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Magnetic resonance imaging computerized assessment in rheumatoid arthritisComment on the article by Goldbach-Mansky et al.

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ARTHRITIS & RHEUMATISM
Vol. 50, No. 3, March 2004, pp 1008–1018
© 2004, American College of Rheumatology
LETTERS
extension along the bone diaphysis.” However, in many cases
(especially in PIP joints), synovitis begins in the region of the
diaphysis and then bulges over to the region of the periarticular bones, which would be the other way around. In most
cases, we see a combination of synovitis and effusion. Because
these different phenomena appear at the same time, we would
prefer to use a scoring system that includes both parameters.
The results show that it is possible to clearly differentiate between healthy and pathologic inflammatory findings in
small finger and toe joints. However, for evaluating a scoring
system, more pathologic joints as well as a healthy control
group to distinguish between healthy and pathologic findings
should be included in longitudinal studies.
DOI 10.1002/art.20202
Ultrasonographic assessment of finger and toe joint
inflammation in rheumatoid arthritis: comment on
the article by Szkudlarek et al
To the Editor:
In their interesting study, Szkudlarek et al (1) demonstrated that musculoskeletal ultrasonography of selected small
finger and toe joints achieved high interobserver agreement
rates for the identification of synovitis and bone erosions. This
is an important issue, and we thank the authors for performing
this study, especially because one of the main disadvantages of
musculoskeletal ultrasound was considered to be operator
dependence, which was disproven in this study. However, we
think that the study raises some points with regard to preselection of the joints and the scoring systems introduced.
The authors decided to evaluate 5 preselected joints
(the second and third metacarpophalangeal [MCP] joints, the
second proximal interphalangeal [PIP] joint, and the first and
second metatarsophalangeal [MTP] joints), because they
thought that the accessibility of these joints for assessment with
ultrasound was representative of all small joints of the hands
and feet. However, the distribution of joint involvement does
change in patients with rheumatoid arthritis: the second and
third MCP joints are clinically involved more often than are
the fourth and fifth MCP joints (2). Also, more erosions have
been described in the second and fifth MCP joints compared
with the third and fourth MCP joints (3). Furthermore, the
accessibility and therefore the interpretation of pathologic
findings of the second MCP joint is easier than in other finger
joints. Because the patient cohort was rather small and an
ultrasonographic examination of all PIP and MCP joints takes
about 10–15 minutes (4), we would suggest an examination of
all of these joints, which is supplemented by the authors’
statement that the “agreements varied from joint to joint
probably reflecting the anatomic localization and availability
for examination” (1).
Semiquantitative scoring systems are frequently used
in radiology (e.g., magnetic resonance imaging evaluation of
synovitis and bone lesions) (5). However, we believe the
ultrasonographic scoring systems introduced for calculating
interobserver agreement may have some limitations. We perform ultrasonographic examinations of finger and toe joints
from the dorsal and volar sides and in 2 planes (see ref. 6), but
in the report by Szkudlarek et al (1), we did not see a clear
description of whether the authors performed the examination
according to a standardized protocol. Our experience shows
that synovitis and effusion can be detected predominantly from
the volar side. It would have been of great interest to see the
typical anatomic landmarks (e.g., metacarpal head, tendon,
synovial membrane) as well as a statement about the orientation (volar or dorsal view, proximal or distal) and specification
(MCP, PIP, or MTP) of the joints in the figures. It therefore
remains unclear whether synovitis and effusion appear similar
or equal in all 3 joint regions.
In the study by Szkudlarek et al, synovitis was classified
on a 4-grade scale (0–3), with a score of 1 defined as “filling the
angle between the periarticular bones, without bulging over
the line linking tops of the bones,” and a score of 2 was defined
as “bulging over the . . . periarticular bones but without
Alexander K. Scheel, MD
Georg-August-University
Göttingen, Germany
Marina Backhaus, MD
Charité University Hospital
Berlin, Germany
1. 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
2003;48:955–62.
2. Weidekamm C, Koller 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.
3. Wakefield RJ, Gibbon WW, Conaghan PG, O’Connor P, McGonagle G, 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. 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.
5. Østergaard M, Klarlund M, Lassere M, Conaghan P, Peterfy C,
McQueen F, et al. Interreader agreement in the assessment of
magnetic resonance images of rheumatoid arthritis wrist and finger
joints: an international multicenter study. J Rheumatol 2001;28:
1143–50.
6. Backhaus M, Burmester GR, Gerber T, Grassi W, Machold KP,
Swen WA, et al, for the Working Group for Musculoskeletal
Ultrasound in the EULAR Standing Committee on International
Clinical Studies including Therapeutic Trials. Guidelines for musculoskeletal ultrasound in rheumatology. Ann Rheum Dis 2001;60:
641–9.
DOI 10.1002/art.20205
Reply
To the Editor:
We thank our colleagues, Drs. Scheel and Backhaus,
for their interest in and comments on our recent study. We are
pleased to be given the opportunity to elaborate on the
description of our methodology.
Except for our intention to assess finger as well as toe
joints, the only criterion for our preselection of joints for
examination was their accessibility for ultrasound. In this
1008
LETTERS
1009
respect, the PIP joints are most accessible and can be assessed
in 4 aspects (dorsal, palmar, medial, and lateral). The accessibility of the MCP joints varies, with the second and fifth MCP
joints being accessible in 3 aspects (dorsal and palmar and,
respectively, medial and lateral), while the third and fourth
MCP joints are accessible in only 2 aspects (dorsal and
palmar). This variability of accessibility is also seen in the MTP
joints, where the first MTP joint is accessible in 2 aspects
(medial and dorsal, due to the presence of the sesamoid
bones on the plantar side of the joint), the fifth MTP joint is
accessible in 3 aspects (dorsal, plantar, and lateral), while the
second, third, and fourth MTP joints are accessible in 2 aspects
(dorsal and plantar). We considered the 5 preselected joints to
be representative of the finger and toe joints involved in
rheumatoid arthritis, with respect to location, size, and accessibility. Thus, the distribution of joint changes in rheumatoid
arthritis had no influence on our selection. However, we think
that the differences described by Drs. Scheel and Backhaus
suggest that our choice of joints for examination included
different frequencies of involvement.
The examinations in our study were performed according to a protocol on which we reached consensus before its
beginning. The preselected joints were examined from all
accessible aspects (see above), in both the longitudinal and
transverse aspects, as shown in the figures. The longitudinal
aspects were used for scoring synovitis, joint effusion, and
power Doppler flow signal, while both longitudinal and transverse aspects were used for scoring the destructive changes.
Our experience is that synovitis and joint effusion are
most often visualized on the dorsal side of the MCP and MTP
joints, but in the PIP joints the findings predominate on the
palmar side. Likewise, in our experience, it is most often joint
effusion in the PIP joints that can be visualized along the
diaphysis. On the basis of a cross-sectional study, we cannot
conclude which of the findings is primary. We can only state
that in our patient population, the combination of synovitis and
joint effusion often occurred in the MTP and PIP joints and
seldom occurred in the MCP joints. In order to elucidate
patterns of localization of these parameters in future longitudinal studies, we prefer to score them separately.
