RHEUMATOLOGY
Rheumatology 2010;49:933–939
doi:10.1093/rheumatology/kep471
Advance Access publication 3 February 2010
Original article
Use of 99mTc-anti-CD3 scintigraphy in the
differential diagnosis of rheumatic diseases
Flávia Paiva Proença Lobo Lopes1, Mário Newton Leitão de Azevedo2,
Edson Marchiori1, Lea Mirian Barbosa da Fonseca1,
Sergio Augusto Lopes de Souza1 and Bianca Gutfilen1
Abstract
Objectives. The aim of this study was to assess the use of anti-CD3, labelled with technetium-99m
scintigraphy, for evaluating the joints of patients with RA, juvenile idiopathic arthritis (JIA), OA and
gouty arthritis, and to establish the diagnosis parameters for each disease.
Methods. We evaluated 2044 joints from 77 patients with rheumatic diseases. The clinical evaluation
consisted of laboratory assays; examination for joint inflammation (pain and/or oedema); and for patients
with RA, the disease activity score of 28 joints. To evaluate the sensitivity and specificity of 99mTc-antiCD3 in detecting disease activity, patients received an injection of the radiopharmaceutical compound
99mTc-anti-CD3, and underwent a scintigraphy scan 1 h later. Scanning was repeated 3 h later. As a
control, after 2 days, the patient was injected with 99mTc-non-specific human immunoglobulins, and
scintigraphy scanning performed at 1 and 3 h after the injection. The intensity of uptake and the pattern
of activity were defined, and Spearman’s correlation and analysis of variance used for statistical
evaluation.
Conclusion. 99mTc-anti-CD3 scintigraphy is a useful method in the differential diagnosis of rheumatic
diseases.
Key words: Scintigraphy, Anti-CD3, Rheumatoid arthritis, Juvenile idiopathic arthritis, Osteoarthritis, Gouty
arthritis, Differential diagnosis, Rheumatic diseases.
Introduction
Adequate management of patients with RA and juvenile
idiopathic arthritis (JIA) sometimes requires differentiation
of RA and JIA from other conditions such as OA and gouty
arthritis (GA), and regular follow-up care. In clinical
1
Serviço de Medicina Nuclear, Departamento de Radiologia and
Serviço de Reumatologia, Departamento de Clı́nica Médica, Hospital
Universitário Clementino Fraga Filho, Universidade Federal do Rio de
Janeiro, Rio de Janeiro, RJ, Brazil.
2
Submitted 1 June 2009; revised version accepted 21 December 2009.
Correspondence to: Bianca Gutfilen, Hospital Universitário Clementino
Fraga Filho, Departamento de Radiologia, Av. Brigadeiro Trompowsky,
s/n., Ilha do Fundão, CEP: 21941-590, Rio de Janeiro, RJ, Brazil.
E-mail: [email protected]
practice, a disease activity score (DAS) is commonly
used for these purposes in patients with RA. In some
cases, even though imaging modalities are desirable,
they are not always available, or have low specificity
and sensitivity. Until now, imaging methods have been
unable to differentiate similar clinical presentations of
RA, JIA, OA and GA, or to evaluate disease activity efficiently, with high specificity and sensitivity [1–3].
In European countries as well as in Latin America, DAS
of 28 joints (DAS-28) is commonly used as a tool for diagnosis of RA and monitoring disease activity. DAS-28 is
endorsed by the European League Against Rheumatism,
but it is a subjective method, based mainly on the clinical
evaluation of pain and assessment of global health.
! The Author 2010. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected]
CLINICAL
SCIENCE
Results. Diagnosis criteria were established for 99mTc-anti-CD3 uptake in different diseases. RA and JIA
showed joint uptake with progressive increase in late images. Gouty arthritis showed joint uptake with
decrease during the late images. Joint uptake was low or absent in patients with OA, although when
present the joint uptake decreased during the examination.
Flávia Paiva Proença Lobo Lopes et al.
Moreover, it may reflect changes that are not related to
the inflammatory process [4–8]. Thus, sensitive methods
are needed to assess the activity and progression of RA,
for improving the patient’s quality of life.
