Safety of intra-articular injection of etanercept in small-joint arthritis: an uncontrolled, pilot-study with independent imaging assessment

Joint Bone Spine 73 (2006) 714–717 http://france.elsevier.com/direct/BONSOI/ Original article Safety of intra-articular injection of etanercept in small-joint arthritis: an uncontrolled, pilot-study with independent imaging assessment Henning Bliddala,*, Lene Tersleva, Etienne Qvistgaarda, Peter v.d. Reckea,b, Christian C. Holma, Bente Danneskiold-Samsoea, Anette Savnika,b, Søren Torp-Pedersena a The Parker Institute, Frederiksberg Hospital, Copenhagen, DK-2000, Denmark b Department of Radiology, Frederiksberg Hospital, Copenhagen, Denmark Received 30 January 2006; accepted 30 May 2006 Available online 20 September 2006 Abstract This study was conducted to test the safety of intra-articular tumor necrosis factor alpha (TNF-α) antagonists in small joints with arthritis. A dose of 2–8 mg etanercept was given intra-articularly guided by ultrasonography (US) in 26 patients with a flare of arthritis in a particular joint (16 wrists, two elbows, two ankles, six finger joints). Primary end points were imaging analyses by independent investigators: US-Doppler measurements were performed in all patients before and after the injection and MRI before and after were obtained in nine patients. The only adverse event was a case of swelling of the hand lasting 2 days after a wrist injection. Two patients had a supplementary glucocorticoid injection and were excluded from efficacy analysis after 4 days and 3 weeks, respectively. VAS for pain decreased after 1 week in 23 of 25 patients (median 0.62), and after 1 month in 14 of 24 patients (median 0.60). No significant changes were seen in erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP). On MRI, all nine cases tested had a reduction in synovial thickness (P = 0.008) and US Doppler signals diminished after treatment (resistance index (RI) P = 0.02, pixels P = 0.09). In conclusion, intra-articular injection of etanercept gave no noticeable adverse events. © 2006 Elsevier Masson SAS. All rights reserved. Keywords: Intra-articular; etanercept; Safety; MRI; Ultrasound Doppler 1. Introduction Tumor necrosis factor alpha (TNF-α) is found in the synovial tissue and cartilage–pannus junctions in patients with rheumatoid arthritis (RA) [1] and has been associated with levels of pain [2]. In arthritis, systemic anti-TNF-α therapy is seemingly as effective as glucocorticoids and might also be used for injections into joint in parallel to the widespread use of intraarticular injections of corticosteroids [3]. Circumstances warranting the more expensive biological medication would include former adverse events to the corticosteroids or a reduction in steroidal load to the individual patient. The few studies published on anti-TNF medications given intra-articularly have varying results [4–8]. Some of this variation may be due to * Corresponding author. Tel.: +45 22 12 1952; fax: +45 38 16 4159. E-mail address: henning.bliddal@fh.hosp.dk (H. Bliddal). 1297-319X/$ - see front matter © 2006 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.jbspin.2006.05.004 extra-articular placement of the injections [9], which can be avoided by giving the injection guided by ultrasound [10]. The aim of this study was to test the safety of TNF-α antagonists by etanercept (Enbrel®) administered intraarticularly in patients with a flare of RA in single joints. The treatment was restricted to small joints in which a limited dose was expected to have a local impact on the arthritis. 2. Methods 2.1. Patients Patients aged over 18 years with RA were recruited from the outpatient clinic at the Department of Rheumatology, Frederiksberg Hospital, Denmark. Patients were eligible irrespective of DMARD treatment; however, none received anti-TNF-α therapy. Intra-articular therapy was indicated because of flare 715 of arthritis activity in single joint(s). Patients were excluded if they had received intra-articular injection of steroids in the joint in the preceding 3 months, or had an increased risk of infection or bleeding after injection. Twenty-six participants (mean age 58.6 years, range 25– 82 years, IgM rheumafactor positive N = 16) were injected with etanercept: 16 wrists, two elbows, two ankles, and six finger or toe joints. 2.2. Design The first 12 participants were randomized to three different doses of etanercept (2, 4, or 8 mg). As no adverse events occurred, the remaining 14 participants were given 8 mg. All participants were followed both clinically and by ultrasonography (US) measurements of the target joint; images were stored and evaluated by investigators blinded to all clinical information. In cases of non-response, participants in the study were offered supplementary injections with steroids, preferably first after the 1-month follow-up. A further injection of etanercept in another joint was also offered after a minimum of 1 month. 