We find our results encouraging for the further use of
ultrasound imaging in rheumatoid arthritis and agree with Drs.
Scheel and Backhaus that a final evaluation of a scoring system
should occur in longitudinal studies, with a higher number of
participants, including both patients and healthy controls.
Marcin Szkudlarek, MD, PhD
Michel Court-Payen, MD, PhD
Søren Jacobsen, MD, DMSc
Mette Klarlund, MD, PhD
University of Copenhagen Hvidovre Hospital
Hvidovre, Denmark
Henrik S. Thomsen, MD, DMSc
University of Copenhagen Herlev Hospital
Herlev, Denmark
Mikkel Østergaard, MD, PhD, DMSc
University of Copenhagen Hvidovre Hospital
Hvidovre, Denmark,
and University of Copenhagen Herlev Hospital
Herlev, Denmark
DOI 10.1002/art.20196
The validity and predictive value of magnetic
resonance imaging erosions in rheumatoid arthritis:
comment on the article by Goldbach-Mansky et al
To the Editor:
We were pleased to see the editorial by GoldbachMansky et al on the use of magnetic resonance imaging (MRI)
in the evaluation of bone damage in rheumatoid arthritis (RA)
(1). In particular, the authors highlighted the increased sensitivity of MRI over plain radiographs in detecting bone damage.
In addition, they raised some important issues regarding the
validity of MRI lesions and their pathophysiologic significance.
It is important to realize that the appearance of a
particular MRI bone abnormality will depend on the sequences acquired. Most important, the presence or absence of
bone edema can complicate interpretation by the reader, so
use of a set of sequences that visualizes both trabecular bone
loss and edema is important. The Outcome Measures in
Rheumatology Clinical Trials (OMERACT) consensus view
(2) defined an MRI erosion as a sharply marginated bone
lesion with correct juxtaarticular localization and typical signal
characteristics visible in 2 planes, with a cortical break seen in
at least 1 plane, and also defined signal characteristics.
Evidence is accumulating that MRI erosions represent
true bone damage and are indeed the predecessors of radiographic erosions. Such evidence includes the following:
1. Based on the above definitions, MRI erosions correlated 100% with sonographically determined cortical
breaks in the radial half of the second metacarpophalangeal (MCP) joints, where ultrasound has access
equivalent to that of MRI (3).
2. Biopsy of a small number of these lesions has demonstrated necrotic tissue consistent with erosion pathology (4).
3. Miniarthroscopy has confirmed the presence of bone
pathology in all examined patients with early or established RA who had MRI bone erosions in their MCP
joints (5).
4. Baseline MRI erosions in early RA markedly increase
the risk (relative risk ⬃5) of radiographic erosions 1–2
years later (6,7).
5. Recent reports have documented that MRI bone
changes have prognostic value in predicting long-term
(5–6-year) radiographic outcome, in established (8) as
well as early RA (9). In the study of early RA, the
baseline MRI status of the wrist was highly predictive
of the total modified Sharp score (hands and feet) 6
years later (9). In the study of established RA, 78% of
new radiographic erosions were detectable by MRI 1–5
years earlier (8).
6. Even though 1-year followup studies have demonstrated only low numbers of baseline MRI erosions
being visualized as radiographic erosions (10–13),
longer-duration studies have demonstrated an increased rate (6,8). McQueen et al (6) reported that at
2 years, 1 of 4 MRI abnormalities had progressed to
radiographic erosions, while Østergaard et al (8) found
that 51% of MRI erosions of the wrist were detected
by radiographs 5 years later, and that the presence of
1010
LETTERS
a baseline MRI erosion in a radiographically noneroded bone increased the risk of a radiographic
erosion at 5 years more than 4-fold.
Goldbach-Mansky and colleagues are to be congratulated on their comparison of MRI lesions with computed
tomography (CT)–based lesions, because CT, like ultrasound,
can determine true cortical breaks. It is to be expected that the
MRI erosions will have larger volumes than those of corresponding lesions on CT images if associated bone marrow
edema is included in the volumes measured. This differentiation of bone erosion and bone edema is not always easy,
particularly if optimal MRI sequences and definitions are not
applied. The CT and MRI acquisitions, the definitions of CT
and MRI erosions, and the criteria for the exact delineation of
the erosions used in the study by Goldbach-Mansky et al were
not provided in the editorial or in the short abstracts published
so far. Consequently, discussion of these topics must await
publication of the original data.
It is likely that MRI lesions will never correspond
exactly with radiographic lesions, due to the following: a) the
tomographic nature of MRI compared with the monoplanar
radiograph; b) the sensitivity of MRI: very small defects may
be visible on MRI, while radiographs are known to be insensitive to small erosions (3); c) use of modern therapeutic
strategies means many lesions will not progress in size, and,
consequently, that small baseline MRI erosions will never
become detectable on radiographs; and d) strict MRI definitions are not being used (see above).
Goldbach-Mansky and colleagues raised the issue of
interrater reliability in scoring MRI erosions. Results from the
most recent OMERACT 6 interrater reliability exercises, both
cross-sectional and longitudinal, were recently published
(14,15). These results reflect that with increased training, there
is improved agreement across readers from multiple centers,
but it is correct that further improvements are desirable.
However, the moderate agreement in readings from multiple
centers is not reflected in reports of single intrareader or dual
interreader agreements between trained readers, which have
shown very good agreement rates (intraclass correlation coefficients generally ⬎0.8) (16,17).
The field of MRI is moving forward rapidly, and the
usefulness of MRI in determining synovial volumes and activity cannot be overstated, given the known relationship of MRI
with erosion progression (11,13). With the increasing use of
effective disease-suppressant therapy, it is important to have a
tool that will sensitively detect bone erosions before radiographic progression is evident. We agree with the authors that
at present we would not recommend MRI for use in large
clinical trials involving multiple centers and readers, but we do
believe that its use in proof-of-concept studies is highly important in providing relevant and timely information about response to therapy.
Philip G. Conaghan, MD, FRACP
Mikkel Østergaard, MD, PhD
Copenhagen University Hospital at Hvidovre
Hvidovre, Denmark
Dennis McGonagle, MB, FRCPI, PhD
Philip O’Connor, MD, FRCR
Paul Emery, MA, MD, FRCP
Leeds General Infirmary
Leeds, UK
1. Goldbach-Mansky R, Woodburn J, Yao L, Lipsky PE. Magnetic
resonance imaging in the evaluation of bone damage in rheumatoid arthritis: a more precise image or just a more expensive one?
Arthritis Rheum 2003;48:585–9.
2. 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.
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. McGonagle D, Gibbon W, O’Connor P, Blythe D, Wakefield R,
Green M, et al. A preliminary study of ultrasound aspiration of
bone erosion in early rheumatoid arthritis. Rheumatology (Oxford) 1999;38:329–31.
5. Ostendorf B, Peters R, Dann P, Becker A, Scherer A, Wedekind
F, et al. Magnetic resonance imaging and miniarthroscopy of
metacarpophalangeal joints: sensitive detection of morphologic
changes in rheumatoid arthritis. Arthritis Rheum 2001;44:
2492–502.
