Radiation synovectomy with (90)Yttrium, (186)Rhenium and (169)Erbium: a systematic literature review with meta-analyses.

OBJECTIVE: To perform a systemic review and meta-analysis on the effectiveness of radiosynoviorthesis (RSO). METHODS: A search of medical databases was conducted. Criteria for inclusion: articles in English, minimum follow-up of 6 months, specification of joint disease, reported outcome of at least 5 RSOs. The studies were scored for quality by the Oxford Centre of Evidenced-based Medicine Levels of Evidence, from 1 to 4. RESULTS: Twenty-one (21) studies were included (3 quality 1b, 5 2b and 13 4), analysing 169Erbium/186Rhenium-RSO used predominantly in small joints and 49 (1 quality 1b, 10 2b and 38 4) on 90Yttrium-RSO used predominantly in knee joints. The reported success rates of 169Erbium/186Rhenium-RSO ranged from 69-100% at 6 months, and from 54-100% at > or =12 months; for 90Yttrium they were 24-100% and 29-94%, res-pectively. Studies comparing the effect of RSO with that of glucocorticoid (GC) or saline injection alone were pooled. At 6 months, the pooled odds ratio favouring RSO of the knee with Yttrium over control is 4 (confidence interval (CI) 95% 1.2-14), p=0.02, but at 12 months the ratio was 1.7 (CI95% 0.69-4), p=0.26. For RSO of small joints with Erbium/Rhenium compared to controls, the pooled odds ratio at 6 months is 2 (CI95% 0.66-6), p=0.22 and at 12 months 2 (CI95% 1.09-3.5), p=0.03. CONCLUSION: Reported success rates of RSO are high, but differences in effect with GC injection are less evident, although there is marked heterogeneity in study design of the (small number of) comparative studies.

[Local treatment for persistent inflammatory arthritis of the knee: intra-articular injection of glucocorticoids and bed rest]. / Lokale behandeling van persisterende inflammatoire artritis van de knie: intra-articulaire injecties met glucocorticoïden en bedrust.

Two studies evaluating treatment options for persistent mono-arthritis are discussed. In one study arthroscopic lavage plus intra-articular glucocorticoids was compared with arthroscopic lavage without glucocorticoids, and with joint aspiration plus glucocorticoids. Both intra-articular glucocorticoids and lavage have their merits, but glucocorticoids appear to be slightly more effective. In the second study radioactive Yttrium plus intra-articular glucocorticoids was compared with glucocorticoids alone. Yttrium provided little additional value. There are some indications that a period of strict bed rest after treatment is beneficial. Intra-articular glucocorticoids should not be administered more frequently than three times per year in the same joint.

Radiation synovectomy of the upper extremity joints: does leakage from the joint to non-target organs impair its therapeutic effect?

Does leakage impair the therapeutic effect of radiosynoviorthesis (RSO)? Are there differences in leakage between (169)Erbium and (186)Rhenium? At baseline and at 6 and 12 months after RSO, six clinical parameters were scored. Changes in clinical variables over time were summed to a change composite index (CCI), ranging from 0 (no effect) to 12 (maximal effect). CCI >or= 6 was considered successful treatment. Differences in leakage between responders and non-responders, and between (169)Erbium and (186)Rhenium were examined. Regression analyses were performed to explore whether baseline variables predicted leakage. Both at 6 and 12 months response rates were 25 of 36 (69%). Five of 11 (45%) non-responders showed leakage versus 20 of 25 (80%) responders (P=0.06). Mean leakage to lymph nodes was 0.4+/-0.7% versus 2.4+/-0.8% (P=0.04). Median leakage to liver/spleen was 0% versus 0.3% (P=0.4). Only age at the time of injection correlated significantly with leakage to lymph nodes. The (169)Erbium group showed leakage in 1 of 7 (14%) versus 24 of 30 (80%) for the (186)Rhenium group (P=0.002). Mean leakage to lymph nodes was 0.11+/-0.3% versus 2.1+/-2.8% (P=0.001). Median leakage to liver/spleen was 0% versus 0.5% (P=0.006). Leakage to non-target organs does not impair the clinical effect of RSO. Only age predicted leakage to lymph nodes significantly. Other baseline characteristics did not predict leakage. (169)Erbium shows significantly lower leakage to non-target organs than (186)Rhenium in RSO.

