Radiosynovectomy in rheumatic diseases.

Radiosynovectomy is a safe and repeatable treatment method of chronic synovitis with synovial overgrowth and refractory chronic or acute inflammatory joint effusion. It consist in the intraarticular administration of a radioactive isotope in the form of a colloid causing the extinguishing of active synovitis. The radiocolloid causes permanent irradiation of the synovium with beta ray electron beams, which ultimately leads to its fibrosis and extinguishes the inflammatory process destroying the joint. The main indications for radiosynovectomy include chronic and acute arthritis in the course of systemic diseases, intraarticular bleeding in hemorrhagic diatheses (hemophilia), selected cases of osteoarthritis, recurrent effusions following surgery, e.g. arthroplasty, or other iatrogenic post-surgery complications causing arthritis. Radiosynovectomy is also performed in pigmented villonodular synovitis and crystal synovitis. The most common method used to determine the eligibility for radiosynovectomy is an ultrasound, which shows the location and activity of the thickened synovium. The administration of a radiocolloid into the joint, sheath or bursa should also be performed under the control of the ultrasound image, as this ensures a precise location of the puncture needle and full control of the isotope administration process. Clinical efficacy of radiosynovectomy depends on the proper qualification of patients for the procedure. The success rate of radiosynovectomy in common indications is 65-80%. It is confirmed by the visualization of avascular (fibrotic) synovium in follow-up ultrasound tests. The aim of this article is to present techniques and indications for the radiosynovectomy treatment.

Introduction

Radiosynovectomy (RS) is a method of treating chronic inflammation of joints and tendon sheaths with thickened, excessively vascularized synovium and recurrent effusions. It is typically used in the absence of other effective therapeutic methods. It consist in the administration of a radioisotope in the form of a colloid into a joint cavity, tendon sheath or bursa. The radiocolloid complex cannot escape through a joint capsule or be absorbed by the lymphatic or blood vessels. It also cannot permanently bond with other intraarticular elements, except for macrophages present within the inflamed synovium. In the process of phagocytosis the phagotic cells permanently incorporate the radiotracer, which ultimately leads to the blocking of inflammatory process by synovial fibrosis(.

A radiocolloid complex contains particles of an optimal size from 2 to 10 mm, which prevents them from getting outside the joint capsule or tendon sheath and causes the total energy of the ionizing radiation to be deposited only within the synovial membrane. The irradiation of the synovium by an appropriate radioisotope through a beta radiation beam results in its structural changes. During irradiation the number of free radicals in the synovial membrane increases significantly, which causes the damage and death of cells, both as a result of radiolysis when a high dose is absorbed, and also indirectly as a result of apoptosis, which ultimately leads to synovial membrane fibrosis(.

The currently used radiosynovectomy method is safe. Despite the use of ionizing radiation (high energetic beta electrons) no increased risk of cancer following RS has been found so far. It is probably because of the local use of radioisotopes and a small radiation dose on adjacent organs and so called critical organs, e.g. bone marrow which is extremely sensitive to ionizing radiation(.

The first report on radiosynovectomy was published in 1952(. Since then, the method has been used in the treatment of many pathologies of the synovium which do not respond to standard medical and typical intraarticular administration of steroids(.

Obtaining optimal ionizing radiation requires the selection of a proper radioisotope. It depends on the thickness of the pathologically modified synovium, the size of the treated joint, as well as the patient's age. Commonly used radioisotopes have different beta energy radiation and, as a consequence, their penetration ranges in the altered synovium is different. Some of them also contain a gamma component, which enables imaging and can be helpful in performing accurate dosimetric calculations of doses deposited within the synovial membrane and the degree of radiation dose absorbed by the other organs or adjacent tissues. This reduces the overall effect of ionizing radiation and ensures simultaneous topical effectiveness(.

