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First published online November 26, 2007
British Journal of Radiology (2008) 81, 25-29
© 2008 British Institute of Radiology
doi: 10.1259/bjr/63780400
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Full paper

Monitoring rheumatoid arthritis synovitis with 99mTc-anti-CD3

F P P Martins, MSc1, B Gutfilen, PhD1, S A L de Souza, MSc1, M N L de Azevedo, PhD2, L R Cardoso, PhD2, R Fraga, MSc3 and L M B da Fonseca, PhD1

1 Departamento de Radiologia and 2 Departamento de Clínica Médica, Universidade Federal do Rio de Janeiro, Faculdade de Medicina, Hospital Universitário Clementino Fraga Filho, Rio de Janeiro, 3 Universidade Federal de Minas Gerais, Departamento de Clínica Médica, Juiz de Fora, Brazil

Correspondence: Prof. B Gutfilen, PhD, Univ Federal do Rio de Janeiro, Hospital Universitário Clementino Fraga Filho, Dep de Radiologia, sub-solo, Av Brigadeiro Trompovsky s/no, Ilha do Fundão, CEP 21941590 Rio de Janeiro, Brasil. E-mail: bgutfilen{at}hucff.ufrj.br


   Abstract
Top
 Abstract
Introduction
 Methods and materials
 Results
 Discussion
 Conclusions
 References
 
The aim of this study was to investigate the feasibility of using a monoclonal antibody (OKT3) labelled with technetium-99m (99mTc) to monitor disease activity in patients with rheumatoid arthritis. We evaluated 38 patients who were diagnosed with rheumatoid arthritis and classified as Classes II and III after functional assessment (according to the revised criteria specified by the American College of Rheumatology). Two sets of planar anterior images of the patients' wrists, metacarpophalangeal and interphalangeal joints, elbows, shoulders and knees joints were obtained 1 h and 3 h after the injection of 99mTc–OKT3. The scintigraphic findings showed significant correlation (p<0.05) between the radiopharmaceutical accumulation of 99mTc–OKT3 and swollen joints, tender joints and the visual analogue scale. They were able to differentiate patients in remission from patients with active synovitis, according to DAS 28. In contrast, there was no correlation between the radiopharmaceutical accumulation and the patients' age, gender, duration of disease or erythrocyte sedimentation rate. A relatively high disease activity score of 28 joints (4.08±1.74) was found in the majority of patients. In conclusion, 99mTc–OKT3 scintigraphy is a reliable and objective method for detecting synovial activity, and can be used to observe disease prognosis.


   Introduction
Top
 Abstract
 Introduction
Methods and materials
 Results
 Discussion
 Conclusions
 References
 
Rheumatoid arthritis (RA) is a chronic inflammatory disease of unknown aetiology that mainly involves the joints but which also has extra-articular manifestations. It is often progressive and results in joint pain, stiffness and swelling. Although its manifestations are variable, persistent inflammation and proliferation of the synovium (pannus) are observed [1, 2].

To date, it has been assumed that most of the tissue damage associated with rheumatoid synovitis is caused by activated macrophages and synoviocytes, whereas tissue-infiltrating lymphocytes have been suspected to orchestrate the inflammatory response [3, 4]. Studies have also demonstrated the presence of CD4+ and CD8+ T lymphocytes in active RA. Thus, these cells are thought to play a central role in the pathogenesis of the disease [2–5].

Clinical and laboratory assays to evaluate synovitis activity are usually indirect, non-specific and rather subjective, and therefore an objective and accurate method to measure disease activity is still needed to determine the efficacy of clinical trials. Although several radiopharmaceuticals have been used for this purpose, bone-seeking agents accumulate non-specifically in arthritic joints because of increased vascular permeability. In addition, they reflect bone metabolism rather than synovial inflammation [1, 6–8].

As T lymphocytes are presented in RA pathogenesis, the use of radioactive-labelled monoclonal antibodies against such cell populations is an attractive method for evaluating disease activity, and may offer a more specific method for monitoring disease [9, 10]. OKT3 is an immunosuppressant drug consisting of a specially engineered monoclonal antibody directed against the CD3 antigen of human T cells, and is used in renal, heart and kidney transplantations at a dose of 5 mg d–1. It is a Class G, Type 2a immunoglobulin (IgG2a) with a heavy chain of 50 kDa and a light chain of 25 kDa [11, 12]. In this study, we investigated whether technetium-99m (99mTc)–OKT3 scintigraphy detects synovial inflammation in patients with RA.