The intra-articular distribution of 90yttrium does not influence the clinical outcome of radiation synovectomy of the knee.

OBJECTIVES: To assess the impact of the intra-articular distribution of (90)yttrium-citrate ((90)Y) on the clinical effect of radiosynoviorthesis (RSO) of the knee and on (90)Y leakage from this joint. METHODS: Patients with arthritis of the knee received 185 MBq (90)Y combined with a glucocorticoid, followed by clinical bed rest. Intra-articular (90)Y distribution, measured with a dual-head gamma camera immediately or after 24 hours, was scored as mainly diffuse or mainly focal. Leakage to regional lymph nodes, the liver and spleen was assessed with a dual-head gamma camera after 24 hours. Clinical effect was scored after 6 months by a composite change index (CCI), range 0-12; responders were defined as having a CCI > or =6. RESULTS: Seventy-eight knees of 69 patients, mostly suffering from undifferentiated arthritis (42%) or RA (28%), were treated. (90)Y distribution was mainly diffuse in 54% and mainly focal in 46% with clinical response rates of 40% versus 56%, respectively, p = 0.3. CCI was not correlated with distribution. (90)Y leakage was found only to the liver and the spleen (mean leakage 0.4% and 1.1%, respectively). Leakage was significantly less in case of diffuse intra-articular (90)Y distribution, whereas leakage to the liver was correlated with distribution (r = 0.68, p<0.001). (90)Y leakage was not correlated with CCI. CONCLUSIONS: Intra-articular (90)Y distribution does not influence the clinical effect of RSO of the knee. Although (90)Y leakage from the joint is less if (90)Y distributes diffusely in the joint cavity, leakage does not seem to hamper the clinical effect.

Clinical effect of radiation synovectomy of the upper extremity joints: a randomised, double-blind, placebo-controlled study.

PURPOSE: To compare the clinical efficacy of radiosynoviorthesis (RSO) with intra-articular radionuclide plus glucocorticoid (GC) injection (group A) with that of placebo plus GC injection (group B) for the treatment of persistent synovitis in joints of the upper extremity. METHODS: At baseline and at 6 and 12 months after intra-articular injection, six clinical parameters were scored. Changes in clinical values over time were summed to provide a change composite index (CCI), ranging from 0 (no effect) to 12 (maximal effect). A CCI > or =6 was considered to indicate successful treatment. Differences in response rate and CCI between groups A and B were examined. Regression analyses were performed to explore whether baseline variables could predict therapeutic effect. RESULTS: Sixty-eight joints in 44 patients were treated. Six months after intra-articular injection, response rates (CCI > or =6) were 69% (25/36) in group A and 29% (9/31) in group B (p=0.001). The mean CCIs +/- standard deviation at 6 months were 6.7+/-3.2 for group A and 3.3+/-3.8 for group B (p=0.001). At 12 months the response rates were 69% (25/36) in group A and 32% (8/25) in group B (p=0.004). The mean CCIs at 12 months were 6.8+/-3.3 for group A and 4.2+/-4.7 for group B (p= 0.046). None of the baseline variables predicted the therapeutic effect. CONCLUSION: RSO (radionuclide plus GC) of upper extremity joints with immobilisation for 72 h shows a significantly better response rate than placebo plus GC in patients with persistent synovitis after at least one failed outpatient intra-articular GC injection.

Radiation synovectomy with yttrium-90 for persisting arthritis has direct harmful effects on human cartilage that cannot be prevented by co-administration of glucocorticoids: an in vitro study.