The maximum radiocolloid radioactivity for adults should not exceed 370 MBq in a single intraarticular administration. For children, the activity is correspondingly smaller. It depends on the patient's age and is usually calculated by body weight. When a standard dose is used in RS, a radiocolloide radiation dose absorbed by the synovial membrane reaches up to 100 Gy(. Beta emission range optimal for radiosynovectomy is 0.5–10 mm (for small joints the range is smaller, for large ones, e.g the knee joint, it is the largest). The half-life of a radioisotope is also important – the shorter it is, the smaller the probability of extraarticular penetration and potential effect on these structures(.

Current clinical practice employs intraarticular administration of the following radioisotope colloids: yttrium silicate/citrate (90Y), rhenium sulfide (186Re) and erbium citrate (169Er). In the U.S., phosphorus-32 (32P) is also commonly used(. Yttrium-90 (90Y) is used in the treatment of knee joints in adults and may be used in larger children, depending on the degree of attachment (thickening) and the size of the knee synovium. Rhenium-186 (186Re) is used in the treatment of medium-sized joints, such as elbow, ankle, shoulder, hip, wrist, and tarsal. It is also applied in the RS of knee joints in children, mostly in the course of juvenile idiopathic arthritis (JIA). Erbium-169 (169Er) is used for small joints, such as the metacarpophalangeal, metatarsophalangeal and digital interphalangeal(. Radionuclides used in RS, their physical properties and the extent of their soft tissue penetration are presented in tab. 1.

Tab. 1

Characteristics of radioisotopes used in RS

	90Y	186Re	169Er
Type of radiation	β	β, γ	β
Half-life duration (days)	2,7	3,7	9,4
Maximum β energy (MeV)	2,27	1,07	0,34
Average β energy (MeV)	0,935	0,349	0,099
Maximum soft tissue penetration (mm)	11,0	3,7	1,0
Average soft tissue penetration (mm)	3,6	1,1	0,3

Radiosynovectomy should be carried out in accordance with the radiological protection guidelines approved by the public legal regulations of relevant authorities (National Atomic Energy Agency). The site of preparation, administration and storage of radioisotopes must meet the requirements specified by the relevant provisions of the law. It must also meet the qualifications required of the performing and assisting personnel(.

Clinical indications for radiosynovectomy(

Indications for radiosynovectomy include synovial joint pathologies in the course of the following diseases:

Rheumatoid arthritis.

Haemolytic arthritis and haemophilic arthropathy.

Spondyloarthropathies.

Crystalopathies, including gout and pseudogout (calcium pyrophosphate dihydrate arthritis, CPPD).

Recurrent effusions following arthroplasty.

Recurrent effusions following arthroscopy.

Undifferentiated arthritis.

Pigmented villonodular synovitis (PNVS).

Contraindications for radiosynovectomy(

Absolute contraindications for radiosynovectomy include:

Pregnancy.

Breastfeeding.

Local skin or joint infection.

Ruptured popliteal cyst/semimembranous bursa – the risk of extraarticular penetration of the radioisotope.

A period of up to six weeks following joint surgery – the risk of extraarticular penetration of the radioisotope.

A period of up to two weeks following the puncture of the joint – the risk of extraarticular penetration of the radioisotope.

Relative contraindications include(:

Significant instability and deformity of the joint with damage to cartilage and subchondral bone – the risk of irradiation of bone tissue and of potential osteonecrosis. Potential benefits and likely side effects should be carefully considered.

The period immediately before a scheduled hip replacement surgery – a potential risk of osteonecrosis and loosening of the implant.

The period immediately before a scheduled reconstructive joint surgery – a potential risk of tissue healing and regeneration disorders.

The recovery period after arthroscopy or joint surgery (6 weeks minimum), or the puncture of the joint (2 weeks minimum).

Eligibility for RS treatment

Patients eligible for RS suffer from active synovitis and usually have experienced at least one ineffective intra-articular administration of long-acting steroids (e.g., methylprednisolone or triamcinolone)(.

