New approaches in radioisotopic evaluation of inflammatory arthritis
(1997)
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- The studies described in this thesis have demonstrated the capacity of radioisotope imaging to accurately assess the extent and severity of rheumatic diseases. The two tracers that were used showed rather comparable results in clinical applications. Both have proven reliable and more objective than clinical methods for assessing disease activity. At this stage, studies with 99mTc-HIG have demonstrated the clinical usefulness of this agent, which can be applied to everyday practice. The data presented confirm the interest of 99mTc-HIG scanning that had been recently emphasised (de Bois et al., 1995c). <BR> On the other hand, imaging of endothelial activation is still in its infancy. Yes, it seems an exciting method to study inflammatory diseases, including inflammatory arthritides. After the pioneer work of Keelan et al. who have shown the potential of noninvasively detecting E-selectin expression as a marker of endothelial activation, tracers suitable for human applications were developed and evaluated in preclinical models of inflammation. The model of acute arthritis in the pig appeared quite satisfactory in establishing the value of anti-E-selectin imaging. Beyond the straightforward question of validation, models of acute skin inflammation have provided more detailed understanding of some of the factors governing E-selectin mAb have demonstrated the feasibility and the efficacy of the method, not only in rheumatoid arthritis but also in inflammatory bowel disease. Of interest, the use of a 99mTc-Fab fragment has resulted in high quality images, in spite of the monovalent binding of the fragment to the antigen. This is most encouraging in view of the development of a small-sized antibody fragment. i.e. a 1.2B6-sFv which should be available soon for preclinical studies. However, the clinical relevance of anti-E-selectin imaging remains to be established on wider cohorts of patient in studies that directly address clinical endpoints such as sensitivity, predictive value on the outcome or impact on patient management. This is indeed a key issue of any imaging modality “…in a wolrd where medicine is reinventing itself to fit the mold of cost-effective care.” (Strauss, 1996). This implies that a diagnostic technique should provide information that is ultimately directed towards patient care. In this regard, anti-E-selectin imaging could be helpful to identify patients who could benefit from new drugs that interfere with adhesion molecule interactions (Haskard, 1994). We should hope that in vivo detection of endothelial activation will not only bring another piece of information but also contribute to a better comprehension of patients’ needs. <BR> Although both tracers presented in this thesis produced accurate images of synovitis their respective merits and drawbacks should be discussed. The advantages of 99mTc-HIG are mainly practical. It is accessible to every nuclear medicine department easy to prepare and leads to high quality images in a reasonably short period of time/ 99mTc-HIG has no known side effects and scintigraphy can be repeated if required. However, it is a blood pool agent and is not ideal for imaging central areas. The lack of specificity of its deposition in inflamed tissues is frustrating since it is always unclear whether uptake represents blood flow, blood pool or capillary leak-age. In any case, there had been no definitely convincing report that demonstrated binding of HIG to any of the actors of inflammatory as a major determinant of uptake in arthritis. Several studies suggested binding of HIG to Fc receptors or to matrix proteins of the interstitial tissue but no striking evidence of that has been reported in vivo as yet. Conversely, in the turmoil of the inflammatory reaction, anti-E-selectin mAbs bind to a single, well-characterized molecule, that is not expressed in normal tissues. As shown in the validation studies in porcine models of inflammation, by comparison with non-specific isotype-matched labelled mAb, it does lead to biochemically specific uptake though, inevitably, there is some degree of non-specific uptake as with any tracer. This results from hyperaemia and extravascular leakage of the antibody as any protein or smaller molecule would do (Oyen et al., 1996c). Whether or not specific antibody uptake is flow-dependant remains to be studied. Nonetheless, the direct access of the antibody to its target is a definite advantage over other mAb especially those used in the oncology field: data in pigs have shown the extreme rapidity of uptake in inflamed knees. <BR> Currently, agents that target E-selectin expression are not widely available and thus tracer preparation and labelling still requires home made techniques. If the method were to be widely used, there is no theoretical obstacle to devise a kit formulation of 1.2B6 that could be readily labelled, at least with 99mTc. The major drawback of the methodology itself is the origin of the antibody. As any monoclonal antibody of murine origin, it is potentially immunogenic which would hinder its repeated use. It is unclear at the immunological level what the long-term effect is of small amounts of Fc portion-lacking fragments (as used in our studies). This problem and the risk of contamination in hybridoma mAb production systems would justify some prudence from the biomedical industry in developing such a compound on a commercial basis. It is to be hoped that efforts will continue in the search for alternative tracers for imaging E-selectin expression such as glycoconjugates or sFv antibodies expressed by bacterial systems. With such agents available, we believe that imaging of endothelial activation would compare favourably with other tracers that are currently being developed for imaging inflammation that are susceptible to be used in arthritis. These agents belong to different families of molecules and comprise cytokines such as IL-1 (van der Laken et al., 1995), IL-2 (Signore et al., 1992), IL-8 (Hay et al., 1993), cytokine-receptor binding molecules such as IL-1 receptor antagonist (van der Laken et al., 1996), neuropeptides such as somatostatin analogues (van Hagen et al, 1994) or substance P (van Hegen et al., 1996), or less specific but powerful tracers such as radiolabelled liposomes (Oyen et al., 1996a). <BR> To conclude, this thesis has focused on tracers that can be used in inflammatory arthritis. We feel that 99mTc-HIG scintigraphy can be helpful for directly addressing clinical questions in individual patients. Such questions might be to objectively and non-invasively demonstrated synovitis in borderline patients with poor compliance to treatment and in whom complaints are sometimes disproportionate to disease intensity, or to exclude active synovial inflammation in the group of patients with unclear symptoms of recurrent arthralgias sine materia, such as observed in fibrositis (Smythe, 1989). Instead of rejection those patients from any form of specific therapeutical decision, an objective tool that is able to rule out inflammation might by useful to put those patients early on the good track. In clinical research, both 99mTc-HIG scanning and imaging of E-selectin expression appear suitable for the evaluation of new drug strategies. As discussed in chapter 4, there are many avenues for future research using E-selectin targeting agents
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Jamar, F. (1997). New approaches in radioisotopic evaluation of inflammatory arthritis. https://hdl.handle.net/2078.5/111410