6. McQueen FM, Benton N, Crabbe J, Robinson E, Yeoman S,
McLean L, et al. What is the fate of erosions in early rheumatoid
arthritis? Tracking individual lesions using x rays and magnetic
resonance imaging over the first two years of disease. Ann Rheum
Dis 2001;60:859–68.
7. Lindegaard H, Hørslev-Petersen K, Vallø J, Junker P, Østergaard
M. Baseline MRI erosions in early rheumatoid arthritis MCP and
wrist joint bones markedly increase the risk of radiographic
erosions at 1 year follow-up [abstract]. Arthritis Rheum 2002;46
Suppl 9:S521.
8. Østergaard M, Hansen M, Stoltenberg M, Jensen K, Szkudlarek
M, Pedersen-Zbinden B, et al. New radiographic bone erosions in
the wrists of patients with rheumatoid arthritis are detectable with
magnetic resonance imaging a median of two years earlier. Arthritis Rheum 2003;48:2128–31.
9. Benton NM, Perry D, Crabbe J, Stewart N, Robinson E, Yeoman
S, et al. Magnetic resonance scanning at first presentation predicts
modified Sharp score at six years in patients with rheumatoid
arthritis [abstract]. Arthritis Rheum 2002;46 Suppl 9:S370.
10. McQueen FM, Stewart N, Crabbe J, Robinson E, Yeoman S, Tan
PL, et al. Magnetic resonance imaging of the wrist in early
rheumatoid arthritis reveals progression of erosions despite clinical improvement. Ann Rheum Dis 1999;58:156–63.
11. 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.
12. Klarlund M, Østergaard M, Jensen KE, Madsen JL, Skjødt H,
Lorenzen I. Magnetic resonance imaging, radiography, and scintigraphy of the finger joints: one year follow up of patients with
early arthritis. The TIRA group. Ann Rheum Dis 2000;59:521–8.
13. Conaghan PG, O’Connor P, McGonagle D, Astin P, Wakefield
RJ, Gibbon WW, et al. Elucidation of the relationship between
synovitis and bone damage: a randomized magnetic resonance
imaging study of individual joints in patients with early rheumatoid
arthritis. Arthritis Rheum 2003;48:64–71.
14. Lassere M, McQueen F, Østergaard M, Conaghan P, Shnier R,
Peterfy C, et al. OMERACT Rheumatoid Arthritis Magnetic
Resonance Imaging Studies. Exercise 3: an international multicenter reliability study using the RA-MRI Score. J Rheumatol
2003;30:1366–75.
15. Conaghan P, Lassere M, Østergaard M, Peterfy C, McQueen F,
O’Connor P, et al. OMERACT Rheumatoid Arthritis Magnetic
Resonance Imaging Studies. Exercise 4: an international multicenter longitudinal study using the RA-MRI Score. J Rheumatol
2003;30:1376–9.
LETTERS
16. Bird P, Lassere M, Shnier R, Edmonds J. Computerized measurement of magnetic resonance imaging erosion volumes in patients
with rheumatoid arthritis: a comparison with existing magnetic
resonance imaging scoring systems and standard clinical outcome
measures. Arthritis Rheum 2003;48:614–24.
17. Østergaard M, O’Connor P, Conaghan P, Ejbjerg B, Szkudlarek
M, Peterfy C, et al. Is intravenous contrast injection necessary for
MRI assessment of inflammatory and destructive changes in
rheumatoid arthritis wrist and MCP joints? European Surgical
Research 2002;34 Suppl 1:141.
DOI 10.1002/art.20197
Magnetic resonance imaging computerized assessment
in rheumatoid arthritis: comment on the article by
Goldbach-Mansky et al
To the Editor:
We believe it is important to clarify 3 issues arising
from the recent editorial by Goldbach-Mansky et al (1). These
relate to computer segmentation processes, validity, and interrater reliability. Goldbach-Mansky et al stated that the live
wire paradigm developed by the National Institute of Health
has been shown to be “more repeatable and more efficient
than manual tracking methods [2], including the method used
by Bird et al.” The reference provided to support this assertion
(3) describes the measurement of magnetic resonance imaging
(MRI) bone volumes of the talus and the calcaneus using 30
2-dimensional sequences from an existing data set. The live
wire technique was compared with a manual tracing method
using 3 observers, and the authors reported that the live wire
method was faster and more repeatable.
It appears, however, that the magnitude of difference
between the 2 segmentation techniques, although statistically
significant, is not substantial in real terms. Furthermore, the
segmentation processes have been examined in large structures
that do not approximate the degree of difficulty encountered
when outlining small bony erosions in the wrist. Therefore, it is
simply not the case that the live wire method is more repeatable and faster than a manual method, and, more important, it
does not appear that the method has been directly compared
with the erosion outlining method used in our study.
Second, we agree that the validation of MRI is an
important step in the development of MRI as an outcome
measure, but this should be explored cautiously. The authors
present their own experiment, which compares MRI with
computed tomography (CT) in the assessment of erosion
volumes in 4 patients with rheumatoid arthrits (RA) (4).
Because the data are currently available only in abstract form,
it is difficult to examine the details. However, the results of the
study demonstrate that there were substantial differences
between the size of erosion volumes when comparing MRI and
CT. The authors concluded that MRI overestimates the size of
erosions in patients with RA, because CT is “considered to be
the best way to assess bony changes.” Such a conclusion does
not acknowledge the fact that this type of construct validity
assumes a surrogate gold standard only, and therefore the only
conclusion that can be reached is that there is or is not a
correlation between the 2 methods. Additionally, the interrater
reliability of both MRI and CT was poor, with the total number
1011
of erosions scored on CT varying between the observers by
nearly 2-fold. Therefore, the study effectively illustrates that
although validation should remain a firm goal for MRI researchers, it is mandatory that we have confidence in the
reliability of the measurement instrument and the measurement technique before embarking upon validation studies.
Interrater reliability is an essential part of any measurement process, and the Outcome Measures in Rheumatology Clinical Trials (OMERACT) MRI-RA group has examined this as a central issue over the past 6 years. GoldbachMansky et al reported that the recent OMERACT exercise (5)
used different scoring systems, but this is erroneous. The
OMERACT exercise referred to used a standarized scoring
system for all readers, estimating erosion size in the metacarpophalangeal joints and the carpus. The development of the
OMERACT MRI-RA scoring system is an iterative process,
and, as such, it represents an international grading system that
will continue to be modified and improved over time. In the
same way, the erosion volume method has been the subject of
an international trial of interrater reliability (6) and also is the
subject of an ongoing study to assess the effect of training and
calibration in improving interrater agreement.
Our study (2) sought to examine the feasibility and
reliability of the erosion volume method, using a software
program that is freely available on the internet and is accessible to all research groups. By doing this, we attempted to keep
the process of development transparent so that the development of MRI computerized assessment in RA remains a
tangible goal rather than a means to its own end. MRI
measurement in RA is still in its infancy, and it is only
continuing peer review and assessment that will develop such
measurement to its full potential.
Paul Bird, BMed (Hons), FRACP
Marissa Lassere, MBBS (Hons), PhD, FRACP, FAPHM
Ron Shnier, MBBS, FACR
John Edmonds, MBBS, MA, FRACP
St. George Hospital
and University of New South Wales
Sydney, New South Wales, Australia
1. Goldbach-Mansky R, Woodburn J, Yao L, Lipsky PE. Magnetic
resonance imaging in the evaluation of bone damage in rheumatoid
arthritis: a more precise image or just a more expensive one?
