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D. Göbel · S. Gratz · T. von Rothkirch · W. Becker
H.-G. Willert

Radiosynoviorthesis with rhenium-186 in rheumatoid arthritis: a prospective study of three treatment regimens Received: 29 October 1996 / Accepted: 10 June 1997 Abstract The aim of this study was to evaluate the effi-
Therefore, we recommend this treatment for articulosyno- ciency of radiation synovectomy with rhenium-186 in vitis with the exception of severe forms, the latter because rheumatoid arthritis. In this prospective, randomized trial of the effective penetration range of rhenium-186.
we compared three different treatment regimens for shoul-der, elbow, wrist, hip and ankle joints: group 1, injection Key words Articulosynovitis · Minimal invasive
of rhenium-186; group 2, injection of rhenium-186 in com- therapy · Radiosynoviorthesis · Rheumatoid arthritis bination with triamcinolone hexacetonide; group 3, injec-tion of triamcinolone hexacetonide alone. Each treatmentgroup included 50 joints. Patients included in the study hadto fulfil the following criteria: (1) they had to have a diag- nosis of rheumatoid arthritis (ARA criteria 1988), (2) theirdisease-modifying drug had to be methotrexate, started at Patients with rheumatoid arthritis quite frequently suffer least 6 months prior to injection therapy and given for the from persistent synovitis of some joints, while other pa- entire study time, (3) their nonsteroidal anti-inflammatory tients are successfully treated by the use of disease-modi- drug had to be diclofenac given at a dose of 150 mg/day fying drugs. In persistent cases or in joints where surgery, or less and (4) they were also given prednisolone at a dose i. e. mostly synovectomy, is difficult to perform, minimal of 7.5 mg/day or less. After 3 years of follow-up, 79 joints invasive treatment by the method of injection therapy met these criteria, i. e. 71 joints were excluded from the seems to be the best alternative. In the literature there are study: 26 joints because the patients changed the disease- controversial reports about the success rate of radiosynov- modifying drug (12 joints from group 1, 4 joints from group iorthesis [1 – 7]. With respect to rhenium-186 (Re-186), our 2 and 10 joints from group 3); 45 joints because of recur- medline inquiries revealed only a few reports and none an- rent synovitis and second-stage treatment (21 joints from swered the question of long-term outcome. No study com- group 1, 5 joints from group 2 and 19 joints from group 3).
pared Re-186 with the results of other forms of injection During the follow-up period, joints were assessed for pain, therapy. Therefore, we compared three different treatment synovitis, joint motion and stage of radiological destruc- protocols during a follow-up period of 3 years.
tion. Best clinical results and slowest progression in radio-logical destruction were achieved with the combined in-jection of rhenium-186 and triamcinolone hexacetonide.
Injection therapy was performed under aseptic conditions on 150 D. Göbel ( )· T. von Rothkirch · H.-G. Willert joints (shoulder, elbow, wrist, hip and ankle) randomized into three groups with 50 joints in each group. We included in our study only patients with rheumatoid arthritis diagnosed according to the crite- ria of the American Rheumatism Association (ARA) of 1988. Pa- tients with another underlying inflammatory disease, such as anky- losing spondylitis, Reiter’s syndrome, psoriatic arthritis, etc., were The medical management of the patients was standardized to min- imize a possible infuence of drug therapy on the results of our study: Department of Nuclear Medicine, University Hospital of Goettingen, 1. All patients received the disease-modifying drug, methotrexate, which was given intramuscularly or orally and was started at least 6 Table 1 Doses of rhenium-186 and triamcinolone hexacetonide
2. All patients received the nonsteroidal anti-inflammatory drug, Fig. 1 Drop-out rate for each treatment group during follow-up;
diclofenac, at a dose of 150 mg/day or less.
group 1, Re-186; group 2, Re-186/Triam; group 3, Triam (Triam tri- 3. All patients received hydrocortisone in the form of 7.5 mg pred- amcinolone, Re rhenium, TDOR total drop out, DORSY drop out due nisolone equivalent or less per day.
to recurrent articulosynovitis with second-stage treatment) Exclusion criteria to and during the study were: 1. Patient’s age less than 40 years [3, 6, 7, 20 – 22]2. Previous surgery or radio- or chemical synovectomy on this/these joint/s3. Change in disease-modifying drug during the study 4. Surgery or injection therapy during the follow-up time Injection therapy was carried out using the doses of Re-186 and triamcinolone hexacetonide outlined in Table 1. Patients in group 1underwent radiosynoviorthesis with Re-186, while in group 2, injec-tion therapy was performed using a combination of Re-186 and tri- amcinolone hexacetonide. Patients in group 3 underwent injection of triamcinolone hexacetonide alone in the doses, outlined in Table 1, which are those recommended by the producer. Immediately after in- jection the joints were immobilized for 48 h to minimize early trans-port of the radionuclide via the perivascular lymphatic vessels.
