Synovectomy using Samarium-153 Hydroxyapatite in the Elbows and Ankles of Patients with Hemophilic Arthropathy.

This study aimed to evaluate synovectomy with samarium-153 hydroxyapatite (153Sm-HA) in synovitis of the elbows and ankles of hemophilic patients. The synovectomy was performed using 185 MBq of 153Sm-HA in 166 joints of 82 hemophilic patients, with a mean age of 24.4 years and follow-up of 12 and 42 months, comprising 63 ankles and 84 elbows. Arthropathy was characterized by recurrent joint bleeding. Episodes of hemarthrosis, use of clotting factors, and pain intensity were evaluated before and after treatment. Scintigraphic controls and adverse effects were also considered. Statistical analyses used P ≤ 0,005 as significant. The results pointed that (a) reduction in hemarthrosis was 78% and 68% in elbows and 82% and 72% in ankles; (b) use of clotting factors was 80% and 70% in elbows and 85% and 75% in ankles; (c) pain was 37% and 34% in elbows and 61% and 57% in ankles, after 12 and 42 months, respectively. Three cases of mild reactive synovitis were observed in ankles and four in elbows. There was no joint effusion in any of the cases. In conclusion, the use of 153Sm-HA in elbows and ankles was effective, very safe, minimally invasive and showed consistency over time, is another material to utilize in median hemophilic joints.

Introduction

Hemophilia is a hereditary disease associated with the X chromosome that predisposes sufferers to bleeding. In Brazil, it is estimated that one in every 20,000 newborns is hemophilic. Genetic changes may be caused by deletions, inversions, or mutations in bridge regions. Since it is associated with the X sex-determining chromosome and is recessive, hemophilia is transmitted by mothers and disease occurs almost exclusively in men.[1]

There are two main types of hemophilia, classified according to deficiency: type A, caused by factor VIII deficiency, and type B, which is rarer and the result of a deficiency in factor IX. These can also be subdivided into degrees in accordance with the plasmatic activity of the clotting factor: mild, function of 5%–25% of normal activity with posttrauma bleeding; moderate, function of 1%–5%; severe, function lower than 1% with spontaneous bleeding. Hemarthroses account for 80% of bleeding in hemophilic patients, with half of these exhibiting deformities and functional joint limitation.[2] The joints that are most affected in decreasing order are knees 45%; elbows 30%; ankles 15%; shoulders 3%; wrists 3%; and hips 2%.[1]

Repeated joint effusion leads to a local inflammatory response, with the formation of hyperplasic and hypertrophic cells and subsequent buildup of hemosiderin. Fibroblasts proliferate and produce collagenases and proteinases that act on the synovium, cartilage, and bone. The buildup of iron leads to chondral destruction which in association with other factors promotes a decrease in the joint space, resulting in bone remodeling. Motion limitation causes muscle atrophy. Acute episodes are usually treated with clotting factor, limb immobilization, and ice, while aspiration is reserved for cases with searing pain and pressure that may result in skin necrosis.[2] Another mechanism involved is the damage caused by direct action of red blood cells on the cartilaginous surface of the joint lining.[3]

Chemical, radioactive, or surgical synovectomies are useful in the event of synovial hypertrophy, preventing further bleeding. Joint contractures can be managed with traction or immobilization by serial casting. Arthroplasties are considered restorative measures.[4]

Radiosynoviorthesis or radiation synovectomy started in 1952 using chromic phosphate (32P) as an alternative treatment for rheumatoid arthritis and later villonodular synovitis, ankylosing spondylitis, collagenosis, and psoriatic arthritis.[56] The use of radioactive material for synovectomy in hemophilia began in 1971.[7] Since then, a number of different materials have been used, including chromic phosphate (32P), rhenium (186Re), yttrium (90Y), erbium (169Er), dysprosium (165Dy), and holmium (166Ho), and the procedure is considered safer and less invasive than arthroscopic synovectomy.

We introduced samarium-153 hydroxyapatite (153Sm-HA) in the treatment of hemophilic arthropathy.[8] The aim of this study was to evaluate the response of hemophilic arthropathy of medium joints – elbows and ankles – to radiation synovectomy with 153Sm-HA at 12 and 42 months.

Materials and Methods

This study was approved by the Ethics Committee of the local government Health Department. Patients and their legal guardians were advised of the risks and benefits of the procedure and signed a consent form.

This prospective study was conducted from 2003 to 2009, assessing a total of 82 hemophilic patients subjected to radiosynoviorthesis using 153Sm associated with hydroxyapatite, including a total of 166 joints, namely 84 elbows (48% affected on the right side and 52% on the left) and 82 ankles (50% for each side). The mean age of patients was 24.4 years (ranging from 5 to 56 years) and follow-up time was 1 year (12 months) and 3.5 years (42 months) after treatment. Patients selected for treatment were those who exhibited chronic synovitis or recurring hemarthrosis (at least once a month) that did not respond to conventional treatment, including clotting factors, braces, physical therapy, pain killers, and anti-inflammatory agents. Fifty-five patients suffered from hemophilia A (39, severe and 16, moderate) and 27 from hemophilia B (20 severe cases and 7 moderate).