Arthritis Rheum 2003;48:585–9.
2. Bird P, Lassere M, Shnier R, Edmonds J. Computerized measurement of magnetic resonance imaging erosion volumes in patients
with rheumatoid arthritis: a comparison with existing magnetic
resonance imaging scoring systems and standard clinical outcome
measures. Arthritis Rheum 2003;48:614–24.
3. Falcao AX, Udupa JK, Samarasekera S, Sharma S. User-steered
image segmentation paradigms: live wire and live lane. Graph
Model Im Proc 1998;60:233–60.
4. Bedair H, Murphy M, Fleming D, Hill S, Schaub C, Thornton B, et
al. A comparison of MRI and CT in detecting carpal bone erosions
in early rheumatoid arthritis [abstract]. Arthritis Rheum 2001;41
Suppl 9:S222.
5. Østergaard M, Klarlund M, Lassere M, Conaghan P, Peterfy C,
McQueen F, et al. Interreader agreement in the assessment of
magnetic resonance images of rheumatoid arthritis wrist and finger
joints: an international multicenter study. J Rheumatol 2001;28:
1143–50.
6. Bird P, Ejbjerg B, McQueen F, Østergaard M, Lassere M, Edmonds
J. OMERACT Rheumatoid Arthritis Magnetic Resonance Imaging
1012
Studies. Exercise 5: an international multicenter reliability study
using computerized MRI erosion volume measurements. J Rheumatol 2003;30:1380–4.
DOI 10.1002/art.20122
What are the real effects of arthritis self-management
education programs on pain and disability? Comment
on the article by Warsi et al
To the Editor:
We read with interest the report by Warsi et al (1)
regarding the meta-analysis of the effects of arthritis selfmanagement education programs on pain and disability. Metaanalysis is a powerful tool for bringing together the results of
different studies, but meta-analysis itself must be undertaken
rigorously if criticism is to be avoided (2). Most important,
such an analysis should be performed within the framework of
a systematic review of the literature, to avoid bias and ensure
appropriate combinability of studies. We have undertaken
such a systematic review for the Cochrane Collaboration (3,4),
examining the effects of patient education for adults with
rheumatoid arthritis (RA) on health outcomes (pain, disability, psychological well-being, disease activity). Our review was
restricted to randomized controlled trials (RCTs) of patient
education interventions in which patients with a confirmed
diagnosis of RA participated. We included all types of patient
education programs, not only programs involving selfmanagement education as did Warsi and colleagues.
There are several reasons why the meta-analysis by
Warsi et al will be criticized and why its value is limited. First,
the search strategy used was not comprehensive, because it
omitted studies published in the last 5 years, considered only
English-language publications, and searched only in Medline,
HealthSTAR, and the reference list of retrieved articles. The
Cochrane Collaboration advises investigators to search at least
in the electronic databases Medline and Embase, and in the
Cochrane Controlled Trials Register (5). (The overlap in
journals listed in Medline and Embase is only ⬃34%.) Warsi et
al did not search PsycINFO, the most comprehensive database
of citations to psychosocial studies, and did not try to locate
unpublished studies. By relying mainly on Medline, it can be
expected that only 30–80% of all relevant studies will be
identified (6). In our review, we searched Medline, Embase,
PsycINFO, and the Cochrane Controlled Trials Register, from
1966 to September 2002 and in all languages, and we searched
for unpublished studies. When publications provided incomplete data, we contacted the authors for more information. As
a result, 50 studies were identified (4), including at least 18
randomized clinical trials that were not included by Warsi et al.
Those trials dealt with patient education programs for patients
with RA that contained a self-management education component. Six of the articles had been published before October 15,
1998 (7–12).
Warsi et al did not assess the methodologic quality of
studies included in their review, yet quality assessment of
individual studies is necessary to limit bias in conducting the
systematic review, gain insight into potential comparisons, and
LETTERS
guide the interpretation of findings (5). The Cochrane review
used 2 independent assessors of methodologic quality to
evaluate 4 criteria: selection bias, attrition bias, detection bias,
and performance bias (4).
There is great variation among the studies included in
the review by Warsi et al with regard to research design
(nonrandomized studies were included), types of interventions, types of disease (RA, osteoarthritis, polyarthritis, fibromyalgia), assessment periods, and assessment instruments. The
authors therefore used a random-effects model in their statistical analyses and performed a subgroup analysis on interventions that closely resembled the Arthritis Self-Help Course
(taught through chapters of the Arthritis Foundation). However, they did not analyze other differences between studies in
relation to outcomes. The Cochrane review presents separate
analyses for 3 types of interventions: information only, counseling, and behavioral treatment (mainly self-management
programs). Furthermore, extensive sensitivity analyses were
performed using only studies with high scores for methodologic quality, only larger studies, studies using the same
instrument to assess each outcome, and studies that assessed
outcomes at a fixed time point (after 2–4 months).
Warsi et al concluded that arthritis self-management
education programs lead to small but significant reductions in
pain and disability. However, the 95% confidence intervals
(95% CIs) for the effect sizes for both pain and disability
included 0, meaning the effects were not significant. The
results of our more comprehensive review of RCTs of patient
education programs for people with RA showed similar overall
results. However, in the subanalysis of educational interventions that included techniques aimed at behavioral change
(mostly self-management programs) we found, at first followup, a significant beneficial effect of such interventions on
disability (standardized mean difference ⫽ ⫺0.23, 95% CI
⫺0.36, ⫺0.10). This effect was quite robust, as shown by
sensitivity analyses, but the benefit was not maintained after
longer followup.
We support Warsi et al in their call for independent
high-quality trials of patient education (some of which have
been included in the Cochrane review), and we believe that
future research should seek to identify which patient characteristics (including the diagnostic category) are relevant to
beneficial outcomes, and which components of patient education programs are effective.
Erik Taal, PhD
Robert P. Riemsma, PhD
John R. Kirwan, MD
Johannes J. Rasker, MD
University of Twente
Enschede, The Netherlands
1. Warsi A, LaValley P, Wang PS, Avorn J, Solomon DH. Arthritis
self-management education programs: a meta-analysis of the
effect on pain and disability. Arthritis Rheum 2003;48:2207–13.
2. Egger M, Smith GD, Sterne JA. Uses and abuses of meta-analysis.
Clin Med 2001;1:478–84.
3. Riemsma RP, Taal E, Kirwan JR, Rasker JJ. Patient education
programmes for adults with rheumatoid arthritis. BMJ 2002;325:
558–9.
4. Riemsma RP, Kirwan JR, Taal E, Rasker JJ. Patient education for
LETTERS
5.
6.
7.
8.
9.
10.
11.
12.
adults with rheumatoid arthritis. Cochrane Database Syst Rev
2003;2:CD003688.
Clarke M, Oxman AD, editors. Cochrane reviewers’ handbook
4.2.0 [updated March 2003]. In: The Cochrane Library: Oxford:
Update Software. Updated quarterly; 2003. Available at: http://
www.cochrane.org/resources/handbook.