During the follow-up period of 3 years, pain and synovitis were assessed on a semiquantitative scale from 0 (= no pain/synovitis) to 4 (= severe pain/synovitis). Total range of motion was measured in degrees, while radiological assessment followed the standard refer- ence films of Larsen et al. [8]. Follow-up dates were: prior to injec-tion, and 8 weeks, 3 and 6 months, and 1, 2 and 3 years post treat- Fig. 2 Degree of pain during follow-up period; 0 = no pain, 1 = slight,
2 = moderate, 3 = intense, 4 = severe (pre pretreatment, we week mo month, y year) Regarding reduction of synovitis, the best short-term During the follow-up time, the drop-out rate was 47.3%, results were achieved by injection of triamcinolone hexa- i. e. 71 joints were excluded from the study. Twenty-six cetonide, but after 1 year synovial swelling increased joints were excluded because the patients changed their again, reaching nearly pretherapeutic levels in the 3rd year.
disease-modifying drug (12 joints from group 1, 4 joints In the other groups, joints remained free from signs of from group 2 and 10 joints from group 3). Because of re- current synovitis, 45 joints underwent surgery or injection The increase in the range of motion correlated with the therapy for a second time and had to be excluded (21 joints reduction in the levels of pain and synovitis, i. e. during the from group 1, 5 joints from group 2 and 19 joints from 1st year following injection the best results were achieved group 3; Fig. 1). After 3 years of follow-up, 79 joints were in group 3, while there was reduction in joint motion in evaluated: 17 joints from group 1, 41 joints from group 2 group 3 in the 2nd and 3rd years. In groups 1 and 2, joint motion did not change during the follow-up period. This There was a marked improvement in pain following tri- correlated with radiological assessment. The radiological amcinolone hexacetonide injection (group 3) during the progression of joint destruction – Larsen stage after 3 years1st year, while in groups 1 and 2 the decrease in pain was minus Larsen stage prior to treatment – was as follows: slower (Fig. 2). After 2 years, pain in group 3 increased group 1 = 1.0; group 2 = 0.62; group 3 = 1.7 (Fig. 4). Com- above the levels of groups 1 and 2. The best results were plications in the form of joint infection, radiation derma- seen in group 2, i. e. patients treated by the combined ther- titis or any periarticular soft tissue damage were not en- 50 – 60% rate of good and excellent results, Gregoir [18] presents a success rate of 83% for the elbow joint 1 year after injection of rhenium. At 2 years follow-up, the suc-cess rate drops down to 65%. However, Gregoir reviewedonly 40% of his patients, i. e. he did not know the outcome of the remaining 60%. Gumpels [2], who compared the in-jection of methylprednisolone with erbium-169 (follow-up = 1 year; review of 99.3% of all joints), has found a rate of improvement of 25% and no difference between the two therapies. Thus, our study seems to be the first random- ized, prospective trial comparing steroid injection with rhenium radiosynoviorthesis and combined treatment, with a 3-year follow-up and 100% review of treated joints.
Taking in mind the total drop-out rate (TDOR), as well Fig. 3 Synovial swelling during follow-up period (0 = no synovitis,
as the drop out because of recurrent synovitis (DORSY) in 1 = slight, 2 = moderate, 3 = intense, 4 = severe) groups 1 (TDOR = 66%, DORSY = 42%) and 3 (TDOR =58%, DORSY = 38%), there was no significant differencebetween rhenium and steroid injection alone, which is inkeeping with the results of Gumpel [2]. On the other hand,high levels of synovitis and pain at 3 years follow-up, aswell as the radiological progression of joint destruction, favoured radiosynoviorthesis over steroid injection.