Relative contraindications may include extensive losses in hyaline cartilage revealed in imaging tests. Determining the eligibility for RS should, however, consider the potential benefits of the treatment. An example may be patients with haemophilia who are usually diagnosed with massive cartilage loss, but are treated with RS to stop the further degradation of the joint(. In order to assess the location and degree of the thickening and the abnormally increased vascularity of the pathologically modified synovium an ultrasonography (US) and occasionally a magnetic resonance imaging (MRI) test is performed( (Figs. 1–3). An ultrasound examination is also carried out to monitor the administration of a radioisotope in the joint cavity or sheath. It is also used to assess the efficacy of radiosynovectomy in follow-up tests. If RS is efficient, the US reveals gradual reduction in the vascularity of the synovial membrane ultimately leading to its fibrosis. Otherwise, the ultrasound test allows the patient to become eligible for another RS which is a repeatable procedure.

Fig. 1

Knee joints of a patient with JIA: A. right joint eligible for RS: synovium of the joint cavity considerably thickened with features of increased vascularity; B. left joint after RS: thickened synovium, with no evidence of increased vascularity, interarticular adipose tissue edema, strands of fibrosis in the joint cavity

Fig. 3

Thickened, highly vascularized synovium of the tendon sheaths of finger flexors on a cross-section (A) and longitudinal section (B)

Thickened, highly vascularized synovium of the joint cavity in the wrist joint

Potential complications following radiosynovectomy and the safety of the procedure

It should be emphasized that RS is a safe procedure. The maximum penetration of the beta radiation usually does not exceed the thickness of the synovial membrane, while the articular cartilage and epiphyseal plate due to their insulating properties almost completely protect the bone marrow within the marrow cavity and the remaining structure of the cancellous bone against radiation exposure. The most sensitive red marrow is located mainly in the marrow cavities of the vertebral bodies, flat bones of the skull cap and the bones of the pelvis and sternum, which are beyond the reach of ionizing radiation during the RS of peripheral joints. RS tests using 186Re showed that the dose of radiation absorbed by the subchondral bone layer did not exceed 4% of the dose absorbed by the synovial membrane, which makes it negligibly small. Additionally, no intraarticular tumor growth was observed in the treated patients over a longer period of time(. For the treatment to be successful, it is important to select an appropriate radioisotope depending on the treated joint. Using isotope 90Y with the penetration of 11 mm for elbow and ankle joints led to local complications in the form of joint capsule fibrosis and a growing contracture(.

Potential complications/side effects after RS(

Local, acute inflammation of the synovial membrane in the treated joint, induced by the administration of radiocolloid, overlaying the present chronic/subacute inflammation (occurring frequently – in approximately 40–50% of patients – with varying degrees of severity).

Intraarticular bleeding (hemarthrosis, most often in patients with severe hemophilia and present inhibitor, usually in the absence of control of bleedings carried out using standard prevention methods).

Contamination of the skin with radiocolloid during removal of the puncture needle (rare).

Radiocolloid leakage outside the joint through a puncture hole in the joint capsule or a ruptured bursa, occurring mostly in case of the rupture of Baker's cyst and causing potential irritation or necrosis of the surrounding tissue (very rare).

Skin infection following RS (very rare).

Infection in the joint after RS (very rare).

Chromosomal disorders (very rare).

Tumors (no confirmed data; see: comments below).

In some cases a local inflammation of the synovial membrane after RS may lead to severe pain and the swelling of the joint. The duration of these symptoms varies – they usually last for the first 2–3 days after the administration of a radioisotope, except for the first hours immediately after RS due to the intraarticular anesthesia used during the procedure. The pain and swelling usually disappear spontaneously after another 2–3 days or as a result of a standard symptomatic treatment (paracetamol or other anti-inflammatory medications and ice packs)(. The expected therapeutic effect of RS is extended over time and visible only after 3–4 weeks(. In case of haemophilic arthropathy the treatment may nevertheless cause hemarthrosis (bleeding), especially in patients with severe form of hemophilia. Possible complications include infection at the site of intra-articular injection and necrosis of the skin and subcutaneous tissue caused by extraarticular radiocolloid leakage through the channel after the injection(. Kisielinski et al. reported five cases of a knee infection following radiosynovectomy( – a ll f ound i n patients treated for recurrent effusions after arthroplasty, which may be a sign of undiagnosed infections around the prosthesis.