Exclusion criteria were local skin infections and other forms of synovitis. None of the patients showed inhibitors against clotting factors.

Radiographs of the joints were taken, and the Pettersson score[9] was established before puncture [Chart 1].

Chart 1

Pettersson score for radiological assessment

The 153Sm-HA used was provided by the Institute of Energy and Nuclear Research (IPEN-São Paulo, Brazil), an organization of the National Nuclear Energy Commission. At the IPEN, 153Sm was combined with hydroxyapatite particles with diameters ranging from 1 to 12 μm and radiochemical purity >95%, over a period of 24 h. Samarium emits beta particles with energies of 808 keV (17.5%), 705 keV (49.6%), and 635 keV (32.2%), allowing maximum penetration into soft tissue of 3.1 mm (average 0.8 mm). It emits gamma radiation of 103.18 keV (30%), enabling its scintigraphic characterization. The stability of the compound used was 96.6%, 1.440 min after processing. The half-life that characterizes decay of the radioactive nuclide 153Sm is 46.3 h; however, its elimination from the body occurs with a biological half-life of 50.6 days.[10]

Before radiosynoviorthesis, a clotting factor was administered to all patients (1–6 h before infiltration). The intra-articular puncture was followed by the administration of 0.5 ml radioactive solution (fixed dose of 185 MBq or 5 mCi). The needle lumen (23-gauge) was then washed using a saline solution, without exceeding the final volume of 2.0 ml. In the presence of clinically evident joint effusion, the joint was punctured using local anesthetic and the radiopharmaceutical was injected through the same route, without further injuries. No immobilization was carried out after the procedure.

Any radioactive material left inside the syringe or on the cotton dressing was measured with a dose calibrator. Applications were performed by experienced orthopedists using an aseptic method in a procedure room suited to sterile injections and handling radioactive material.

Images of all the patients were captured 1–2 h and 3–7 days after the procedure using a gamma-camera Millennium GE® with a wide field of vision, low-energy collimator, and the window centered at the 100 KeV photopeak.

Pain level (visual analog scale from 1 to 10), frequency of hemarthrosis, and monthly use of a clotting factor were recorded at all visits before and after the procedure.

The Student's t-test was applied for statistical analysis of qualitative variables (P < 0.05).

Results

Analysis of the Pettersson score showed a mean score of 3.78 for ankles and 5.5 for elbows [Table 1].

Table 1

Assessment of the Pettersson score

In the sample under study, the degree of pain relief as assessed by the visual scale was higher for ankles (71% and 61% improvement after 12 and 42 months, respectively) as compared to elbows (46% and 37% at 12 and 42 months, respectively), and both showed significant improvement in pain following radiosynoviorthesis (P < 0.05) [Table 2].

Table 2

Pain reduction following radiosynoviorthesis with samarium-153 hydroxyapatite (scale from 1 to 10)

There was a significant reduction of 85% and 74% in the use of the clotting factor in ankles at 12 and 42 months after radiosynoviorthesis and 80% and 70% in elbows for the same periods, despite the fact that some patients also exhibited bleeding and/or synovitis in their knees, which prevented a more thorough assessment of the actual decrease. These data are shown in Table 3.

Table 3

Reduction in the use of the clotting factor after treatment with samarium-153 hydroxyapatite

The decline in hemarthrosis episodes following radiosynoviorthesis with 153Sm-HA was statistically significant (P < 0.05), namely 82% and 72% for ankles and 78% and 68% for elbows after 12 and 42 months, respectively, [Table 4].

Table 4

Reduction in the number of hemarthrosis episodes after treatment with 153Sm-hydroxyapatite

No cases of infection (septic arthritis) were observed during the study. Mild clinical symptoms of reactive synovitis occurred in three ankle and four elbow joints.

The scintigraphic controls found no joint effusion in any of the patients, indicating adequate intra-articular distribution of the radioactive material. Counts of the puncture material were found to be consistently slightly above the background radiation.

Discussion

In primary prophylaxis, initiated before or shortly after the first hemorrhagic episode, patients are regularly given a sufficient dose of a specific clotting factor concentrate every 3 days, which is maintained above 1% to prevent spontaneous hemarthrosis and the emergence of a “target joint.”[11]

The aim of secondary prophylaxis is to prevent additional damage to the previously hemorrhaging joint[4] and involve administering a specific clotting factor concentrate on a daily basis or every 3 days until the joint returns to its normal state. However, when a patient has experience repeated hemarthrosis and chronic synovitis, the prophylactic use of a clotting factor does not provide the expected results.