2.3. Injection technique described in detail [12]. Coronal T1-weighted fast-field-echo (FFE) images were obtained before and after Gadodiamid (Gd, Nycomed Amersham A/S). The thickness of the enhanced synovial membrane was outlined on the slice (post Gd images). 2.8. Ultrasound A Sequoia® (Acuson, Mountain View, CA, USA) was used with an 8–13 MHz linear array transducer and color Doppler and spectral Doppler applied. A computerized estimate of the relative pixel area with perfusion in the synovial tissue was calculated at each examination along with measurements of resistance index (RI) for synovial blood flow measured by spectral Doppler technique [13,14]. 2.9. Ethical considerations The local Ethical Committee and the Danish Medicines Agency approved the study (KF 02-003/01) and all patients signed an informed consent form. 2.10. Statistical analysis Before injection, the skin and subcutaneous tissue above the joint cavity were anaesthetized with 1 ml of 1% lidocaine and the joint cavity was aspirated. US was used to determine the placement of aspiration and injection into the joint cavity. No significant difference between different joints or doses was found and for the final calculations all data were pooled because of the limited material. Non-parametric statistical analyses were chosen: the Wilcoxon matched-pairs signed rank test for the comparison of baseline with 1-month data of imaging. Level of significance was chosen at 0.05. 2.4. Safety 3. Results After injection of etanercept, the first 12 participants were examined both clinically and with ultrasound daily for 3 days. All participants were seen weekly during the first month after receiving etanercept and again after the second and third month. Participants were questioned about adverse events at all visits. 3.1. Safety 2.5. Pain and blood tests Self-reported pain was registered and blood samples were obtained for analysis of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). 2.6. Joint score Participants were tested by an independent clinician, who evaluated swelling and tenderness of the joint treated on a scale 0–3 [11] and filled in a joint score. Only one participant reported an adverse event during the study. This participant had received etanercept 4 mg in the wrist and developed a slight, diffuse swelling on the back of the hand the day after the aspiration/injection. No redness or induration of the tissue was present and the swelling subsided 2 days later. This participant responded well to therapy and had no other noticeable effects. The remaining participants had no adverse events, apart from temporary local soreness. No symptom flare, local skin reaction, or signs of infection or any other reactions at the joints or their surroundings were seen on the clinical or ultrasound examinations. Six participants with a very good response received a second injection of etanercept in another joint a minimum of 1 month after the first injection. These joints responded equally well and no adverse events were seen. 3.2. Clinical evaluation 2.7. MRI imaging MRI was performed using a 1.5 T MR-system (Gyroscan ACS-NT, Philips, Best, The Netherlands) as previously Two of the initial participants were not included all through this analysis due to an intra-articular steroid injection (one within the first week, the other after 3 weeks) before the 1- 716 month control. In the rest of the participants, both tenderness and swelling decreased significantly after 1 week (P < 0.02) and 1 month (P < 0.03). After 3 months, joint evaluation was not significantly different from baseline. VAS normalized to the level at onset (defined as 1.0) decreased after 1 week in 23 of 25 participants to median 0.62 (P < 0.001), and after 1 month in 14 of the 24 participants to median 0.60 (P < 0.05). No significant changes were seen in CRP or ESR. 3.3. Ultrasound results All participants had abnormal blood flow at the ultrasound examination before the injections, as evidenced by Doppler signals from the synovial membrane and by low RI values. The change in pixel fraction obtained with the injections was associated with the amount of diseased synovial tissue at the beginning of the study as measured by total pixel area (grey scale) (P < 0.02). 3.4. MRI A reduction in synovial thickness was demonstrated in all nine cases tested (Table 1). The reduction in synovial thickness was related to the baseline value (Rs = 0.90) indicating an association between the amount of diseased tissue and the responsiveness. 