Dickersin K, Scherer R, Lefebvre C. Identifying relevant studies
for systematic reviews. BMJ 1994;309:1286–91.
Brus HL, van de Laar MA, Taal E, Rasker JJ, Wiegman O. Effects
of patient education on compliance with basic treatment regimens
and health in recent onset active rheumatoid arthritis. Ann Rheum
Dis 1998;57:146–51.
Goeppinger J, Arthur MW, Baglioni AJ Jr, Brunk SE, Brunner
CM. A reexamination of the effectiveness of self-care education
for persons with arthritis. Arthritis Rheum 1989;32:706–16.
Kraaimaat FW, Brons MR, Geenen R, Bijlsma JW. The effect of
cognitive behavior therapy in patients with rheumatoid arthritis.
Behav Res Ther 1995;33:487–95.
Lindroth Y, Brattstrom M, Bellman I, Ekestaf G, Olofsson Y,
Strombeck B, et al. A problem-based education program for
patients with rheumatoid arthritis: evaluation after three and
twelve months. Arthritis Care Res 1997;10:325–32.
Parker JC, Smarr KL, Buckelew SP, Stucky-Ropp RC, Hewett JE,
Johnson JC, et al. Effects of stress management on clinical
outcomes in rheumatoid arthritis. Arthritis Rheum 1995;38:
1807–18.
Taal E, Riemsma RP, Brus HL, Seydel ER, Rasker JJ, Wiegman
O. Group education for patients with rheumatoid arthritis. Patient
Educ Couns 1993;20:177–87.
1013
quality scores in the meta-analysis. We assessed the methods of
each study and outlined these in table format. However, we
elected to not explicitly include a score in the analysis because
of the lack of any standard method for scoring the quality of
such literature. Other authors have shown that the results of
meta-analyses including such quality scores are very sensitive
to the scoring system chosen (Juni P, Witschi A, Bloch R,
Egger M. The hazards of scoring the quality of clinical trials for
meta-analysis. JAMA 1999;282:1054–60).
We found it encouraging that the results of the review
by Taal et al on programs for RA and the results of our review
were similar—that the long-term effects of self-management
education are not significant. Taal and colleagues also examined the results of these programs at first followup and found
significant improvement. However, these short-term improvements did not persist.
Because RA and osteoarthritis are chronic diseases,
optimal self-management education programs would require
the demonstration of a long-term benefit. Unfortunately, as a
group, the current programs have not demonstrated such an
effect. Further research efforts need to focus on increasing the
persistence of benefit for arthritis self-management education
programs, determining subgroups of patients that are most
likely to benefit, and improving the methods for conducting
and reporting the results of such trials.
Daniel H. Solomon, MD, MPH
Michael P. LaValley, PhD
Philip S. Wang, MD, ScD
Jerry Avorn, MD
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA
DOI 10.1002/art.20207
Reply
To the Editor:
We appreciate the comments by Dr. Taal and colleagues regarding our review article on arthritis selfmanagement education programs. They recently published a
similar review on education for patients with RA (Riemsma
RP, Kirwan JR, Taal E, Rasker JJ. Patient education for adults
with rheumatoid arthritis. Cochrane Database Syst Rev 2003;
2:CD003688). Taal and associates express concern regarding
the results of our search strategy. Although it is true that the
search strategy they used yielded several articles that we had
not found, the majority of nonoverlapping references either
were published after 1998, the end of our search period, or
include interventions that we did not consider primarily educational. We required that education be a major focus of the
intervention programs, to limit the heterogeneity of the included studies. Thus, several articles were excluded that described interventions primarily involving innovations in physical therapy, occupational therapy, or psychological counseling
programs. Taal et al also suggest “that only 30–80% of all
relevant studies will be identified” by relying on Medline;
however, more recent research suggests that the proportion
has improved substantially, and that the risk of bias from using
only Medline in a meta-analysis is small (Sampson M, Barrowman NJ, Moher D, Klassen TP, Pham B, Platt R, et al. Should
meta-analysts search Embase in addition to Medline? J Clin
Epidemiol 2003;56:943–55).
Another criticism concerns our decision not to include
DOI 10.1002/art.20208
Association of the proinflammatory haplotype
(MICA5.1/TNF2/TNFa2/DRB1*03) with polymyositis
and dermatomyositis
To the Editor:
Polymyositis (PM) and dermatomyositis (DM) are
systemic inflammatory connective tissue disorders that likely
result from interactions between genetic and environmental
risk factors. Earlier studies indicated that certain HLA class II
alleles, including HLA–DRB1*03 (HLA–DR3) in Caucasian
populations (1) and HLA–DRB1*14 in Korean patients (2),
confer risk for development of PM and DM. However, it is not
clear whether this is a primary association or an association
due to other genes in the HLA region. Because of linkage
disequilibrium, the markers in the HLA region may be important not alone, but in the context of common haplotypes. The
8.1 ancestral haplotype (HLA–A1;B8;DRB1*03) includes the
TNF2 allele of the TNFA gene (the conventional name for the
G-308 TNFA allele is TNF1 and that for the A-308 TNFA
allele is TNF2). This haplotype has been associated with high
in vitro production of tumor necrosis factor (TNF) by peripheral blood mononuclear cells and also with high circulating
serum levels of TNF, and was thus considered a proinflamma-
1014
LETTERS
Table 1. TNFA ⫺308 alleles, genotypes, and haplotype frequency in PM/DM patients compared with controls*
TNF1
TNF2
TNF1/TNF1
TNF1/TNF2
TNF2/TNF2
MICA5.1/TNF2/TNFa2/DRB1*03
PM/DM
(n ⫽ 65)
Controls
(n ⫽ 65)
P
Pcorr
OR
95% CI
60 (92)
38 (58)
27 (42)
33 (51)
5 (8)
34 (26)
61 (94)
22 (34)
43 (66)
18 (28)
4 (6)
12 (9)
NS
0.0081
0.0081
0.0116
NS
0.0005
–
0.016
0.024
0.0348
–
0.030
–
2.75
0.36
2.69
–
3.48
–
1.35–5.61
0.18–0.74
1.30–5.58
–
1.71–7.09
* Values are the number (%) of patients (or, for MICA5.1/TNF2/TNFa2/DRB1*03, the number [%] of 130 chromosomes). PM/DM ⫽
polymyositis/dermatomyositis; Pcorr ⫽ corrected P (corrected for 2 alleles [TNF2], 3 genotypes [TNF1/TNF1 and TNF1/TNF2], or 61 haplotypes
[MICA5.1/TNF2/TNFa2/DRB1*03]); OR ⫽ odds ratio; 95% CI ⫽ 95% confidence interval; TNF1 ⫽ G-308 TNFA; NS ⫽ not significant; TNF2 ⫽
A-308 TNFA.
tory haplotype (3,4). In patients with juvenile DM the TNF2
allele of the TNFA gene has been found to be associated with
increased in vitro production of TNF by peripheral blood
mononuclear cells and with a more severe disease course (5).