Of the hemophilic patients with synovitis, only 40% achieved adequate control of hemarthrosis through a carefully supervised prophylactic clotting factor protocol, even with the use of higher doses than those recommended for primary prophylaxis during a 9-month follow-up period.[12] In addition to the limited therapeutic benefit, other drawbacks of this treatment include its high cost and the inherent risks of prolonged exposure to plasma products, especially if viral inactivation is not performed. With respect to chronic synovitis, this study demonstrated that radiosynoviorthesis can be considered an important method for inhibiting further bleeds and the likely worsening of arthropathy.

Surgical excision of a hypertrophied synovial membrane can be performed through open or arthroscopic interventions and in our view should be used after failed radiosynoviorthesis when synovectomy is still recommended.

In chemical synoviorthesis, substances with fibrosing ability are used for the synovial membrane, such as the broad-spectrum antibiotics rifampicin or oxytetracycline hydrochloride. We opted to use radioactive substances rather than antibiotics in our study due to their higher effectiveness as previously confirmed. Chemical synoviorthesis with antibiotics is a low-cost procedure but is usually painful, and several weekly interventions are needed to obtain satisfactory results.[1314]

Radiation synovectomy and/or radiosynoviorthesis are terms commonly used to describe the synovial fibrosis achieved by an intra-articular injection of radioisotopes. Although multiple isotopes are used for this purpose, the ideal isotope should have a suitable half-life and limited range of beta emission. Thus, the effect is concentrated in the synovial membrane, preventing the risk of radiation to surrounding tissues with potential degradation of the joint cartilage and early progression to arthrosis.[15] Chromic phosphate 32P is most used in the United States and Canada,[6] while in Europe and Latin America, including Brazil, yttrium Y 90 and 153Sm-HA are preferred.[41617]

There are several advantages to using 153Sm in association with hydroxyapatite. The first is that the substance is produced in Brazil, reducing costs and providing a certain degree of independence from imported raw materials. Moreover, the emission of low-energy gamma rays allows for the scintigraphic monitoring of its biological distribution, radioactive half-life, and low-energy beta emission, resulting in a material that is not aggressive to the extra-articular tissue (low penetration). The use of yttrium on joints with thinner cartilage lining, such as the elbow (average thickness of 2 mm), may result in a chondral lesion since penetration is deeper than that of samarium.[181920]

In regard to joint effusion, there is an inverse relationship with particle size. Binding samarium to hydroxyapatite to produce 153Sm-HA results in particles that are suitably sized for incorporation by the existing macrophages in the inflamed synovium, with less possibility of joint effusion, making the compound safer to use. The 153Sm-HA bond is highly stable, and on dissociation, samarium is found in the trivalent form, resulting in the formation of insoluble compounds with synovial fluid elements, precipitating in the joint. These properties differentiate samarium from other materials due to its higher deposition on the joint and lower systemic circulation.[21] In this study, scintigraphy performed 1–2 h and 3–7 days later revealed no leakage, as well as homogeneous distribution on the joint [Figure 1].

Figure 1

Scintigraphic evaluation showing no scape from joints

After almost 40 years using radiosynoviorthesis, no damage has been reported in terms of radioactive materials.[14] A major concern regarding radiosynoviorthesis is the risk of carcinogenesis; however, analysis of chromosomal aberrations has yet to confirmed this hypothesis.[2223]

There was a significant decrease in the amount of the clotting factor used, which was similar to previously published studies, showing an improvement by 76%–80%.[416242526] This aspect has an economic impact because the cost of blood products is still high.

Assessment of the Pettersson score showed a mean score of 3.78 and for ankles and 5.5 for elbows, demonstrating that hemophilic arthropathy was more advanced in elbows than in ankles, explaining the higher level of pain. Decreased pain following radiosynoviorthesis with 153Sm-HA, assessed using a visual scale (1–10), was shown to be higher in ankles when compared to elbows. One explanation is the fact that the elbows exhibited more advanced degrees of hemophilic arthropathy: the procedure treats synovitis and not the existing joint lesion.[27]

Adverse reactions were limited and mild in intensity, occurring in three ankles and four elbows. There was no need for the systematic use of simultaneously injected corticosteroids to reduce reactive synovitis as reported in the literature. This study is one of the few that evaluates only the therapeutic effect of the intra-articular radioactive material. This is because its administration in association with corticosteroids creates bias in result analysis since these are also used with the same purpose in hemophilic arthropathy therapy.[2829] This association has previously been called into question[30] and was therefore not used here;[8] in addition, there was no information in the literature characterizing the nature of its effect, whether competitive, addictive, or synergic.

Conclusion

The use of 153Sm-HA for the treatment of hemophilic arthropathy in elbows and ankles was a safe, cost-effective, minimally invasive, and effective procedure in controlling bleeding and pain. The results of this study corroborate those reported in the literature, demonstrating the benefits of radiosynoviorthesis with 153Sm-HA and consistency over time.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.