. J Pediatr 1999;135(2 Pt
1):182–8.
DOI 10.1002/art.20505
Reply
To the Editor:
We would like to thank Dr. Burnham and his colleagues for their comments regarding the challenges of interpreting DXA results in the pediatric population. As they point
out, the use of an appropriate reference database is very
important for correct interpretation of DXA results in children. In our study, we used the database that is incorporated
into the Hologic (Hologic, Bedford, MA) densitometer software (1). Although the database described by Faulkner et al
(2) has the advantage of providing sex-specific Z scores for
Canadian children, 6 of our 15 patients were outside the age
range of the Faulkner reference data. The Hologic manufacturer’s pediatric reference database has the advantage of
including subjects between the ages of 1 and 19 years (1). One
of the discrepancies in our reported Z score results compared
with the Z scores calculated by Burnham et al using the
Hologic reference data was due to a typographic error in the
BMD for patient 14, which was recorded as 0.422 but actually
was 0.631.
As Burnham et al indicate, one of the disadvantages of
the Hologic manufacturer’s reference data is the lack of sex
specificity. Unfortunately, there is not a sex-specific database
for the Hologic scanner that includes children of young ages.
Sex-specific reference data appear to be especially important
in early adolescence, because the BMD of healthy peripubertal
girls tends to be greater than that of boys in the same age
group, presumably due to the earlier onset of puberty in girls
(2). Lack of a sex-specific reference database can therefore
result in peripubertal boys being misclassified as having low
BMD. If one controls for maturity, this sex difference is no
longer seen (2,3).
Pubertal status was assessed in our population, and the
lack of a sex-specific normative database was unlikely to have
resulted in misclassification of the 3 prepubertal males, the
postpubertal male, and 1 peripubertal male (patient 15) who
had documented compression fractures. In 1 male patient
(patient 2), failure to use a sex-specific database likely contributed to the apparently low baseline BMD Z score; however, his
followup BMD Z score was normal.
Although misclassification was not a significant problem, the fact that we did not use sex-specific reference data
may have contributed to the significantly greater Z scores
calculated by Burnham et al using the Faulkner reference data.
In addition, it is recognized that even with the use of appropriate databases, a child’s Z scores may vary depending on the
reference database selected (4).
Burnham et al also raise the important issue of the
effect of skeletal size on DXA measurements in children. It has
been well documented in the literature that areal BMD
measurement by DXA may be underestimated in a child with
short stature due to smaller bone size, and that volumetric
BMD may better reflect a child’s bone health status (4–6). The
use of age-specific normative data may therefore not be
appropriate for children who are unusually small for age (4).
The patients in our study population were not unusually small
for age. In 10 of 15 patients, height at baseline was at or greater
than the 25th through 50th percentile; at followup, the height
of 8 patients was at or above the 25th percentile. No patient
had a height below the 5th percentile. Nevertheless, the mean
height Z scores at baseline and followup as calculated by
Burnham et al suggest that relative short stature may have
contributed to the reduction in BMD at baseline and followup.
Although stature is important to consider in the interpretation of areal BMD, we believe that a reduction in bone
mass, even in the absence of a large decrease, should not be
dismissed as insignificant in our population of steroidrequiring patients, given the evidence of significant bone
morbidity, with vertebral compression fractures documented in
one-third of children. There is evidence to suggest that in
adults, symptomatic bone morbidity may be greater in corticosteroid-treated patients compared with postmenopausal subjects, despite relative preservation of BMD in the former (7).
This may relate to alterations in bone architecture in addition
to reductions in BMD.
Burnham et al correctly point out that compression
fractures of L1–L4 may result in a falsely high BMD measurement. This may have led to underestimation of bone mass and
density reductions in the baseline BMD measurements for patients 13 and 15. At the time of their followup BMD assessments,
and in the case of patient 1, the radiologist documented normal
lumbar vertebrae, including recovered height.