For the past 20 years, several studies have aimed to
develop scintigraphic techniques for assessing the
degree of arthritis intensity in chronic inflammatory autoimmune diseases such as RA and JIA, and monitor the
success of their therapies. The studies have focused on
the use of polyclonal antibodies and mAbs labelled with
technetium-99m (99mTc) [9–13]. Marcus et al. [10] developed an indirect method for labelling the mAb anti-CD3
with 99mTc for the assessment of disease activity in
RA patients. The images showed a strong correlation
with clinical outcome and disease activity, which was
proposed to be a consequence of specific binding to
CD3, in this case to a CD3-receptor–T-cell complex [10].
Subsequently, Martins and co-workers [1, 14] developed
a simple, reproducible, high-efficiency technique for labelling anti-CD3 using a direct method. The technique
allowed the use of 99mTc-anti-CD3 as a radiopharmaceutical for the evaluation of rheumatological diseases like RA
and JIA, in which mature T lymphocytes are associated
with the pathological immunological processes. The
Martins et al. [1] method gave high-quality images and
strong correlation with disease activity, as measured by
the DAS-28 [6], and clinical and laboratory parameters. It
also had the advantage of not showing the side effects of
the Marcus et al. [10] method, in which studies were discontinued when patients experienced tremors and
sudoresis. In addition, 99mTc-anti-CD3 scintigraphy has
the ability to scan the entire patient at once, and use the
uptake pattern as a proxy for measuring disease progression and assessing clinical outcome. The methodology is
essential, as there is no cure for RA or JIA, or means to
prevent it [1–3, 9, 11, 13].
In rheumatic diseases, especially RA and JIA, methods
of diagnostic imaging are used so that physiopathological
processes and morphological changes are recognized
without the need for invasive procedures such as
biopsy. Evaluations must be conducted periodically to
determine the disease stage, which is essential for establishing the best therapeutic approach for each individual
[3, 15]. In addition to evaluating therapeutic success, imaging is used to differentiate RA and JIA from other rheumatological diseases such as OA and GA, which can
eventually present with similar signs, symptoms and radiological findings. Since this is a new scintigraphic method,
diagnostic criteria must be established so that it can be
used by any nuclear medicine department as a reproducible and routine method for patient evaluation. The aim of
this study was to evaluate the use of an anti-CD3 molecule labelled with 99mTc in patients with RA, JIA, OA and
GA, and to establish criteria for differential diagnosis of
each disease.
Materials and methods
The Committee of Ethics in Research of Hospital
Universitário Clementino Fraga Filho (Universidade
934
Federal do Rio de Janeiro) (CIC: 129/03 and CEP: 080/
03) approved the study protocol, and written consent was
obtained from all patients. We evaluated 77 patients with
rheumatic diseases (44 with a clinical diagnosis of RA, 5
with JIA, 15 with OA and 13 with acute GA).
At the initial assessment, medical history, including
laboratory assays was considered. A complete physical
examination covering symptoms, functional status, objective evidence of joint inflammation (pain and oedema,
together or separately), joint mechanical problems and
the presence of extra-articular involvement was given.
All patients had one or more joints with a clinical pattern
of oedema and pain, together or separately, and these
were assessed by the same physician in order to standardize articular examinations.
The patients were diagnosed with RA according to the
revised criteria of the ACR [15] and DAS-28 score was
calculated to determine the pattern of disease activity
for this study. Patients with RA were classified into two
groups: patients with disease in remission (DAS-28 < 2.6)
and patients with disease in activity (DAS-28 > 2.6).
The criteria for JIA was: age <16 years, mono or polyarticular arthritis for at least 6 weeks, the presence of
systemic manifestations, exclusion of other causes of
arthritis and changes in ESR [16].
We considered patients with OA as those who presented at the time of scintigraphy with a positive clinical
examination for the disease, ESR within reference values
of the Westergren method (average rates 0–25 mm/h for
men and 0–30 mm/h for women) and negative Waaler
Rose and/or latex test.