   Methods and materials
Top
 Abstract
 Introduction
 Methods and materials
Results
 Discussion
 Conclusions
 References
 
38 consecutive patients who met the American College of Rheumatology criteria for RA, and who were classified as Class II or III according to functional assessment [6], were evaluated. The Institutional Review Board of the Hospital Universitário Clementino Fraga Filho approved the study protocol, and fully informed written consent was obtained from all patients before clinical and 99mTc–OKT3 scintigraphic evaluation. Patients who had traumatic, septic or microcrystalline arthritis, previous joint surgery or isotopic synovectomy within the past 24 months were excluded from the study.

Treatment, which included oral steroids, non-steroidal anti-inflammatory drugs and disease-modifying anti-rheumatic drugs, remained unchanged during the course of the study. Clinical and laboratory data collected included age, sex, erythrocyte sedimentation rate (ESR), disease activity score of 28 joints (DAS-28; considered, in this study, to be the gold standard in the assessment of joint inflammation), disease duration and rheumatoid factor. Clinical evaluation was performed by the same rheumatologist throughout the study. The DAS-28 was calculated according to the number of swollen and tender joints using 28 joint counts (28 tender and 28 swollen); the ESR was measured in millimetres per hour. In addition, patients' general health (GH) was measured on a visual analogue scale (VAS) from 0 mm to 100 mm, according to the physician evaluation [13]. Joint swelling and tenderness were scored as "present" or "absent". The joints evaluated clinically and scintigraphically were the wrist, metacarpophalangeal and interphalangeal joints, elbows, shoulders and knees. Bilaterally, a total of 28 joints in each patient, and 1064 joints in the entire group, were evaluated.

The DAS-28 was calculated using the formula below:


Formula 001

The DAS-28 produced a number between 0 and 10, indicating the disease status. A number <2.6 presumes disease that it is remission; 2.6–3.2 indicates low disease activity; 3.2–5.1 indicates moderate disease activity, and >5.1 indicates high disease activity. In this study, DAS-28 >2.6 was considered as active synovitis.

OKT3 (150 µg) was labelled with 99mTc according to the technique previous described by Martins and Gutfilen [11]. Briefly, OKT3 was incubated with a chelant and a reductor agent, and then 185 MBq (5 mCi) of 99mTc was dispensed. Filtration with Milipore 0,45 µ followed to separate unbound 99mTc and colloid from 99mTc–OKT3.

Scintigraphs were obtained within 2 days of the DAS-28 evaluation using a Siemens Gamma Camera (Siemens Diacam; Siemens, Erlangen, Germany) set for the major energy peak of 99mTc (140 keV) using a 15% window. Planar anterior views of the regions of interest were obtained 1 h and 3 h after endovenous injection. All images were acquired for 5 min. Scintigraphic scans were evaluated visually and independently by two nuclear medicine specialists who were unaware of each patient's clinical status. Each joint was scored as "present" or "absent" depending on the uptake pattern: present (definite uptake maintained in late images after 3 h) or absent (no uptake or faint uptake with no accumulation of the radiopharmaceutical in the 3 h image). If there was a discrepancy on scores, the decision was made by consensus. Metacarpophalangeal and interphalangeal joints scores were obtained by averaging the results of the 10 joints of each hand because the area of articular surface exhibited by each joint is relatively small compared with that in other peripheral joints [14].

Spearman's correlation and variance analysis were used as statistical tools to compare scintigraphic data and clinical and laboratory parameters. p-values of <0.05 were considered significant. Sensitivity was defined by accumulation of 99mTc–OKT3 scintigraphy in the joints showing swelling and/or tenderness, and specificity was defined as a lack thereof.


   Results
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 Abstract
 Introduction
 Methods and materials
 Results
Discussion
 Conclusions
 References
 
28 out of 38 patients (73.7%) tested positive for rheumatoid factor, and a relatively high average DAS-28 (4.08±1.74) was found. Table 1Go summarizes clinical information for all of the patients studied.


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  		Table 1. Demographic, clinical and laboratory characteristics of patients evaluated with99mTc–OKT3

 
The labelling yield of 99mTc–OKT3 was over 90% and no side effects of its administration were observed during the study. Anterior spot views of the inflamed joints showed that 99mTc–OKT3 accumulates as a layer in, and directly next to, the joint space, suggesting a selective uptake by the inflamed synovium. Abnormal uptake of 99mTc–OKT3 was observed in 73 (68.8%) out of 111 joints with tenderness. When swelling was considered, 56 (71.8%) out of 78 joints showed abnormal uptake. When swelling and tenderness were both present, 59 (88.1%) out of 67 joints were diagnosed.