We agree with Burnham and colleagues that BMD
measurement by DXA in children is imperfect. Nevertheless,
this pilot study has documented significant bone morbidity in
2380
LETTERS
our juvenile DM population and suggests that further study of
this population is needed.
Bianca Lang, MD, FRCPC
Phil Acott, MD, FRCPC
IWK Health Centre
Halifax, Nova Scotia, Canada
Wendy Stewart, MD, PhD, FRCPC
Neurology Associates of Eastern Maine
Bangor, ME
3.
4.
5.
6.
1. Southard RN, Morris JD, Mahan JD, Hayes JR, Torch MA,
Sommer A, et al. Bone mass in healthy children: measurement with
quantitative DXA. Radiology 1991;179:735–8.
2. Faulkner RA, Bailey DA, Drinkwater DT, McKay HA, Arnold C,
7.
Wilkinson AA. Bone densitometry in Canadian children 8–17 years
of age. Calcif Tissue Int 1996;59:344–51.
Bonjour JP, Theintz G, Buchs B, Slosman D, Rizzoli R. Critical years
and stages of puberty for spinal and femoral bone mass accumulation
during adolescence. J Clin Endocrinol Metab 1991;73:555–63.
Gafni RI, Baron J. Overdiagnosis of osteoporosis in children due to
misinterpretation of dual-energy x-ray absorptiometry (DEXA).
J Pediatr 2004;144:253–7.
Leonard MB, Propert KJ, Zemel BS, Stallings VA, Feldman HI.
Discrepancies in pediatric bone mineral density reference data:
potential for misdiagnosis of osteopenia. J Pediatr 1999;135:182–8.
Schonau E. Problems of bone analysis in childhood and adolescence. Pediatr Nephrol 1998;12:420–9.
Luengo M, Picado C, Del Rio L, Guanabens N, Montserrat JM,
Setoain J. Vertebral fractures in steroid dependent asthma and involutional osteoporosis: a comparative study. Thorax 1991;46:803–6.
DOI 10.1002/art.20435
Clinical Images: Syrinx-induced Charcot shoulder
The patient, an 80-year-old retired engraver, presented with a ⬎10-year history of pain in the right hand and in both knees
and shoulders. Radiographs of the knees demonstrated chondrocalcinosis, and arthrocentesis of the right knee confirmed the
presence of calcium pyrophosphate dihydrate crystals. The right hand exhibited severe degenerative changes in the proximal and
distal carpal rows and second and third metacarpophalangeal joints; the left showed degenerative changes in the glenohumeral and
acromioclavicular joints. Radiography of the right shoulder (A) revealed severe destructive changes with loss of bone and joint
architecture, consistent with a Charcot joint. Although pseudoneuropathic arthritis in patients with calcium pyrophosphate
deposition disease has been described (1–3), concern about syringomyelia was heightened when the patient presented with
second-degree burns on the right arm, from use of a heating pad for right shoulder pain. T2-weighted sagittal magnetic resonance
imaging (MRI) of the cervical spine (B) revealed a syrinx throughout the cervical cord, with extension into the upper thoracic region
(arrows) with mild diffuse volume loss. Neurologic evaluation confirmed differential loss of pain and temperature sensation in the
right arm. MRI of the thoracic spine did not demonstrate further extension of the syrinx, and the brain showed no intra- or extraaxial
lesions or Arnold-Chiari malformation.
1. Fidler WK, Dewar CL, Fenton P.V. Cervical spine pseudogout with
myelopathy and Charcot joints. J Rheumatol 1996;23:1445–8.
2. Sequeira W. The neuropathic joint. Clin Exp Rheumatol 1994;12:
325–37.
3. Jacobelli S, McCarty DJ, Silcox DC, Mall JC. Calcium pyrophosphate dihydrate crystal deposition in neuropathic joints. Ann Intern
Med 1973;79:340–7.
Anthony M. Turkiewicz, MD
Gail Kerr, MD
Veterans Affairs Medical Center
Washington, DC
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