Patients with GA were characterized clinically and by
the presence of hyperuricaemia using conventional
values of 1.5–5.5 mg/dl, and moderately increased ESR
during acute crisis.
Scintigraphies using 99mTc-anti-CD3 were performed
after intravenous injection of 10 mCi (370 MBq) of the
radiopharmaceutical. Anterior planar images of the joints
were obtained 1 and 3 h after injection, using a dual
gamma camera (Millennium MG; GE Medical Systems,
Milwaukee, WI, USA) with low-energy, high-resolution,
parallel whole collimators. Images were acquired at a
matrix size of 256 256. Counts were acquired for 10
min in a 15% window centred at 140 KeV. Images taken
at 1 and 3 h were evaluated for intensity of uptake and
pattern of activity. Increase or decrease of uptake over
time was measured as counts per minute, with a correction for decay.
To evaluate the sensitivity and specificity of
99mTc-anti-CD3 scintigraphy in detecting disease activity, a negative control scan was performed on all patients,
after an interval of 2 days, using a pool of non-specific
human immunoglobulins labelled with Tc-99m. Images
were acquired using the same protocol as for 99mTcanti-CD3.
Spearman’s correlation and analysis of variance were
used as statistical tools for comparing scintigraphic findings and clinical and laboratory parameters. Results were
considered significant at P < 0.05. All IP and MCP joints
www.rheumatology.oxfordjournals.org
www.rheumatology.oxfordjournals.org
(21.1)
(6.5)
(2.1)
(1.1)
(3.2)
(4.7)
80
3
4
10
97
83a (69.7)
25a (75.7)
0
0
108 (25.0)
(9.7)
(23.6)
(77.8)
1232
140
360
312
2044
RA
JIA
OA
GA
Total joints
Values are represented as n (%). aJoints with high uptake that increased at 3-h image; bjoints with mild uptake, decreasing at later images; cjoints with moderate uptake that decreased
at later images.
(78.3)
(22.1)
(19.4)
(95.8)
(66.8)
965
31
70
299
1365
60a (88.2)
73a (100.0)
1b (16.6)
3c (100.0)
137 (91.3)
(5.5)
(52.1)
(1.7)
(1.0)
(7.3)
68
73
6
3
150
Pain +
oedema
Diseases
Pain
Oedema
Abnormal uptake
of 99mTc-anti-CD3
in patients with
oedema
Total
joints
evaluated
Advances in the current knowledge of the physiopathology of RA and JIA are leading to the development of new
medicines that offer patients the opportunity to stabilize
the progression of their disease and improve their quality
of life. Several drugs have been studied in clinical trials
and evaluated by radiological examination to test their
effectiveness. The sensitivity and specificity of these
imaging methods are not always adequate, reflecting
the need for further studies on non-invasive diagnostic
methods [3, 13].
One promising method is the use of 99mTc-anti-CD3.
This radiopharmaceutical shows specificity for mature T
lymphocytes, which are a part of the physiopathological
processes of RA and JIA. The different uptake patterns
observed by dual-time scintigraphy scanning reflect the
different roles of the TCR–CD3 complex in the activation
of T lymphocytes in the inflammatory process of different
rheumatic diseases. The inflamed synovia in RA and JIA
are due to major T-lymphocyte activation when the TCR–
CD3 complex recognizes an antigen. A decrease in synovial clearance has also been described for these diseases
[17, 18]. Therefore, the uptake of 99mTc-anti-CD3 would
be expected to be increasingly positive in joints affected
by RA or JIA.
TABLE 1 Clinical and 99mTc-anti-CD3 scintigraphy evaluation by joint
Discussion
Abnormal
uptake of
99mTc-anti-CD3
in patients
with pain
Number of joints
Abnormal uptake
of 99mTc-anti-CD3
in patients with
pain + oedema
No clinical
complaints
No side effects were observed after administration of the
radiopharmaceuticals, even after multiple scintigraphic
examinations. In total, 1232 joints were evaluated from
patients with RA, 140 from patients with JIA, 360 from
patients with OA and 312 from patients with GA (Table 1).