The present study was conducted to analyze associations between individual genotypes from the HLA region
(single-nucleotide polymorphisms [SNPs] in HLA–DRB1, and
TNFA genes, and microsatellite markers in TNF and MICA
genes), as well as various haplotypes including these genetic
markers, with PM and DM in an adult population. Sixty-five
patients who fulfilled classification criteria for PM (n ⫽ 36) or
DM (n ⫽ 29) (6) were studied. Data from healthy unrelated
controls, who were matched to the patients by age, sex, and
race, were included for comparison. All patients and controls
were genotyped for HLA–DRB1 and TNFA ⫺308 SNPs and
for TNF and MICA microsatellites. All subjects gave their
informed consent to participate in the study. The protocol was
approved by the ethics committee at Karolinska Hospital.
We analyzed 4 markers within this HLA region, which
spread over 1.2 Mbp on the short arm of chromosome 6. The
frequencies of the TNF2 allele of the TNFA ⫺308 gene (Table
1), the TNFa2 and DRB1*03 alleles, as well as MICA5.1-5.1
genotype were all significantly higher in patients with PM/DM
compared with controls. Our analysis confirmed earlier findings that the HLA–DR3 genotype is associated with PM/DM
in Caucasians (2). We also demonstrated that the TNF2 allele
of the TNFA gene was associated with PM and DM in adult
patients, consistent with previous findings in juvenile DM (5).
Our investigation also revealed that the frequency of the
MICA5.1 allele in a homozygous state (MICA5.1-5.1 genotype) was significantly increased in adult PM and DM patients
compared with controls, although correction for multiple
comparisons weakened this finding. There was no difference
between PM and DM patients regarding the frequencies of any
investigated markers, and there was no effect of sex on the
frequencies of the investigated markers.
Using the expectation-maximization algorithm and
correcting the P value for the maximum number of observed
haplotypes, we determined that among 61 reconstructed haplotypes, 1 particular haplotype with 4 markers (MICA5.1/
TNF2/TNFa2/DRB1*03) was significantly more frequent in
the PM and DM patients compared with the controls (52% and
18%, respectively, P ⬍ 0.05). This haplotype was identified in
34 PM/DM patients and in 12 controls (Table 1).
The 8.1 ancestral haplotype (HLA–A1;B8;DRB1*03),
together with the TNF2 allele, is common in Caucasian
populations and was previously demonstrated to confer susceptibility to autoimmune diseases such as systemic lupus
erythematosus and Sjögren’s syndrome (4). Extending this
ancestral proinflammatory haplotype with MICA5.1 and
TNFa microsatellite markers resulted in a haplotype with 4
markers (MICA5.1/TNF2/TNFa2/DRB1*03), which was found
to be significantly more frequent in PM and DM patients
compared with controls. Additional genetic factors as well as
environmental factors are likely involved in the development
of myositis, since some patients lack some of the analyzed
alleles of the proinflammatory haplotype.
In conclusion, our observations suggest that the ancestral haplotype (A1;B8;DRB1*03) together with the TNF2
allele, rather than the HLA–DR3 gene itself, is an important
susceptibility factor for the development of polymyositis and
dermatomyositis. Our data also demonstrate that the TNFa2
microsatellite and MICA5.1 alleles should possibly be included
in the extended 8.1 ancestral haplotype.
Supported by grants from the Swedish Rheumatism Association,
the King Gustaf V 80-Year Foundation, the Swedish Research Council
(2001-74-X14045), the Vårdal Foundation, the Professor Nanna Svartz
Foundation, Magnus Bergvalls stiftelse, Stiftelsen Clas Groschinskys
Minnesfond, and the Karolinska Institutet Foundation.
Adla B. Hassan, MD, PhD
Liene Nikitina-Zake, MD
Carani B. Sanjeevi, MD, MSc, PhD
Ingrid E. Lundberg, MD, PhD
Karolinska Institutet
Stockholm, Sweden
Leonid Padyukov, MD, PhD
Karolinska Institutet
Stockholm, Sweden
and Mechnikov Research Institute
for Vaccines and Sera
Moscow, Russia
1. Hausmanowa-Petrusewicz I, Kowalska-Oledzka E, Miller FW, Jarzabek-Chorzelska M, Targoff IN, Blaszczyk-Kostanecka M, et al.
Clinical, serologic, and immunogenetic features in Polish patients
with idiopathic inflammatory myopathies. Arthritis Rheum 1997;40:
1257–66.
2. Rider LG, Shamim E, Okada S, Pandey JP, Targoff IN, O’Hanlon
TP, et al. Genetic risk and protective factors for idiopathic inflammatory myopathy in Koreans and American whites: a tale of two
loci. Arthritis Rheum 1999;42:1285–90.
LETTERS
3. Lio D, Candore G, Colombo A, Colonna Romano G, Gervasi F,
Marina V, et al. A genetically determined high setting of TNF-alpha
influences immunologic parameters of HLA-B8,DR3 positive subjects: implications for autoimmunity. Hum Immunol 2001;62:
705–13.
4. Degli-Esposti MA, Leaver AL, Christiansen FT, Witt CS, Abraham
LJ, Dawkins RL. Ancestral haplotypes reveal the role of the central
MHC in the immunogenetics of IDDM. Immunogenetics 1992;36:
345–56.
5. Pachman LM, Liotta-Davis MR, Hong DK, Kinsella TR, Mendez
EP, Kinder JM, et al. TNF␣-308A allele in juvenile dermatomyositis: association with increased production of tumor necrosis factor
␣, disease duration, and pathologic calcifications. Arthritis Rheum
2000;43:2368–77.
6. Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two
parts). N Engl J Med 1975;292:344–7.
DOI 10.1002/art.20097
Effect of infliximab treatment on T cell cytokine
responses in spondylarthropathy: comment on the
article by Zou et al
To the Editor:
We read with interest the article by Zou et al (1)
describing the down-regulation of T cell cytokines by infliximab treatment in patients with ankylosing spondylitis (AS).
Intracellular flow cytometric analysis of tumor necrosis factor
␣ (TNF␣) and interferon-␥ (IFN␥) in CD4⫹ and CD8⫹
peripheral blood lymphocytes after nonspecific (phorbol myristate acetate [PMA]/ionomycin) and antigen-specific (peptides derived from aggrecan) stimulation indicated that infliximab down-regulates the production of both Th1 cytokines for
at least 6 weeks.
These results and their interpretation are intriguing in
a number of respects. First, there was a large difference in the
baseline data (before infliximab treatment) between the
treated group in Zou and colleagues’ recent study (16.5%,
35.7%, 18.4%, and 23.8% IFN␥⫹ CD4⫹, IFN␥⫹ CD8⫹,
TNF␣⫹ CD4⫹, and TNF␣⫹ CD8⫹ cells, respectively), the
placebo group in that study (13.0%, 23.7%, 9.0%, and 8.6%,
respectively) and AS patients in a previous similar study by the
same authors (8.7%, 24.9%, 5.1%, and 2.7%, respectively) (2).
This variability raises questions concerning the validity of the
technical approach and hampers correct interpretation.