BACKGROUND: It was recently shown that radiation synovectomy with yttrium-90 (90Y) and glucocorticoids is not superior to intra-articular glucocorticoids alone in the treatment of persistent gonarthritis. In that study, it seemed that in patients treated by radiation synovectomy, progression of radiographic joint damage occurred. OBJECTIVE: To test in vitro the direct effects of radiation synovectomy with 90Y on human cartilage. METHODS: Human cartilage tissue was exposed to 90Y, glucocorticoids or the combination. 1:2000 to 1:20 dilutions of the clinical dose of 5 mCi/ml 90Y and 20 mg/ml glucocorticoids were used. After a 4-day exposure and a subsequent 12-day recovery period, proteoglycan synthesis, proteoglycan release and proteoglycan content were measured. In addition, human synovial tissue was cultured for 4 days with 90Y or glucocorticoids. Culture supernatants were analysed for cartilage-destructive activity. RESULTS: 90Y, glucocorticoids and the combination inhibited proteoglycan synthesis considerably and dose dependently, an effect that sustained for at least 12 days. Proteoglycan release was transiently increased by 90Y, an effect that was not changed by addition of glucocorticoids, which had no effect on its own. Proteoglycan content was eventually adversely affected by 90Y, an effect hardly influenced by glucocorticoids. Neither 90Y nor glucocorticoids changed the cartilage-destructive properties of synovial tissue. CONCLUSIONS: 90Y, but not glucocorticoids, has direct harmful effects on cartilage in vitro. Indirect beneficial effects of 90Y via inhibition of cartilage-destructive properties of synovial tissue could not be shown. These observations may explain the possible radiographic joint damage on radiation synovectomy.

Pretreatment macrophage infiltration of the synovium predicts the clinical effect of both radiation synovectomy and intra-articular glucocorticoids.

OBJECTIVE: To explore whether pretreatment features of synovial tissue in patients with gonarthritis could predict the clinical effect of radiation synovectomy with yttrium-90 (90Y) and glucocorticoids or with intra-articular glucocorticoids alone. METHODS: A synovial biopsy was carried out blindly 2 weeks before treatment in 66 patients with persistent gonarthritis, who were randomised to treatment either with 90Y and triamcinolone or with placebo and triamcinolone. Immunohistochemistry was used to detect T cells, macrophages, B cells, plasma cells, fibroblast-like synoviocytes, adhesion molecules and pro-inflammatory cytokines. Stained sections were evaluated by digital image analysis. Individual patient improvement was expressed using a composite change index (CCI; range 0-12). Successful treatment was defined as CCI > or = 6 after 6 months. RESULTS: Patients with rheumatoid arthritis, psoriatic arthritis, undifferentiated arthritis and other causes of gonarthritis were included. The overall response rate was 47%. Clinical efficacy in both therapeutic groups was similar and not dependent on diagnosis. No significant differences were noted between baseline microscopic features of synovial tissue inflammation in patients with rheumatoid arthritis and in those with non-rheumatoid arthritis (ie, all diagnoses other than rheumatoid arthritis). The number of macrophages in the synovial sublining was significantly higher in responders than in non-responders (p = 0.002), independent of treatment group and diagnosis. The clinical effect was positively correlated with pretreatment total macrophage numbers (r = 0.28; p = 0.03), sublining macrophage numbers (r = 0.34; p = 0.005) and vascular cell adhesion molecule 1 expression (r = 0.25; p = 0.04). CONCLUSION: The observations support the view that intra-articular treatment either with 90Y and glucocorticoids or with glucocorticoids alone is especially successful in patients with marked synovial inflammation.

The effect of radiation synovectomy in patients with persistent arthritis: a prospective study.

OBJECTIVE: To investigate and compare the effects of radiation synovectomy of various joints in a rheumatological practice. METHODS: Consecutive patients referredfor radiation synovectomy to Medical Center Alkmaarfrom 1993 till 1996 were analyzed (n = 138). Patients had to have persistent arthritis despite at least two intra-articular glucocorticoid injections with 20 mg triamcinolone hexacetonide. The knees were treated with 185 MBq Yttrium-90; shoulders, elbows, wrists, hips and talocrural joints received 185 MBq Rhenium-186 and meta-carpophalangeal joints and proximal interphalangeal joints 37 MBq Erbium-169. The radionuclide injection was followed by injection of 20 mg triamcinolone in order to prevent flare-up of synovitis (due to chemical irritation) and needle-track burn. The clinical effect was assessed by evaluating VAS pain (0-10 point scale), functional disability, tenderness and swelling of the treated joint and patient's and physician's global assessments of the effect of therapy (each on a 4-point scale). RESULTS: The overall success rate for radiation synovectomy one year after treatment was 70% with a significant improvement in the variables VAS pain, functional disability and joint tenderness and swelling, when compared to baseline values (p < 0.000001). Moderate to considerable satisfaction of patients and physicians one year after treatment was found for > 50% of cases. Wrists and shoulders were the joints with highest success rate of treatment, followed by the elbows. Lowest success rates were found for hips and ankles. In RA treatment was effective in 76% of cases whereas patients with OA exhibited a success rate of 50%. In RA all treated joints, except the ankles, exhibited a success rate of > or = 75%. No short-term clinical adverse side effects were noted. CONCLUSION: Radiation synovectomy seems to be a successful treatment for persistent arthritis when other therapeutic modalities have failed.