4. Discussion Experience with intra-articular administration of etanercept is limited. In the present study, 25 of the 26 participants were treated without any adverse events that could be ascribed to the injected etanercept, while one participant had local swelling of the hand for 2 days. The safety of etanercept in the joint was a major concern as subcutaneous administration of etanercept may induce a local reaction [15]. Also, a local reaction has been speculated in one case of inflammatory reaction in a knee joint injected twice with etanercept within a few weeks [8]. Our intra-articular injections, including six repeated injecTable 1 Imaging parameters at baseline and 1 month after the injection with Etanercept in a joint with flare of arthritis (the target joint) The median and ranges are given for the 24 patients evaluated at both times with ultrasound (nine patients with MRI). The resistive index (RI) is inversely correlated to inflammatory activity [20]. Independent observers performed the imaging analyses. Parameter Mean, median and (range) MRI post-contrast thickness in mm: Baseline Mean 4.89, median 3.33 (2.53–10.80) 1 month Mean 2.48, median 1.97 (1.40–5.27)*** US Doppler pixel area: Baseline Mean 0.22, median 0.24 (0.08–0.68) 1 month Mean 0.17, median 0.18 (0.00–0.55)* US Doppler RI value Baseline Mean 0.67, median 0.69 (0.46–0.88) 1 month Mean 0.73, median 0.70 (0.49–1.00)** Wilcoxon matched-pairs signed ranks test (baseline to 1 month): * P < 0.09, ** P < 0.05, *** P < 0.01. tions in another joint of the same participants, did not provoke untoward reactions of this type. If repeated injections were indicated, using etanercept instead of methylprednisolone steroids would reduce the load of steroids, both locally and systemically. This advantage of etanercept must be weighed against a considerable increase in economical costs. The number of participants in our study was too small to demonstrate possible differences between the 2 and 8 mg doses of etanercept; and further experience may clarify an optimal dosage interval. The changes in objective imaging parameters resemble those demonstrated after corticosteroid injections into joints of corticosteroids [16]; however, there is no direct comparison between these substances. Two participants had neither objective nor subjective effect from the etanercept injection but had responded to an earlier injection with corticosteroid. Conversely, some others had a very pronounced effect from the local anti-TNF therapy. It is possible that responsiveness to anti-TNF locally varies in parallel to the experience with systemic therapy [17]. Both MRI and US are now established methods to evaluate arthritic joints [18,19]. We have found that the Doppler ultrasound technique was a reliable tool for measuring the synovial vascularization, with a high intra- and inter-observer reliability [13]. In this study, both MRI and Doppler values indicated a change after the injection of etanercept. The changes in MRI were correlated to the amount of diseased synovial tissue in the joint at baseline as a possible indication of a more extensive disease. Conflicting results have been seen with infliximab given intraarticularly in knee joints, which may be due to differences in patient selection [6,7], although other joints may be treated with success [4]. Intra-articular injections of 2–8 mg of etanercept may safely be given at least once into small joints. The range of possibilities for local therapy with intra-articular anti-TNF needs clarification in further controlled trials including comparisons with glucocorticoid injections. Acknowledgements We would like to thank study nurse Merete Wille, secretary Mette Gad, and the laboratory technicians Inger Wätjen and Tove Riis Johannessen for skilled assistance. This study was supported by grants from the Oak Foundation. Conflicting interests Henning Bliddal has received a grant from Wyeth Pharmaceuticals, which supported this study economically and donated the etanercept. None of the authors is employed by or receives salary from any company. References [1] Deleuran BW, Chu CQ, Field M, Brennan FM, Mitchell T, Feldmann M, et al. Localization of tumor necrosis factor receptors in the synovial tissue and cartilage–pannus junction in patients with rheumatoid arthritis. 717 Implications for local actions of tumor necrosis factor alpha. Arthritis Rheum 1992;35:1170–8. [2] Beckham JC, Caldwell DS, Peterson BL, Pippen AM, Currie MS, Keefe FJ, et al. 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