An adverse side effect of RS which occurs usually immediately after the procedure, is a radioisotope leakage outside the articular cavity and its local impact as well as potential spread through the physiological pathways of lymph and blood. It can lead to chromosomal damage, including malignant lesions(. However, in clinical practice, due to the size of the administered doses and exceptional infrequency of such events, there is insufficient data on the risk of developing cancer as a result of RS. Few studies indicate the occurrence of premalignant lesions and damage of 2% of the chromosome when the administered radioisotope contained a significant component of gamma rays, e.g. gold 198Au or phosphorus 32P which are not in use in Europe(. Tests carried out in these patients after 6 years showed only minor differences compared to the examinations conducted before the RS treatment. The frequency of chromosomal aberrations after radiosynovectomy is comparable with the changes that occur during treatment with non-steroidal anti-inflammatory drugs or during antiviral therapy(. Chromosomal damage was also observed after the administration of 90Y and 186Re, but its intensity was lower, and the period after which the frequency of changes achieved the baseline was also shorter. There was no correlation between the size of the leak and the number of chromosomal aberrations. Particularly noteworthy is the fact that in the case of 186Re no precancerous forms were revealed(. Furthermore, with regard to malignancy risk, so far only two cases of acute leukemia were found in hemophiliac patients treated with radiosynovectomy( and five cases of tumor growth i n patients treated for rheumatoid arthritis(. In none of these cases a direct relationship between the procedure and the development of cancer was confirmed. A cohort study by Infante-Rivard et al. ( conducted on a group of 2412 patients who had undergone RS between 1976–2001 showed no increased risk of cancer in comparison to the control group. On the contrary, Vuorela et al. ( found a lower incidence of cancer in patients after RS compared to the control group.

In summary, no increased risk of cancer or articular pathologies associated with the toxic effects of radioisotopes on the joint structures has been found either in adults or children. Despite initial doubts regarding the use of radionuclide therapy in pediatric patients, there currently prevails a tendency for the earliest possible termination of the pathological cycle in affected joints by deactivating the inflamed synovium. In many cases this is the only way to block the development of arthropathy and disability of the involved joint(.

RS technique

Radiosynovectomy involves administering a radiocolloid radioisotope into the joint or into the lumen of the sheath or bursa. The puncture of the joint is performed under standard local anesthesia with a sterile injection administered to a previously washed and disinfected puncture site. Due to the risk of complications resulting from the extraarticular administration, it is necessary to ensure proper intraarticular position of the needle. For this purpose, it is optimal to use US, which enables monitoring of the treatment, including the position of the needle. After intraarticular administration of a radiocolloid the needle is withdrawn while a saline solution is being administered. The purpose is to wash out the residues of the radiocolloid from the lumen of the needle and to perform intraarticular administration (or an injection into the lumen of the sheath or bursa) of the previously prepared entire radioisotope dose. Many authors recommend intraarticular administration of a steroid drug to increase the effectiveness of the treatment and prevent inflammation. The authors of this study do not share this view and do not use any steroids in their clinical practice. The only analgesic administered during RS is a 1% or 2% solution of lidocaine including a radionuclide colloid. The administered dose, the type of a radioisotope and the amount of the solution administered into the joint depend on its size: adult volume is 3.5 ml for the knee joint and 2.5–3 ml for the shoulder joint, 1.5 ml for the elbow and 1 ml for the ankle. The other joints require individual selection of the volume of the solution. Once the needle gets outside the joint, a few millimeter bolus of saline is fed into the subcutaneous tissue, which increases the pressure outside the joint and “seals” the hole in the joint capsule. After a sterile dressing is put on, the patient should perform active and passive movements for about 1 minute for even distribution of the radiocolloid in the joint cavity. The joint is then immobilized in a stabilizer or brace for three days.