Second, the findings after infliximab treatment contrast with those described in 2 previous reports. In the first, we
analyzed, by the same technology, IFN␥ and interleukin-2
(IL-2) levels in 20 infliximab-treated spondylarthropathy
(SpA) patients and demonstrated restoration of a normal Th1
profile (3). Differences between that study and the one by Zou
et al (1) were that we used freshly isolated lymphocytes
whereas Zou et al used lymphocytes after freezing/thawing,
and that we analyzed different SpA subtypes whereas Zou and
colleagues analyzed only AS. The second report (4), by the
same group of authors as in the current report by Zou et al (1),
describes a study in which the investigators used the same
approach as in their recent study (freezing/thawing; AS patients only). In that study the results were similar to ours, i.e.,
TNF␣ and IFN␥ responses increased after 2 weeks of inflix-
1015
imab treatment. This is intriguing since 2 similar studies
performed by the same group led to opposite conclusions.
In order to address the discrepancies with our study
(3), we performed additional experiments. First, we assessed
the variability of intracellular cytokine detection on frozen
peripheral blood mononuclear cells (PBMCs) since Zou et al
indicate that they “cannot exclude the possibility that the
freezing/thawing process altered the cytokine expression by T
cells” (1). Intraassay variability after freezing/thawing was
assessed by analyzing IFN␥ in 24 samples in duplicate: the
mean variance was 0.52% (SD 0.43%) for CD4⫹ cells and
0.65% (SD 0.52%) for CD8⫹ cells. Interassay variability was
assessed by analyzing 5 samples for IFN␥, IL-2, and TNF␣
after thawing, at 2 different time points: the mean variance was
2.63% (SD 1.89%) and 3.35 (SD 3.73%) for CD4⫹ and CD8⫹
T cells, respectively. The variability due to freezing/thawing
was assessed by analyzing 5 samples for IFN␥, IL-2, and TNF␣
production by paired freshly isolated and frozen PBMCs:
freezing/thawing induced a clear increase of IFN␥ (from 15.7%
to 23.4% in CD4⫹ cells, from 25.1% to 34.3% in CD8⫹ cells;
P ⫽ 0.007), a decrease of IL-2 (from 48.0% to 36.6% in CD4⫹
cells, from 9.1% to 4.8% in CD8⫹ cells; P ⫽ 0.022) (Figure
1A), and a nonsignificant increase of TNF␣ (from 53.1% to
57.3% in CD4⫹ cells, from 19.4% to 23.2% in CD8⫹ cells; P ⫽
0.203). Thus, although intra- and interassay variability is small,
freezing/thawing of the samples induces a systematic bias.
Second, considering the above-mentioned differences
between studies, we performed a new study of IFN␥, IL-2, and
TNF␣ production by frozen CD4⫹ and CD8⫹ T cells stimulated with PMA/ionomycin at baseline and at week 6 of
infliximab treatment in 7 HLA–B27⫹ AS patients, i.e., we used
exactly the same patient population, treatment, sample collection and preparation, and analysis as did Zou et al (1). In
CD4⫹ cells there was a nonsignificant decrease in IFN␥
production (15.2% at baseline versus 10.8% at week 6; P ⫽
0.063) and a decrease in IL-2 production (36.2% and 31.9% at
baseline and week 6, respectively; P ⫽ 0.028) (Figure 1B), but
no difference in TNF␣ production (50.9% and 49.0%, respectively; P ⫽ 0.499). In CD8⫹ lymphocytes, infliximab had no
effect on IFN␥ (34.3% and 34.1%, respectively; P ⫽ 0.398),
IL-2 (9.1% and 11.3%, respectively; P ⫽ 0.866) (Figure 1B), or
TNF␣ (18.78% and 24.5%, respectively; P ⫽ 0.866).
Third, in order to exclude a bias caused by possible
differences between SpA subgroups, we reanalyzed our data
focusing on the 9 AS patients included in our original study.
Confirming our previous results in SpA patients, the analysis in
AS patients at baseline and at week 6 of infliximab treatment
showed an increase in IFN␥ levels in CD4⫹ T cells (13.1% and
18.9%, respectively; P ⫽ 0.066) and CD8⫹ T cells (33.6% and
48.1%, respectively; P ⫽ 0.038) and an increase in IL-2 in
CD4⫹ cells (22.0% and 39.1%, respectively; P ⫽ 0.008) and
CD8⫹ cells (9.0% and 15.5%, respectively; P ⫽ 0.008) (Figure
1C). Although TNF␣ was not measured, this study shows no
systematic difference in the Th1/Th2 profile between AS and
other SpA subtypes.
In summary, our results indicate that freezing/thawing
as done by Zou and colleagues (1) induces a systematic bias in
T cell cytokine profiles after PMA/ionomycin stimulation.
Using frozen samples in a protocol completely identical to that
used by those authors, we were unable to confirm the downregulation of IFN␥ and TNF␣ production by T lymphocytes of
1016
LETTERS
Figure 1. Intracellular T lymphocyte cytokine levels analyzed by 4-color flow cytometry after phorbol myristate acetate/ionomycin stimulation.
Results are expressed as the percentage positive cells. A, Effect of freezing/thawing (fresh versus frozen lymphocytes from the same samples) on
interferon-␥ (IFN␥) and interleukin-2 (IL-2) production by CD4⫹ and CD8⫹ T lymphocytes from 5 healthy controls. B, Effect of infliximab
treatment (week 0 versus week 6) on IFN␥ and IL-2 production by CD4⫹ and CD8⫹ T cells from 7 ankylosing spondylitis (AS) patients, after
freezing/thawing. C, Effect of infliximab treatment (week 0 versus week 6) on IFN␥ and IL-2 production by freshly isolated CD4⫹ and CD8⫹ T cells
from 9 AS patients.
AS patients during infliximab treatment. In contrast, data from
studies of freshly isolated lymphocytes confirm that infliximab
restores the production of Th1 cytokines in HLA–B27⫹ AS
patients, as was previously described for different subtypes of
SpA (3).
Dr. Baeten is a Senior Clinical Investigator of the Fund for
Scientific Research–Vlaanderen.
Dominique Baeten, MD, PhD
Bernard Vandooren, MD
Leen De Rycke, MD
Eric M. Veys, MD, PhD
Filip De Keyser, MD, PhD
Ghent University Hospital
Ghent, Belgium
1. Zou J, Rudwaleit M, Brandt J, Thiel A, Braun J, Sieper J.
Down-regulation of the nonspecific and antigen-specific T cell
cytokine response in ankylosing spondylitis during treatment with
infliximab. Arthritis Rheum 2003;48:780–9.
2. Rudwaleit M, Siegert S, Yin Z, Eick J, Thiel A, Radbruch A, et al.
Low T cell production of TNF␣ and IFN␥ in ankylosing spondylitis:
its relation to HLA-B27 and influence of the TNF-308 gene
polymorphism. Ann Rheum Dis 2001;60:36–42.
3. Baeten D, van Damme N, van den Bosch N, Kruithof E, De Vos M,
Mielants H, et al. Impaired Th1 cytokine production in spondyloarthropathy is restored by anti-TNF␣. Ann Rheum Dis 2001;60:
750–5.
4. Braun J, Xiang J, Brandt J, Maetzel H, Hainel H, Wu P, et al.
Treatment of spondyloarthropathies with antibodies against tumour
necrosis factor ␣: first clinical and laboratory experiences. Ann
Rheum Dis 2000;59 Suppl 1:i85–9.