99mTc–OKT3 scintigraphic results were compared with clinical assessment of tenderness and swelling (Table 2Go). 99mTc–OKT3 uptake/accumulation showed a significant correlation (p<0.05) with swollen joints, tender joints and the VAS score, and was able to distinguish patients with active synovitis from those in remission of disease according to DAS-28. In contrast, no correlation between 99mTc–OKT3 uptake and patients' age, sex, duration of disease or ESR was found. Table 3Go compares all parameters used to calculate DAS-28 and 99mTc–OKT3 scintigraphy.


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  		Table 2. 99mTc–OKT3 sensitivity and specificity for tenderness and swelling

 

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  		Table 3. Correlation between scintigraphic, clinical and laboratory variables in patients evaluated with99mTc–OKT3 (Spearman's correlation)

 
Figure 1Go shows a 99mTc–OKT3 scintigraphy of a patient in remission of disease, whereas Figure 2Go shows 99mTc–OKT3 scintigraphy of a patient with high disease activity, according to DAS-28.


Figure 1
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  		Figure 1. Normal pattern of99mTc–OKT3 scintigraphy of the knees in a patient with RA. Scans were obtained (a) 1 h and (b) 3 h after endovenous injection of the radiopharmaceutical in a patient with medium activity disease (according to DAS-28). The images show no areas of uptake.

 

Figure 2
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  		Figure 2. Patient with RA classified as high-activity disease, according to DAS-28. 99mTc–OKT3 scintigraphy of the knees shows areas of uptake in these joints (a) 1 h and (b) 3 h after endovenous injection of the radiopharmaceutical.

 

   Discussion
Top
 Abstract
 Introduction
 Methods and materials
 Results
 Discussion
Conclusions
 References
 
Monitoring disease activity in patients with RA is still challenging owing to the fact that its most defining feature is chronicity, which by definition takes time to identify. Furthermore, there is a lack of specific methods for this purpose. Even though DAS-28 has been widely used in Europe and Brazil to audit responses to treatment, its value is questionable, as the main response criterion in individual patients is the VAS for which there are often score conflicts between the patient and the clinician. In these cases, misinterpretation may be avoided by careful evaluation of individual components of the DAS-28 [15–19]. Our results showed that 99mTc–OKT3 uptake correlates with active inflammation (p<0.05). However, there was no correlation between these findings and either the VAS or the ESR.

The use of the ESR has limited utility in RA despite being largely used to guide the clinician. Several studies have found it not useful as a screening test for the presence of disease in asymptomatic patients; therefore, it is not a gold standard in disease diagnosis or follow-up. It has been shown that no specific entity is ruled "in" or "out" by an elevated or normal ESR. As such, when clinical data suggest a specific diagnosis, it should be investigated regardless of the ESR [20, 21]. In this study, there was no statistical significance between 99mTc–OKT3 and the ESR, demonstrating that it is of low value in the follow-up of these patients. These data also suggest that 99mTc–OKT3 uptake was able to detect synovitis and inflammation prior to laboratory changes in the ESR, and that this might be a useful diagnostic marker of early RA.

Conventional methods for measuring the degree of disease activity in RA do not provide sufficient or reliable information, as they are non-specific and indirect. Pain may relate to damage and/or inflammation, and swelling might not be present in inflamed joints [7, 15, 22, 23]. Compared with other imaging techniques, advantages of 99mTc–OKT3 scintigraphy include the possibility of imaging all joints and detecting its inflammation in an early phase before joint destruction.

The imaging gold standard for RA is conventional radiography, which is widely available, reproducibile, reasonably cost-effective and familiar. Although this method has its advantages, the exam cannot identify synovitis in its early stages. In addition, there are reports of discordance between clinical disease activity and the progression of erosion, which conceptually limits the use of radiography, as it may not reflect the inflammatory process [16, 17, 23].

The use of MRI in the assessment of early RA is becoming more and more important. Several reasons have contributed to this, including the development of MRI sequences for evaluating different tissues and the unparalleled multiplanar imaging of soft tissue and bone. However, MRI is expensive, time consuming and still not generally available for routine use in some countries, including Brazil [24, 25].

Several studies have demonstrated the many advantages of high-frequency ultrasound. It is more accurate for detecting joint effusion and synovitis than either MRI or arthroscopic visualization. It allows imaging of soft tissues, as well as bone, and can be repeated safely. In addition, the power Doppler ultrasound detects indirect signs of increased vascularization associated with musculoskeletal soft-tissue inflammatory and infectious diseases. One weakness, however, is that it is limited by the absence of examination protocols or standard settings for the evaluation of RA; it also depends on the operator's skill [26–28].