RS in rheumatic diseases

Rheumatoid arthritis (RA) is one of the most common indications for RS. Most studies have demonstrated superior efficacy of radiosynovectomy compared to chemical synovectomy and intra-articular steroid drug administration. The meta-analysis conducted by Kresnik et al. ( revealed improvement after surgery in 66.7% of patients with RA. In the study by Matryba et al. ( improvement in 68.7% of the treated knee joints and as much as 100% in the hand joints was observed. However, due to a small number of symptoms of hand arthritis the result should be interpreted with caution. A higher efficacy of the treatment was observed in over 50 year old patients. A more significant reduction in effusions was demonstrated in male compare to female patients, while in women the radiosynovectomy resulted in greater of pain relieve. In another randomized clinical trial presented by Menkes et al. (, in patients with rheumatoid arthritis 69.6% good and very good post-radiosynovectomy results were found, compared to 54.4% after chemical synovectomy, and only 38.9% after intraarticular administration of steroids.

As for other rheumatic diseases, a study by Jahangier et al. c onfirmed s ignificant i mprovement i n 7 6% o f patients who underwent radiosynovectomy due to psoriatic arthritis, and in 75% of patients with ankylosing spondylitis. Gazda et al. ( demonstrated significant clinical, biochemical and ultrasound improvement in 66% children who had undergone RS due to juvenile idiopathic arthritis. The average period of remission of symptoms was 20 months.

RS in haemophilic arthropathy

Radiosynovectomy is the treatment of choice in arthropathy associated with recurrent bleeding into the join/joints (hemarthroses) in patients with hemophilia. An indication for treatment is determination of a so-called target joint in which at least three bleedings have occurred over the past 6 months(. Rodriguez-Merchan et al. ( found 85% of good and very good results with a follow-up median of 3.5 years. Other studies of haemophiliac patients revealed the improvement in 80% of patients who underwent the RS procedure(. One study revealed a complete remission of bleeding (hemarthroses) over a period of 18 months in 67% of patients(. Our study showed a reduction in the frequency of intraarticular bleedings from 2.6 per month to 0.6 per month over 2 years following the RS. The efficacy of radiosynovectomy was confirmed in inhibitor patients as well(.

RS in osteoarthritis

Radiosynovectomy is often used to relieve osteoarthritis symptoms. The method is particularly effective in active synovitis and recurrent effusions. However, one must be careful when scheduling RS to patients with advanced joint and extensive hyaline cartilage damage, especially damage to the subchondral bone. Preserved articular cartilage protects the subchondral bone layer before irradiation. In its absence there is a heightened irradiation of the bone, which can potentially lead to necrosis – this is of particular importance in patients scheduled for hip replacement. There have been cases of early migration of the implant caused by osteonecrosis after radiosynovectomy conducted prior to the surgery(.

In the previously published meta-analysis of RS treatments an improvement following RS was observed on average in 56% of patients in the group(. Better results were obtained in cases of less advanced degenerative and overload-induced changes within the joint. A subsequent analysis of radiosynovectomy efficacy in patients with intraarticular effusions resulting from the degenerative disease revealed 40% of positive results, but negative results were found in 9% of patients. In the remaining patients the disease was stabilized and there was no further progress of the disease(.

Other joint diseases

In pigmented villonodular synovitis RS is particularly useful as an adjuvant therapy after the surgical/arthroscopic removal of the synovium(. In the treatment of arthritis resulting from Lyme disease radiosynovectomy efficacy ranged from 25% to 82%(. The procedure has also been used in patients with crystal-induced arthritis and significant improvement was observed in 40–70% of the cases(.

Summary

Radiosynovectomy is a highly effective and safe method of treating the diseases of thickened and excessively vascularized (actively inflamed) synovium or intraarticular haemorrhages resulting from bleeding disorders. RS efficacy largely depends on determining the correct eligibility for the procedure which should be carried out by multidisciplinary diagnostic and therapeutic teams in order to achieve optimal results.