The long-term success rate of 34% for the rhenium in- jection was far below the values of Menkes and Gregoir [18, 19], while for the combined treatment the success rate of 82% was promising. The additional injection of triam- cinolone hexacetonide seemed to prevent at least part of the transient local reaction and therefore reduced painfaster than was observed following the injection of the ra- dionuclide alone. This seemed to have beneficial effects on the progression of radiological destruction. Therefore,our theory is that the long-term success of radiosynovior- thesis depends on the control of synovitis during the first 8 weeks after injection therapy. If transient local synovitis Fig. 4 Radiological stage of joint destruction according to standard
caused by the radionuclide injection results in a build up of a synovial layer that is thicker than the effective pene-tration range of Re-186, this will lead to fibrosis in thesuperficial layer of the synovium, while deeper structuresare still able to perpetuate an exudative synovitis [24 – 27].
The effective penetration range is, according to John- son and Yanch [23], “. . . the distance from the source at which 90% of the absorbed dose is deposit . . .”, which forrhenium is 0.9 mm. In other publications [5, 7] we found Currently, radiation synovectomy seems to be the only es- a mean range of 1.2 mm. Therefore, in future a synovitis tablished alternative to open or arthroscopic surgery. De- of much more than 1 – 1.5 mm could be considered a con- pending on the size of the joint there are different radio- traindication to radiosynoviorthesis with Re-186. How- nuclides available: yttrium-90 for the knee joint [9 – 13], ever, this theory has to be proved in future studies, e. g.
erbium-169 for finger joints [2, 4, 14, 15] and Re-186 for evaluating synovial thickness by ultrasound scan prior to shoulder, elbow, wrist, hip and ankle joints [5, 6]. While gold-198 is not used any longer, dysprosium-165, mainly In conclusion, we believe that, in patients over 40 years used for the knee joint [16], has some major disadvantages of age who have undergone 6 months of an overall success- for general use in Germany: (1) it is not a registered drug ful treatment with a disease-modifying drug, radiosynovi- in Germany, (2) it is around 10 times more expensive than orthesis is indicated in joints with remaining synovitis. We yttrium and (3) the place of production and the place of ap- also believe that radiosynoviorthesis is indicated in patients plication have to be close together [5]. Consistent with the who are unable to undergo surgery. We prefer to give the ra- report of Deutsch et al. [1], we observed that most reports dionuclide in combination with triamcinolone hexacetonide in the literature present their experience with yttrium-90, and to immobilize the joint for 48 h to minimize radionu- while there are only a few reports of radiosynovectomy clide leakage from the joint. In marked synovitis, i. e. syn- with Re-186 [17 – 19]. While Menkes [19] reports a ovial swelling above the effective range of Re-186, we recommend surgery because lower layers of the synovium 13. Will R, Laing B, Edelman J, Lovegrove F, Surveyor I (1992) are not reached by radiosynoviorthesis and the destructive Comparison of two yttrium-90 regimes in inflammatory and os-teoarthopathies. Ann Rheum Dis 51: 262 – 265 process will continue. In patients who do not respond to ra- 14. Boussina I, Toussaint M, Ott H, Hermans P, Fallet GH (1979) A diosynoviorthesis, we do not recommend that therapy be re- double-blind study of erbium-169 synoviorthesis in rheumatoid peated because of the unacceptably high failure rate [28]. In digital joints. Scand J Rheumatol 8: 71 – 74 the case of additional tenosynovitis or bursitis, we favour 15. Tubiana R, Menkes CJ, Galmiche B, Delbarre F (1979) Die surgical treatment by teno- and articulosynovectomy to pre- intraartikuläre Injektion von β-Strahlern. Therapiewoche 29:507 – 513 vent further damage to tendons and soft tissues [29]. With 16. Zuckerman JD, Sledge CB, Shortkroff S, Venkatesan P (1987) these exceptions in mind, we believe that radiosynoviorthe- Treatment of rheumatoid arthritis using radiopharmaceuticals.
sis with Re-186 has proved it’s efficacy in the long-term and can be considered as an alternative to surgery.