99mTc-pertechnetate and 99mTc-phosphate compounds have been used in patients with RA for over a decade to detect disease activity. However, bone-seeking agents reflect bone blood flow and bone metabolism only and, although substantial bony changes may accompany synovitis, bone remodelling may not correlate linearly with the degree of synovitis and can persist following acute synovitis. Lately, different radiopharmaceuticals have been tested, such as 67Ga-citrate, 111In-chloride, 99mTc-labelled liposomes, 99mTc-nanocolloid, 111In-lymphocytes, 111In- or 99mTc-labelled human non-specific immunoglobulins and 111In-labelled antibodies against CD3, CD4, E-selectin, tumour necrosis factor-{alpha}, interleukin (IL)-1, IL-2, IL-6 and somatostatin; however, most of these are too expensive for routine use and the labelled lymphocytes are unstable [9]. 99mTc–OKT3 scintigraphy, which has been shown to be a simple technique, has low cost and is stable for over 24 h. Kinne et al [10] used an anti-CD4 monoclonal antibody to evaluate RA arthritic joints. In experimental studies in rats with adjuvant arthritis, joint uptake of an anti-rat monoclonal antibody did not differ from that of an isotype-matched control monoclonal antibody, with irrelevant specificity. As OKT3 is directed to the CD3 complex, which is associated with the T cell receptors CD4 and CD8 that are expressed in RA, we obtained high average specificity (>74.5%) in all studied joints.

Marcus et al [9], using a different labelling technique with 99mTc–OKT3, showed a high correlation between visual and quantitative analyses of the scans. However, side-effects noted in the patients (shaking chills and neck pain approximately 1 h after injection) limited their studies. In our study, the procedure was well tolerated and no side-effects were observed. Based on their studies, we did not use a quantitative analysis of 99mTc–OKT3 scintigraphy.

Imaging of 111In-E-selectin expression in RA could be a valuable alternative to 99mTc-labelled non-specific scintigraphy, as it is a more specific and more sensitive targeting method. However, studies are time consuming, as images cannot be performed on the same day. Moreover, 99mTc has better physical properties and is widely available [29]. As such, 99mTc–OKT3 may be a valuable alternative to these methods because of its biological, physical and chemical properties.


   Conclusions
Top
 Abstract
 Introduction
 Methods and materials
 Results
 Discussion
 Conclusions
References
 
Our results showed that 99mTc–OKT3 uptake correlated with active inflammation. In RA, the exam was able to distinguish active synovitis from remission of the disease. In this way, this study demonstrates the potential application of 99mTc–OKT3 in the evaluation of disease activity in RA characterized by lymphocytic infiltration of the joint tissue and possibly its early diagnosis.

Received for publication February 6, 2006. Revision received February 8, 2007. Accepted for publication March 5, 2007.


   References
Top
 Abstract
 Introduction
 Methods and materials
 Results
 Discussion
 Conclusions
 References
 