Toxicity of anti-rheumatic drugs in a randomized clinical trial of early rheumatoid arthritis.

OBJECTIVE: To evaluate the toxicity of slow-acting anti-rheumatic drugs (SAARDs) and non-steroidal anti-inflammatory drugs (NSAIDs) in early rheumatoid arthritis. METHODS: Patients were randomized to receive a SAARD-hydroxychloroquine (HCQ; n=120), i.m. gold (n=114) or methotrexate (MTX; n=118)-or a NSAID only (n=67). Patients in the three SAARD groups were allowed to take NSAIDs. Follow-up included 545 patient-years (p-yr). Adverse effects were attributed to specific medications using the Naranjo scoring method. RESULTS: Fifty-five per cent of the patients suffered from adverse effect(s). Adverse effects were most common during i.m. gold therapy (87 per 100 p-yr), which led to permanent discontinuation of this treatment in 31 cases. The incidences of adverse effects that were probably attributable to NSAIDs in patients treated simultaneously with a SAARD were similar for the three SAARD groups. The mean period until the first adverse effect was longer in the MTX group (39 weeks) than in the HCQ group (27 weeks). Baseline clinical and sociodemographic parameters were not predictive of the occurrence of adverse effects. CONCLUSION: No adverse effect could be classified as definitely related to either SAARDs or NSAIDs by the Naranjo scoring method. The incidence of possible adverse effects of NSAIDs and SAARDs was 72 per 100 p-yr, and adverse effects led to permanent discontinuation of the therapy in 56 cases (13%) (31 patients receiving i.m. gold, 12 receiving MTX, 10 receiving HCQ and three receiving NSAID only).

Persistent synovitis treated with radiation synovectomy using yttrium-90: a retrospective evaluation of 83 procedures for 45 patients.

The objectives were to investigate the efficacy and safety of yttrium-90 colloid (Y-90) synovectomy in joints with persistent synovitis and to examine the effect of a second synovectomy using a double dose after an initial inadequate response. Of the 45 patients at the University Hospital Utrecht who underwent Y-90 synovectomy between July 1987 and October 1995, the effectiveness and side-effects of all yttrium procedures (n = 83) were assessed retrospectively. Glucocorticoids were administered together with the yttrium, except in 1987. Radiation synovectomy had an overall success rate of 75% (complete or almost complete remission of synovitis) initially, i.e. within 1 month of the procedure, partly due to co-administration of glucocorticoids. However, in October 1995, only 17 joints (22%) were still in remission with a mean (S.D.) duration of remission of 20.8 months (22.0), range 1-95 months (median 16 months). In 60 joints (78%), synovitis was present at that time because of an unsatisfactory initial response to the Y-90 injection (19 joints) or recurrent synovitis during follow-up (41 joints); the mean (S.D.) duration of remission of these 60 joints was 3.3 months (5.9), range 0-22 months. A second injection of a double dose of Y-90 after an initial inadequate response (n = 8) did not contribute significantly to a better result. Short-term side-effects occurred in two cases after two Y-90 injections (2%) without glucocorticoid co-administration: a post-injection flare-up of synovitis and a local skin burn lesion. Persistent synovitis can be treated by Y-90 synovectomy with an overall success rate of 75% within 1 month. However, prolonged remission of synovitis is only achieved in 29% of joints with a good initial response. It does not appear worthwhile to perform a second synovectomy with a double dose if the initial response was inadequate. Y-90 synovectomy leads to only minor short-term side-effects (2%).

[SAPHO syndrome: common denominator for various bone and skin diseases]. / SAPHO-syndroom: gemeenschappelijke noemer voor enkele bot- en huidziekten.