17. Chinol M, Vallabhajosula S, Goldsmith J, et al. (1993) Chemis- try and biological behavior of samarium-153 and rhenium-186-labeled hydroxyapatite particles: potential radiopharmaceuti-cals for radiation synovectomy. J Nucl Med 34: 1536 – 1542 18. Gregoir C, Menkes CJ (1991) Rheumatoid elbow: patterns of joint involvement and the outcome of synoviorthesis. Ann Hand 19. Menkes CJ (1979) Radioisotope synoviorthesis in rheumatoid 1. Deutsch E, Broddack JW, Deutsch KF (1993) Radiation syn- ovectomy revised. Eur J Nucl Med 20: 1113 – 1127 20. Edmonds J, Smart R, Laurent R, et al. (1994) A comparative 2. Gumpel JM, Matthews SA, Fisher M (1979) Synoviorthesis with study of the safety and efficacy of dysprosium-165 hydroxide erbium-169: a double-blind controlled comparison of erbium- macro-aggregate and yttrium-90 silicate colloid in radiation syn- 169 with corticosteroid. Ann Rheum Dis 38: 341 – 343 ovectomy – a multicentre double blind clinical trial. Br J Rheu- 3. Lueders C, Feinendegen LE (1993) Die Radiosynoviorthese.
21. Noble J, Jones AG, Davies MA, Sledge CB, Kramer RI, Livni 4. Menkes CJ, Le-Go A, Verrier P, Aignan M, Delbarre F (1977) E (1983) Leakage of radioactive particle systems from synovi- Double-blind study of erbium 169 injection (synoviorthesis) in al joint fluid studied with a gamma camera. J Bone Joint Surg rheumatoid digital joints. Ann Rheum Dis 36: 254 – 256 5. Mödder G (1995) Die Radiosynoviorthese – Nuklearmedizi- 22. Stevenson AC, Bedfort J (1973) Cytogenetic and scanning study nische Gelenktherapie und -diagnostik in Rheumatologie und of patients receiving intra-articular injections of gold-198 and yttrium-90. Ann Rheum Dis 32: 112 – 132 6. Müller-Brand J (1990) Grundlagen der Radiosynoviorthese.
23. Johnson LS, Yanch JC (1991) Absorbed dose profiles for radio- nuclides of frequent use in radiation synovectomy. Arthritis 7. Weber M (1993) Lokale Gelenkbehandlung bei chronischer Polyarthritis (cP): intraartikuläre Kortikosteroide und radioak- 24. Combe B, Krause E, Sany J (1989) Treatment of chronic knee tive Isotope. Schweiz Rundsch Med Prax 82: 353 – 358 synovitis with arthroscopic synovectomy after failure of intra- 8. Larsen A, Dale K, Eek M (1977) Radiographic evaluation of articular injection of radionuclide. Arthritis Rheum 32: 10 – 14 rheumatoid arthritis and related conditions by standard reference 25. Guaydier-Souquieres C, Beguin J, Ollivier D, Loyau G (1989) Knee arthroscopy after yttrium or osmic acid injection. Arthros- 9. Bridgman JF, Bruckner F, Bleehen NM (1971) Radioactive yttri- um in the treatment of rheumatoid knee effusions. Ann Rheum 26. Mohr W, Mohing W, Hersener J (1977) Morphologische Veränderungen am Gelenkkapselgewebe nach vorausgegange- 10. Isomäki AM, Inoue H, Oka M (1972) Uptake of 90Y resin col- ner Synoviorthese. Z Rheumatol 36: 316 – 331 loid by synovial fluid cells and synovial membrane in rheuma- 27. Yates DB (1973) Arthroscopy of the knee after the injection of toid arthritis. Scand J Rheumatol 1: 53 – 60 11. Jaworski R, McLean R, Choong K, Smart R, Edmonds J (1993) 28. Stucki G, Bozzone P, Treuer E, Wassmer P, Felder M (1993) Re-evaluating the need for hospitalization following synovec- Efficacy and safety of radiation synovectomy with yttrium-90: tomy using Yttrium-90 silicate. Br J Rheuamtol 32: 1012 – 1017 a retrospective long-term analysis of 164 applications in 82 pa- 12. Webb FWS, Lowe J, Bluestone R (1969) Uptake of colloidal ra- dioactive yttrium by synovial membrane. Ann Rheum Dis 29. Peters W, Lee P (1994) Radiation necrosis overlying ankle joint after injection with yttrium-90. Ann Plast Surg 32: 542 – 543


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