  1. King R. Rheumatoid arthritis. Arthritis Rheum 2002;48:216–26.
  2. Kim JM, Weisman MH. When does rheumatoid arthritis begin and why do we need to know? Arthrithis Rheum 2000;43:473–84.[CrossRef]
  3. Namekawa T, Wagner UG, Goronzy JJ, Weyand CM. Functional subsets of CD4 T cells in rheumatoid synovitis. Arthritis Rheum 1998;41:2108–16.[CrossRef][Medline]
  4. Breedveld FC, Verweij CL. T-cells in rheumatoid arthritis. Br J Rheumatol 1997;9:236
  5. Abbas AK, Lichtman AH, Pober JS. Imunologia celular e molecular. 2nd edition. Rio de Janeiro: Revinter; 1998.
  6. American College of Rheumatism Association. 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;39:723–31.[CrossRef]
  7. van der Heijde DMFM, Martin van't HOF, van Riel PLCM, van de Putte LB. Validity of single variables and indices to measure disease activity in rheumatoid arthritis. J Rheumatol 1993;20:538–41.[Medline]
  8. Kraus VB. Pathogenesis and treatment of osteoarthritis. Med Clin N Am 1997;81:85[CrossRef][Medline]
  9. Marcus C, Thakur ML, Huynh TV, Louie M, Leibling M, Minami C, et al. Imaging rheumatic joint diseases with anti-T lymphocyte antibody OKT3. Nucl Med Comm 1994;15:824–30.[CrossRef][Medline]
  10. Kinne RW, Becker W, Schwab J. Imaging rheumatoid arthritis joints with technetium-99m labelled specific anti-CD4 and non-specific monoclonal antibodies. Eur J Nucl Med 1994;21:176–80.[Medline]
  11. Martins FPP, Gutfilen B. Estudo da marcação do anticorpo monoclonal OKT3 com tecnécio-99m: aplicações clínicas. Radiol Bras 2002;35:286
  12. Martins FPP, Souza SAL, Gonçalves RT, Fonseca LM, Gutfilen B. Preliminary results of 99mTc-OKT3 scintigraphy to evaluate acute rejection in renal transplants. Transplantation Proceedings 2004;36:2664–7.[CrossRef][Medline]
  13. Prevoo ML, van't Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. Modified disease activity scores include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 1995;38:44–8.[Medline]
  14. Jamar F, Manicourt DH, Leners N, Berghe MV, Beckers C. Evaluation of disease activity in rheumatoid arthritis and other arthrides using 99mTc-labeled nonspecific human immunoglobulin. J Rheumatol 1995;22:850–4.[Medline]
  15. van Riel PL, Schumacher HR. How does one assess early rheumatoid arthritis in daily clinical practice? Pract Res Clin Rheumatol 2001;15:67–76.[CrossRef]
  16. Welsing P, Landewé R, van Riel PL, Boers M, van Gestel AM, van der Linden, et al. The relationship between disease activity and radiologic progression in patients with rheumatoid arthritis: a longitudinal analysis. Arthritis Rheum 2004;50:2082–93.[CrossRef][Medline]
  17. Wolfe F, Sharp JT. Radiographic outcome of recent-onset rheumatoid arthritis: a 19-year study of radiographic progression. Arthritis Rheum 1998;41:1571–82.[CrossRef][Medline]
  18. Leeb BF, Andel I, Sautner J, Nothnagl T, Rintelen B. The DAS 28 in rheumatoid arthritis and fibromyalgia patients. Rheumatology 2004;43:1504–7.[Abstract/Free Full Text]
  19. Gardiner PV, Bell AL, Taggart AJ, Wright G, Kee F, Smyth A, et al. A potential pitfall in the use of disease activity score (DAS 28) as the main response criterion in treatment guidelines for patients with rheumatoid arthritis. Ann Rheum Dis 2005;54:969–70.
  20. Santos VM, Cunha SFC, Cunha DF. Velocidade de sedimentação das hemácias. Rev Ass Med Bras 2000;46:232–6.
  21. Sox HC, Liang MH. The erythrocyte sedimentation rate. Guidelines for rational use. Ann Intern Med 1986;104:512–23.
  22. Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, et al. American College of Rheumatology Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995;38:727–35.[Medline]
  23. Cohen MD. Update: treatment of rheumatoid arthritis. Arthritis Rheum 2001;45:530–2.[CrossRef]
  24. Dawson J, Gustard S, Beckman N. High-resolution three-dimensional magnetic resonance imaging for the investigation of knee joint damage during the time course of antigen-induced arthritis in rabbits. Arthritis Rheum 1999;42:119–28.[CrossRef][Medline]
  25. Gandy SJ, Brett AD, Dieppe PA, Keen MC, Maciewicz RA, Taylor CJ, et al. Measurement of cartilage volumes in rheumatoid arthritis using MRI. Br J Radiol 2005;78:39–45.[Abstract/Free Full Text]
  26. Grassi W, Cervini C. Ultrasonography in rheumatology: an evolving technique. Ann Rheum Dis 1998;57:268–70.[Free Full Text]
  27. Terslev L, Torp-Pedersen S, Savnik A, von der Recke P, Qvistgaard E, Danneskiold-Samsoe B, et al. Doppler ultrasound and magnetic resonance imaging of synovial inflammation of the hand in rheumatoid arthritis: a comparative study. Arthritis Rheum 2003;48:2434–41.[CrossRef][Medline]
  28. Teh J, Stevens K, Williamson, Leung J, McNally EG. Power Doppler ultrasound of rheumatoid synovitis: quantification of therapeutic response. Br J Radiol 2003;76:875–9.[Abstract/Free Full Text]
  29. Jamar F, Chapman PT, Manicourt DH, Glass DM, Haskard DO, Peters AM. A comparison between 111-In-anti-E-selectin mAb and 99mTc-labelled human nonspecific immunoglobulin in radionuclide imaging of rheumatois arthritis. Br J Radiol 1997;70:473–81.[Abstract]




This Article
Right arrow Abstract Freely available
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