The acronym 'SAPHO' stands for synovitis, acne, pustulosis, hyperostosis and osteitis. Three subtypes of SAPHO can be distinguished which have the following features in common: sternoclavicular hyperostosis and sterile inflammatory lesions in both bone and skin. These subtypes are: sternocostoclavicular hyperostosis, chronic recurring multifocal osteomyelitis, and pustular arthro-osteitis. Hyperostosis and osteitic lesions may be similar to those seen in malignant bone tumours. Synovitis generally does not lead to bone erosions and one-third of the patients develop sacroiliitis. The SAPHO syndrome and seronegative spondyloarthropathy share some common features (a higher prevalence of the HLA-B27 antigen, occurrence of sacroiliitis and a higher incidence of chronic inflammatory bowel disease and psoriasis). Aetiology and pathogenesis of SAPHO are unknown; prognosis is good. The SAPHO syndrome often runs a protracted course, with intermittent relapses and remissions without resulting serious disability. Treatment is aimed only at symptomatic relief and mainly consists of analgetics and nonsteroidal antiinflammatory drugs.

Methods to score vertebral deformities in patients with rheumatoid arthritis.

The objective was to compare four different scoring methods for vertebral deformities: the semiquantitative Kleerekoper score and three quantitative scores (according to Minne, Melton and Raymakers) in patients with rheumatoid arthritis (RA). Lateral radiographs of the thoracic and lumbar vertebral column were scored in 52 RA patients treated with corticosteroids (Cs) and 52 RA patients not Cs treated (matched for age and gender). Clinically manifest vertebral fractures were defined as a vertebral deformity leading to the prescription of therapy: bedrest and/or analgesies. The number of Cs-treated RA patients with vertebral deformities was only increased according to the Kleerekoper score (relative risk 2.31; 95% confidence interval 1.36-3.90). The total number of vertebral deformities was increased in Cs-treated RA patients according to the method of Kleerekoper. Minne and Raymakers, but not according to Melton. The Spinal Deformity Index was increased in the Cs-treated RA patients according to Minne (P < 0.05), but not according to Raymakers. In both patient groups, the number of patients with clinically manifest vertebral fractures was much lower than that of vertebral deformities, e.g. in the Cs-treated patients 13% vs 35.79% (depending on the scoring method used). All eight patients with clinically manifest vertebral fractures had severe height loss (25% or more) in at least one vertebra. Vertebral deformities seem to occur more often in Cs-treated patients than in those not Cs-treated. However, differences exist in the number of patients with vertebral deformities and in the total number of vertebral deformities between different scoring methods. This emphasizes the need for a gold standard or consensus for defining vertebral deformities, in which, in our opinion, a Spinal Deformity Index has to be included. Clinically manifest vertebral fractures are predominantly characterized by severe vertebral deformities on X-rays.

Vertebral fractures in patients with rheumatoid arthritis treated with corticosteroids.

OBJECTIVES: To examine the relationship between roentgenological deformities of the vertebral column and clinical manifestations of vertebral fractures in patients with RA, treated with glucocorticosteroids (Cs). METHODS: In all outpatients of Utrecht University Hospital with RA, who were currently using Cs (n = 52), roentgenograms of the thoracic and lumbar vertebral column were taken. Roentgenological deformities were scored à vue using the Kleerekoper score, and quantitatively using the Heidelberg and Utrecht scoring methods. Clinical manifestation of a vertebral fracture was defined as a vertebral deformity leading to prescription of therapy: bedrest and/or analgesics. Clinical manifestations of fractures were also recorded in a control group of 55 RA patients not on Cs, matched for age and gender. RESULTS: The prevalence of vertebral deformities in the Cs-treated RA patients, assessed with the Kleerekoper score, was 58% (30 of 52 patients). In 7 of the Cs-treated patients clinical manifestations of a vertebral fracture were present, versus 1 in the control group (p = 0.03). No significant correlation between the 3 deformity scores and the cumulative dose of Cs was found. No (inverse) correlation between serum osteocalcin and the daily dosage of prednisone was found. CONCLUSION: Corticosteroids in active RA are associated with fractures, even when low doses are used: the prevalence of vertebral deformities (58%) in the Cs-treated RA patients was much higher than the frequency in postmenopausal women of the same age reported in the literature, and the reported incidence of clinically manifestations of vertebral fractures was higher in the Cs-treated RA patients than in the control group of RA-patients not treated with Cs.