There is a large body of evidence supporting RS in hemophilia (Table 10.1). The largest such study, performed by Rodriguez-Merchan et al. over a 40-year period, comprises more than 500 cases of RS (knee, elbow and ankle) either with yttrium-90 (Y-90) or rhenium-186 (Rh-186). Between one and three injections were performed with a 6-month interval between them [59]. RS was performed under factor coverage to avoid the risk of re-bleeding during the procedure. For the knee, they used Y-90 at a dose of 185 megabecquerels (MBq) – 1.48 mSv. Rh-186 was used for elbows and ankles. Yttium-90 (Y-90) or Rheinum-186 (Rh-186) emit beta radiation, and have a therapeutic penetration power (TPP) of 1 mm (Rh-186) and 2.8 mm (Y-90). The authors performed joint scintigraphy using a small amount of Tc99 (Technetium-99) after the procedure to check the correct distribution of the radioactive material into the joint. After RS, bleeding frequency declined by 65 %. The size of the synovium (on clinical examination and imaging) declined by 30 % and clinical scores improved by 20 %. However, radiological scores did not improve. The rate of complications of RS was 1 %. The most serious complication was septic arthritis which occurred in 1 patient. Other complications included cutaneous burns if the radioactive material was injected out of the joint, and transient inflammatory reactions following injection which are successfully treated with rest and non-steroidal anti-inflammatory drugs. RS was considered an effective option for the treatment of chronic hemophilic synovitis (Fig. 10.2) [33–70].

Regarding the potential genotoxic effect of RS, no increase in the risk of cancer has been reported in the literature. In 1977, Ahlberg et al. reported chromosome changes in the circulating lymphocytes of patients undergoing Gold-198 (Au-198) RS [47]. However, in 1985 Rivard et al. did not find an increase of chromosome aberrations after ³²P RS, reporting <4 % extra-articular escape of radiation compared to intra-articular counts [58]. Several authors have reported chromosomal changes in patients after RS. In 2000, Falcón de Vargas and Fernandez-Palazzi reported reversible premalignant or nonspecific changes in chromosomal structure in the lymphocytes of hemophilia patients after using Au-198, Rh-186, Y-90; such changes persisted in a low proportion of metaphases up to 2 years after injection when ¹⁹⁸Au was used [51]. In 2001, Fernandez-Palazzi and Caviglia reported that chromosomal changes could be observed in equal numbers and frequency in patients after RS as in non-irradiated patients. Furthermore, the changes due to the radiation disappeared with time, never reaching more than 2 %, the threshold considered to be dangerous [35].

The report by Dunn in 2002 alerted the community to the occurrence of two cases of acute lymphocytic leukemia (ALL) in children with hemophilia after P-32 RS [64]. The children, ages 9 and 14 years, developed ALL within 1 year of RS. Although a causal relationship could not be established, the authors recommended the use of RS only in patients with clearly defined risk/benefit situations, e.g. the treatment of synovitis in patients with inhibitory antibodies or in extremely non-compliant patients whose bleeding is not manageable with factor replacement alone.

Following this report, two publications by Turkmen et al. showed that RS with Rh-186 and : Y-90 in hemophilic children did not induce genotoxic effects [37, 38]. The effects of specific isotope doses and the number of RS treatments were analyzed by Infante-Rivard et al. [66]. These authors found no increase in the risk of cancer and there was no dose–response relationship with the amount of radioisotope administered or number of RS treatments. This study provided some reassurance of the safety of the procedure but groups of younger hemophilia patients receiving RS may still need further study. To highlight this position, Silva et al. stated that unresolved questions regarding the safety of radiation exposure argues against the use of RS in children with hemophilia [67].

The dose of radiation after RS in patients with hemophilic synovitis is minimal and does not approach dangerous levels. The dose of radiation incurred during a single session of RS is less than that received due to natural sources (approximately 2 mSv –millisieverts per year). It is estimated that the lifetime cancer risk increases about 0.5 % with exposures of at least 100 mSv per year. Knee RS in children provides an approximate radiation dose of 0.74 mSv (90 megabecquerels-MBq) [46]. Although two cases of ALL in children with hemophilia treated with RS have been reported, no causal relationship could be established and no further cases have been reported.

The data suggest that the risk of cancer after RS is not increased. The author recommends that clinicians consider RS in children with hemophilic synovitis when the potential benefits are clearly defined, such as in children with inhibitors or in pediatric patients whose recurrent joint bleeding is unmanageable with factor replacement alone. Importantly, in countries where the availability of factor replacement is limited, RS should be considered early in the patient’s clinical course before osteochondral changes are evident. The authors also recommend that clinicians avoid unnecessary radiation exposure whenever possible [59].

In our practice, AS is indicated after the failure of three episodes of RS with 6-month intervals. In our series, only 28 (6.3 %) joints eventually had to be subjected to AS or total knee arthroplasty (TKA) [59]. We have never used CS because it requires multiple painful weekly injections. Global results of treatment with CS in the literature have been less favorable than with RS [71].

RS is our first option for treatment of hemophilic synovitis; the procedure is highly cost effective in comparison to AS (€3,000 per injection). Our second-line therapy is AS (€ 60,000 per procedure) [59].