We observed that in RA and JIA, the initial scan showed
a high uptake per affected joint at the first scan, which
increased at the 3-h scan. Joint uptake was absent or
minimal in cases of OA, with a subsequent decrease
observed in the second scan at 3 h. Moderate joint
uptake was observed in the initial scan in patients diagnosed with GA, with the mean uptake decreasing at the
second scan. Thus it was possible to differentiate RA
(Fig. 1) and JIA (Fig. 2) from OA (Fig. 3) and GA (Fig. 4)
according to the uptake pattern. The method was unable
to differentiate patients with RA in disease remission, who
showed a normal scan, from those with OA. Anterior
images of affected joints showed that the 99mTc-antiCD3 built up as a layer, not only in the joint directly, but
also in the periarticular region, suggesting selective
uptake by inflamed synovia. The results observed in
99mTc-anti-CD3 scintigraphies strongly correlated with
the DAS-28 parameters (Table 2). Table 3 shows a
comparison of the uptake of 99mTc-anti-CD3 scintigraphy
at 1 and 3 h. No statistically significant differences were
observed with regard to individual assessment of joints
or their evaluation as a group.
119
33
280
0
432
Results
58a (72.5)
3a (100.0)
1b (25)
10c (100.0)
72 (74.2)
Abnormal
uptake of
99mTc-anti-CD3
in patients with
no clinical complaints
were grouped as one articulation because of vagueness in
patient reports about which joint was in pain.
34b (3.5)
0
15b (21.4)
0
49 (3.5)
99mTc-anti-CD3 in rheumatic diseases
935
Flávia Paiva Proença Lobo Lopes et al.
FIG. 1 Patient classified with high-activity RA, according to DAS-28.
Scintigraphy with 99mTc-anti-CD3 of the knees shows an increase in the uptake of these areas in late images. Images
taken (A) 1 h and (B) 3 h after endovenous injection of the radiopharmaceutical.
FIG. 2 Patient with active JIA. Scintigraphy with 99mTc-anti-CD3 of the knees shows increase in the uptake of these
areas in late images.
Images taken 1 h (A) and 3 h (B) after endovenous injection of the radiopharmaceutical.
FIG. 3 Patient with OA.
Images of 99mTc-anti-CD3 scintigraphy showing a normal pattern (no joint uptake) in a patient with OA, 1 h after injection
of the radiopharmaceutical (A). The same pattern, observed in the late images (3 h), considered a normal examination
according to the parameters established in this study (B).
936
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99mTc-anti-CD3 in rheumatic diseases
FIG. 4 A 49-year-old patient with acute crisis of GA on the left ankle, treated with diclofenac and colchicine.
Physical examination shows the presence of intense pain and oedema. (A) Scintigraphy with 99mTc-anti-CD3 reveals
uptake areas mainly in the left ankle, with gradual decrease in late images (3 h) (A). Reduction in the number of radiation
counts per minute (arrows) (B).
TABLE 2 Correlation between DAS-28 parameters and
99mTc-anti-CD3 scintigraphy results expressed
according to Spearman’s test (P < 0.05)
Parameters
99mTc-anti-CD3
scintigraphy
DAS-28
Disease in remission
Disease in activity
Painful joints
Swollen joints
ESR
*P < 0.05; **no
Spearman’s test.
statistical
0.856*
0.950*
0.513*
0.563*
0.289**
significance
according
to
Joints affected by GA contain monourate monosodium
crystals, which lead to an inflammatory process. Recent
studies provide new knowledge about the physiopathology of the inflammatory response elicited by GA.
The urate crystals bind to innate immune receptors, leading to cell activation, typically of phagocytic cells, as well
as the release of cytokines and chemokines that orchestrate the initial inflammatory response [19]. Based
on these data, a possible explanation for the 99mTcanti-CD3 uptake, as observed in the early scan taken 1 h
after injection, is increased vascularity and cell infiltration
in patients for whom the main complaint was oedema,
and for whom pain and oedema occurred together.