LETTERS
DOI 10.1002/art.20209
Reply
To the Editor:
In their letter discussing our report, Baeten et al raise
some important questions about the investigation of intracellular T cell cytokine staining in general and about the specific
results presented by us. We would like to address these
questions here.
Unlike measuring soluble cytokines by enzyme-linked
immunosorbent assay, standardization of the flow cytometry
method is difficult. There are many variables such as the
medium used for short-term culture of the T cells, the anticytokine antibodies and the type of fluorescence dye coupled to
these antibodies, and the experience and skill of the person
who performs the experiments. These make it impossible, in
our opinion, to compare baseline levels of cytokine-positive
cells in experiments performed by different investigators and at
different time points. Because there is always the risk that the
experimental conditions vary from one time point to another,
we decided in our study to use frozen cells obtained from
patients before and during infliximab treatment. These cells
were thawed and investigated by the same person on the same
day. We believe this affords the best conditions to assess any
change in the potential of T cells to secrete cytokines during a
treatment trial. We agree that there is a difference between T
cell responses using fresh cells versus frozen/thawed cells, but
this difference is stable. However, in contrast to the examples
presented by Baeten et al, we have always found downregulation of T cell function when comparing frozen T cells
with fresh ones.
We indeed reported in a previous publication that we
observed an increase in the number of IFN␥- and TNF␣positive T cells during infliximab therapy in AS patients (1).
However, these were very early results, reported in preliminary
form, from an investigation of individual patients in an overview of the first clinical and laboratory experiences in treating
AS patients with infliximab. The results reported from that
study were obtained after 1 or 2 weeks of treatment. In our
more recent study we did not perform assessments at those
early time points, but only after 6 weeks and 12 weeks of
treatment. Thus, as stated also in our recent publication, we
cannot comment on cytokine production by T cells in the first
days after inflixmab infusion.
The preliminary results prompted us to perform 2
systematic studies in AS patients treated with either infliximab
or etanercept. In those studies, T cells from AS patients before
and during treatment with one of the TNF blockers or with
placebo were investigated at the same time and by the same
person. In the group initially treated with placebo we did not
find any difference in the percentage of cytokine-positive T
cells during placebo treatment, whereas we found the same
changes as in the TNF blockade–treated patients once placebo
treatment was switched to infliximab (recent study) or etanercept (2). Interestingly, in patients treated with infliximab, we
observed a down-regulation of the percentage of TNF␣- and
IFN␥-positive cells, while these cells were up-regulated in
patients treated with etanercept.
Baeten et al reported in 2001 (3) that impaired Th1
cytokine production in SpA patients was restored by antiTNF␣ treatment. However, in their data from 4 weeks after the
1017
second or third infliximab infusion, a time point that is close to
our 6-week postinfusion measurements, there were no significant changes in the number of IFN␥⫹ T cells (20.9% before
infusion versus 22.0% after infusion in the study by Baeten and
colleagues). Furthermore, the results presented in the letter by
Baeten et al show, similar to our results, a down-regulation of
the number of IFN␥⫹ CD4⫹ T cells at week 6 after the
initiation of treatment with infliximab. The small number of
patients tested by those authors and the fact that we found an
even clearer down-regulation of the number of Th1 cytokine–
positive T cells after 12 weeks might explain why this difference
was not significant. For the percentage of TNF␣-positive T
cells as well, we found a clearer down-regulation after 12 weeks
of continuous treatment, compared with 6 weeks.
Finally, restoration of an impaired Th1 response by
infliximab would be in clear contrast to the observed exacerbation of latent tuberculosis in infliximab-treated patients.
Intact function of Th1 cells is crucial to fight Mycobacterium
tuberculosis effectively. Thus, our findings could better explain
this clinical observation.
In summary, we cannot fully explain the differences
found in our study and the experiments reported by Baeten et
al. We have suggested some possible explanations, and we are
confident that we used a proper experimental design in our
study. Future treatment studies should also address this very
important question of whether TNF␣-blocking agents suppress
or restore Th1 function and whether there is a difference
between the available TNF␣-blocking agents with a similar
study design and also including other diseases such as rheumatoid arthritis and Crohn’s disease.
Joachim Sieper, MD
Jiangxiang Zou, MD
Martin Rudwaleit, MD
Jurgen Braun, MD
University Hospital Benjamin Franklin
Berlin, Germany
1. Braun J, Xiang J, Brandt J, Maetzel H, Haibel H, Wu P, et al.
Treatment of spondyloarthropathies with antibodies against tumour
necrosis factor ␣: first clinical and laboratory experiences. Ann
Rheum Dis 2000;59 Suppl 1:i85–9.
2. Zou J, Rudwaleit M, Brandt J, Thiel A, Braun J, Sieper J. Up
regulation of the production of tumour necrosis factor ␣ and
interferon ␥ by T cells in ankylosing spondylitis during treatment
with etanercept. Ann Rheum Dis 2003;62:561–4.
3. Baeten D, van Damme N, van den Bosch F, Kruithof E, De Vos M,
Mielants H, et al. Impaired Th1 cytokine production in spondyloarthropathy is restored by anti-TNF␣. Ann Rheum Dis 2001;60:
750–5.
DOI 10.1002/art.20210
Recurrent pregnancy loss in the context of
antiphospholipid antibodies: comment on the article
by Triolo et al
To the Editor:
We read with interest the article by Triolo et al (Triolo
G, Ferrante G, Ciccia F, Accardo-Palumbo A, Perino A,
1018
LETTERS
Castelli A, et al. Randomized study of subcutaneous low
molecular weight heparin plus aspirin versus intravenous immunoglobulin in the treatment of recurrent fetal loss associated with antiphospholipid antibodies. Arthritis Rheum 2003;
48:728–31). There is indeed renewed controversy regarding the
benefit of low molecular weight (LMW) heparin with or
without aspirin for the treatment of antiphospholipid antibody
(aPL)–positive recurrent pregnancy loss, despite the fact that a
few years ago it was considered the standard of care. It would
be useful to have clarification on 2 issues raised by the study
design.
First, given the lack of consensus in the literature
regarding the value of intravenous immunoglobulin (IVIG) for
aPL-positive recurrent pregnancy loss, it was surprising to see
it referred to as one of the most efficacious therapeutic
regimens for this problem. Could the authors please describe
their rationale for selecting this particular treatment rather
than aspirin alone, or even placebo, as a comparator for LMW
heparin?
Second, although we understand and fully sympathize
with the difficulties in accruing sufficient numbers of patients
who fulfill these inclusion criteria, the small sample sizes in the
2 treatment arms in this study raise some concern. In addition,
there was no information in the Methods section regarding the
expected event rates for either treatment. An analysis of the
raw data, for both first trimester losses and live birth rates, did
not result in the same P values as those provided, and indicated
insufficient statistical power to draw any conclusions regarding
the comparative efficacy of IVIG and LMW heparin.
We and other investigators studying recurrent pregnancy loss in the context of aPL are still struggling to determine the most appropriate treatment. We very much appreciate the authors’ presentation of their experience with these 2
regimens.
C. A. Laskin, MD
C. A. Clark, BSc
K. A. Spitzer, BSc
University of Toronto
Toronto, Ontario, Canada
DOI 10.1002/art.568
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