While a myriad of factors contribute to the utility of RSV, selection of an appropriate β⁻-emitting radionuclide is critical since the synovial thickness of different joints in the human body (e.g., finger, wrist, knee, etc.) varies substantially. Also, joints at different stages of the disease show different degrees of swelling and may also call for a beta emitter of different penetration. The β⁻ radiation energy should be sufficient to penetrate and ablate proliferating layer of the inflamed synovium with minimum radiation-induced damaged to the underlying articular cartilage or adjacent bone underneath (Chakraborty et al. 2015) (Fig. 14.4). The radionuclide dose should be small enough to be phagocytosed, and it should be given in amounts that are limited enough so that leakage does not occur from the joint (Schneider et al. 2005). The radionuclide should have a half-life suffice for adequate, but not excessively prolonged, to deliver cytotoxic radiation dose to the synovium and should be substantially less than the retention time of the radiolabeled particle in the joint to be treated. The penetration depth of the β⁻ radiation energy should correspond to the thickness of the synovium in the joint to be treated, as inadequate penetration will give an inferior therapeutic effect and excessive penetration depths may constitute a safety hazard. As the thickness of the diseased membrane varies in different joints, treatment of diseased synovium in joints of disparate size requires radionuclide of different β⁻ particle energies with high-energy beta emitters such as ⁹⁰Y and ¹⁸⁸Re for the large joints such as the knees and the ¹⁶⁹Er low beta emitter for treatment of the finger joints. A medium beta energy emitter such as ¹⁸⁶Re is useful for irradiation of medium-sized synovial joints such as the elbow. The other important issues are leakage of the radioisotope form the joint, which must be minimized by the characteristics of the preparation, and the gradual particle adsorption by the synovium. The half-life should be long enough to allow good distribution within the synovium and adequate exposure, while being short enough to avoid excessive irradiation and significant leakage from the joint. There is no evidence that the use of radioisotopes is a therapeutic option for the treatment of osteoarthritis (Moskowitz 2007).

Table 14.1 summarizes the principal radioisotopes and preparations which have been evaluated or which are in current use as approved radiopharmaceutical agents for the treatment of rheumatoid arthritis. These agents are approved for clinical use in many countries, but interestingly, radiation synovectomy is not practiced in the USA and these agents have not yet been approved by the regulatory authorities, presumably because of the potential ramifications of joint leakage, although extensive studies as discussed later in this chapter have demonstrated the safety and efficacy of this method. The first reports of this last treatment were published as early as 1924 (Ishido 1924) and subsequent later (Fellinger and Schmid 1952) and paved the way for the contemporary broad clinical application of radionuclide synovectomy.

So the challenges in developing a useful agent for the treatment of synovitis include the selection of the appropriate radionuclide(s). In addition to radionuclidic properties, another key issue is availability and radionuclides used for this application decay by beta emission and thus are generally reactor-produced (Table 14.1). One example which can be either reactor or accelerator produced is ¹⁸⁶Re (see Chaps. 6 and 7). Key radionuclidic properties include emission of a beta particle with the requisite energy which matches the joint dimensions and required soft tissue penetration requirements (Table 14.2). For radiation safety considerations, these radioisotopes should decay without emission of significant abundance of accompanying high-energy gamma photons. However, the emission of gamma photons which can be imaged is important to substantiate homogeneous distribution within the joint space and to evaluate the possibility of any leakage of activity.

An additional important characteristic is the availability of a particulate preparation which is stable for a sufficient time period after administration prior to synovial resorption. As summarized in Table 14.1, there are many therapeutic radioisotopes which have been evaluated for radionuclide synovectomy. Selection of particulate for use in RSV is primarily based on the ability for facile and reproducible preparation and demonstration of effective synovial targeting/uptake. The particulates should also be sufficiently robust enough to withstand the radiolabeling reaction conditions and should exhibit chemical characteristics which must form a stable complex with the radionuclide and should exhibit good stability to circumvent loss of the radioisotope from radiolysis or during application. The particle chemical characteristics should permit simple and efficient radiolabeling, and they should be nontoxic, nonallergenic, biocompatible, and preferably biodegradable. The binding between the radionuclide and the particle should be irreversible throughout the course of the radiotherapy. Another prerequisite is that the particle must be sufficiently small to be phagocytized; however it should not be too small that would allow joint leakage before phagocytic trapping. The appropriate medium major diameter size range for this application is considered to be from 2 to 10 μm. Following intra-articulation, the radiolabeled particles should be distributed homogeneously in the joint without initiating an inflammatory response.

There are a variety of materials and particulate preparations used for synovectomy, which include preparations based on citrate, sulfide colloids, hydroxyapatite particles, and chitosan (Karavida and Notopoulos 2010; Teyssler et al. 2013; Kasteren et al. 1993; Davis and Chinol 1989; Song et al. 2001; Brecelj et al. 2007). Ideally, the particle size distribution should be in the 2–10 μm range. Depending on the particles, it is possible to incorporate the activity, label throughout the entire volume, or label only in certain structures, such as the surface and the outer or inner wall. The binding of radioactivity to particles can be done by covalent bonds, by chelation, by adsorption processes, or by indirect means. In the light of the perceived need to preclude leakage of the radioactive isotope from the microsphere, the prospect of enclosing the nonradioactive precursor of the radioisotope in the microsphere matrix and subsequent activation in a nuclear reactor shortly before use seemed attractive.

There are of course regulatory guidelines which must be followed for the use of such agents for treatment of synovitis and Table 14.2 summarizes guidelines used in the European community. It is interesting to note that although the first development and the first demonstration of clinical efficacy was reported in the USA (Sledge et al. 1986), radiation synovectomy is not practiced in the USA evidently due to a regulatory concern that potential joint leakage of the radioisotope would expose non-target tissues to unacceptable radiation dose.