Since T lymphocytes are not activated by the TCR–CD3
complex, a decrease in uptake is observed in later
images. In painful joints with GA, the inflammatory process may not be present, which explains the absence of
radiopharmaceutical uptake in the affected joints.
OA is a chronic degenerative disease in which the
inflammation process is not acute, and is therefore
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independent of the activation of T lymphocytes by the
TCR–CD3 complex. Consequently, significant uptake of
anti-CD3 labelled with technetium was not expected.
During the remittance phases of RA, the inflammatory
process caused by activation of T lymphocytes by the
TCR–CD3 complex diminishes or disappears [20].
Consequently, 99mTc-anti-CD3 uptake is expected to
be minimal or absent. For this reason, this method
cannot differentiate patients with RA in remission from
those with OA. Synovitis in patients with OA indicates activation of T lymphocytes by the TCR–CD3 complex, which
is difficult to differentiate from RA. In these cases, however, the finding of an abnormal scan may be an indication
for early treatment of these patients, in order to avoid
bone and cartilage destruction.
Current methods of assessing the degree of RA and JIA
disease activity do not allow a precise diagnosis, because
they lack specificity, and indirectly assess disease activity
based on painful and oedema joints. The assessment of
pain is directly related to trauma or inflammation, and
oedema may or may not be present in affected joints.
Moreover, in some studies, pain was found to be occasionally associated with bone destruction, while oedema
was related only to events of synovitis or inflammation [3].
These findings are consistent with the negative results of
99mTc-anti-CD3 scintigraphies observed in 36 joints of
patients with RA, 8 joints of patients with JIA and all
joints of patients with OA and GA. Therefore, the use of
less subjective methods for diagnosis and monitoring is
essential.
In patients with RA, 99mTc-antiCD3 scintigraphy
showed an increased joint uptake in 83 (69.7%) of 119
painful joints. For the presence of oedema, increased
uptake of the radiopharmaceutical was observed in 58
(72.5%) of 80 joints. When oedema and pain are considered together, scintigraphy and clinical findings were concordant in 60 (88.2%) of 68 joints. The 99mTc-anti-CD3
937
Flávia Paiva Proença Lobo Lopes et al.
TABLE 3 Comparison of uptake of 99mTc-anti-CD3 scintigraphy in 1- and 3-h images according to disease
Diseases
Number of joints
clinically affecteda
RA
JIA
OA
GA
267
109
290
13
Number of joints with
abnormal uptake of
99mTc-anti-CD3
in 1-h image
235
101
17
13
(88.0)
(92.7)
(0.34)
(100)
Number of joints with
abnormal uptake of
99mTc-anti-CD3
in 3-h image
201 (75.3)
101 (92.7)
0
0
Values are represented as n (%), unless otherwise mentioned. aWith pain and/or oedema.
scintigraphy showed a significant correlation (P < 0.05)
between radiopharmaceutical uptake and joints with
oedema or pain, allowing the differentiation of patients
with active synovitis from those in disease remission
scored by DAS-28. No correlation was seen between
age or sex and 99mTc-anti-CD3 scintigraphy results.
Table 2 shows the comparison between DAS-28 parameters and 99mTc-anti-CD3 scintigraphy. In patients
with JIA, 99mTc-anti-CD3 scintigraphic findings were
consistent in most cases. From 109 joints of patients
with JIA with clinical complaints of pain and/or oedema,
101 were detected by 99mTc-anti-CD3. The eight joints
with discordant results were those in which the clinical
complaint was pain.
For joints of OA patients in which clinical examination
showed the presence of pain, all scintigraphies were considered normal, with no radiopharmaceutical uptake. In
joints (n = 4) where the presence of oedema was the
main complaint, in only one joint did the scan show mild
uptake of the radiopharmaceutical. For six joints with pain
and oedema, only one scintigraphy showed mild uptake of
radiopharmaceutical, and 21.4% of joints without changes
by clinical examination showed mild radiopharmaceutical
uptake. One patient clinically diagnosed with OA presented an ESR above the reference value, and corresponding 99mTc-anti-CD3 scintigraphic images showed
uptake areas in the knees and hands, with increased
uptake in delayed images, which was considered an indication of RA. In these joints (n = 4), the patient had pain
and oedema on physical examination. This case was
referred to the Department of Rheumatology for further
clinical evaluation, where a diagnosis of RA was confirmed. For all patients with GA, clinical and physical
examinations were compliant with changes in the
99mTc-anti-CD3 scintigraphy for joints with oedema
(n = 10) and pain and oedema (n = 3).
The ESR, despite being widely used for monitoring
patients with RA and JIA, is questionable, as it leads to
inconclusive results, with many false positives and false
negatives reported even in healthy patients [21]. In this
study, 99mTc-anti-CD3 scintigraphy had no significant
correlation with ESR, consistent with previous studies in
which the value of ESR for assessing RA and JIA was
found to be debatable [21]. The ESR is not considered a
standard test for the diagnosis of RA and JIA, since
938
changes in ESR do not accurately characterize the stage
of disease. In addition, some discordant examinations
of elderly patients indicated that deviations can be attributed to other diseases or even be inherent in these
patients [21].
Currently, polyclonal antibodies and mAbs labelled with
radionuclides by different methods, such as 99mTcanti-CD3, have been used for the diagnosis of disease
by immunoscintigraphy [1, 10–12]. In many cases, for
example in the Marcus et al. study [10], uptake of
99mTc-anti-CD3 by the joint indicated synovitis before
clinical evidence of the condition. However, this study
was discontinued because of side effects. Although
these reversed spontaneously within a few hours, they
are a limiting factor to using 99mTc-anti-CD3 marked by
that method. In this study, using a direct method, we
obtained results consistent with clinical findings. Uptake
of the radiopharmaceutical was observed in joints
affected by the disease, without the observation of any
side effects after scintigraphy.
Scintigraphy with 99mTc-polyclonal immunoglobulin G
has been used for high-specificity detection of synovial
inflammation in RA, and for distinguishing disease activity
and remission, although the correlation of scintigraphic
shoulders with clinical findings is low [11]. In this study,
significant correlation was observed for RA and pain
(69.7%), oedema (72.5%) and when oedema and
pain were considered together (88.2%); and for JIA and
pain (75.7%), oedema (100.0%) and oedema and pain
(100.0%). These findings are probably attributable to the
high specificity of anti-CD3 for the physiopathology of RA
and JIA. The use of non-specific immunoglobulins labelled
with 99mTc has also been reported in RA and JIA
patients. However, because uptake of these radiopharmaceuticals is non-specific, results varied depending
on blood flow and, in cases of synovitis, endothelial
permeability, limiting their use [12].
Scintigraphy results with 99mTc-anti-CD3 showed a
high correlation between clinical findings and laboratory
assays in the evaluation of MCP and IP joints, which are
considered difficult to diagnose. However, a limitation of
the method was the evaluation of the hip joints and spine,
because the normal biodistribution of 99mTc-anti-CD3
in the liver and kidneys obscures diagnosis in these
regions. Another limitation of the method is the inability
www.rheumatology.oxfordjournals.org
99mTc-anti-CD3 in rheumatic diseases
to differentiate a patient without disease, who shows
normal scan, from a patient with OA.
The establishment of the diagnostic parameters developed in this study made it possible to differentiate RA and
JIA from the other rheumatic diseases such as OA and
GA. Moreover, the method is easily reproducible using
these criteria. In addition, the costs of using 99mTc-antiCD3 for routine examination of patients with RA and JIA
are relatively low, since most of the reagents are routinely
used.
In conclusion, this study demonstrates that 99mTc-antiCD3 scintigraphy is a useful tool for diagnosis and
follow-up of different rheumatic diseases, using the criteria established here. The technique has the advantages of
simplicity, reproducibility and reliability, particularly since
no other specific, non-invasive methods are available for
adequate evaluation of these patients.
Rheumatology key messages
99mTc-anti-CD3 can help in the differential diagnosis of rheumatic diseases.
. 99mTc-anti-CD3 strongly correlates with clinical
findings for patients with RA.
.
Disclosure statement: The authors have declared no
conflicts of interest.
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