Ultrasonography and color Doppler in juvenile idiopathic arthritis: diagnosis and follow-up of ultrasound-guided steroid injection in the wrist region. A descriptive interventional study
© Laurell et al; licensee BioMed Central Ltd. 2012
Received: 10 December 2011
Accepted: 21 April 2012
Published: 21 April 2012
The wrist region is one of the most complex joints of the human body. It is prone to deformity and functional impairment in juvenile idiopathic arthritis (JIA), and is difficult to examine clinically. The aim of this study was to evaluate the role of ultrasonography (US) with Doppler in diagnosis of synovitis, guidance of steroid injections, and follow-up examinations of the wrist in JIA.
In 11 patients (median age 12.5 years, range 2-16), 15 wrists with clinically active arthritis were assessed clinically by US and color Doppler (Logiq 9, GE, 16-4 MHz linear transducer) prior to and 1 and 4 weeks after US-guided steroid injection.
US detected synovitis in the radio-carpal joints, the midcarpal joints, and the tendon sheaths in 87%, 53% and 33% of the wrists, respectively. Multiple compartments were involved in 67%. US-guidance allowed accurate placement of steroid in all 21 injected compartments, with a low rate of subcutaneous atrophy. Synovial hypertrophy was normalized in 86% of the wrists, hyperemia in 91%, and clinically active arthritis in 80%.
US enabled detection of synovial inflammation in compartments that are difficult to evaluate clinically and exact guidance of injections, and it was valuable for follow-up examinations. Normalization of synovitis was achieved in most cases, which supports the notion that US is an important tool in management of wrist involvement in JIA.
KeywordsUltrasonography Color Doppler Juvenile idiopathic arthritis US-guided steroid injection Wrist
The wrist region is one of the most complex joints of the human body, and it is prone to deformity and functional impairment in juvenile idiopathic arthritis (JIA) [1, 2] and is difficult to examine clinically. Inflammation in the wrist region is an indicator of poor outcome in JIA . In the first detailed account of the natural history of wrist arthritis in children, Chaplin and colleagues  described late changes, visualized on plain radiographs, in 59% of the patients they studied. The trend towards early suppression of inflammation has probably improved the outcomes in many patients with JIA , but it has also increased the need for more sensitive imaging techniques.
The aim of the present study was to investigate the usefulness of ultrasonography (US) with Doppler in JIA, focusing on diagnosis of synovitis, guidance of steroid injections, and follow-up examinations of the wrist region.
Clinical and laboratory assessment of 11 JIA patients with 15 symptomatic wrists*
Enthesitis related arthritis
Age at injection, years
Disease duration, years
Number of joints (n = 15) with
Limited range of motion
VAS wrist pain patient/parent, cm
VAS global assessment patient/parent, cm
VAS global assessment physician, cm
CRP level, mg/l
HLA B27 positive, number of patients
ANA positive, number of patients
RF positive, number of patients
MTX + Etanercept
MTX + Systemic corticosteroids
Ten of the 11 children (91%) were female, and the median age was 12.5 years (range 2-16 years). Five had oligoarticular (oligo) JIA, two had polyarticular (poly) JIA, two had undifferentiated arthritis, one had enthesitis related arthritis (ERA) and one systemic JIA. At the time of inclusion, seven had ongoing systemic treatment: five with methotrexate, one with methotrexate and etanercept, and one with methotrexate and systemic corticosteroids (prednisolone 0.1 mg/kg). One patient had received an intra-articular steroid injection within the previous 3 months, but not in the arthritic wrist or the same extremity.
The local research ethics committee approved the study. All parents gave informed consent for their children to participate, and oral agreement was obtained from the children themselves.
Clinical and US assessment
Patients who had previously been diagnosed with JIA based on the revised criteria of the International League of Associations for Rheumatology (ILAR, 2004)  were examined by either of two experienced pediatric rheumatologists for clinical signs of involvement of the wrists. The following clinical variables were recorded: swelling, pain assessed by the patient/parent visual analogue scale (VAS, 0 - 10 cm), tenderness to palpation, pain on motion, and limited range of motion.
US diagnosis of tenosynovitis in 15 wrists before steroid injection
Tendon sheath compartments examined
Number with tenosynovitis
abductor pollicis longus and extensor pollicis brevis
extensor carpi radialis longus and brevis
extensor pollicis longus
extensor digitorum communis
extensor digiti minimi
extensor carpi ulnaris
flexor carpi radialis
flexor pollicis longus
flexor digitorum superficialis and profundus
The results in this study are presented as absolute qualitative values without any statistical calculations due to the small size of the sample.
US-guided steroid injection
Follow-up after injection
In all patients, the clinical and US assessment was repeated at 1 and 4 weeks after the steroid injection. The ultrasonographer performing the assessments was blinded to clinical data. For the joint recesses and tendon sheaths, the presence (no effect) or absence (normalization) of synovial hypertrophy after treatment was recorded. In the follow-up of synovial hyperemia, residual presence (no effect) or total absence (normalization) of color Doppler flow was noted.
US results before injection
US diagnosis of synovial hypertrophy and hyperemia in 15 wrists before steroid injection
US-guided steroid injection
US diagnosis of synovial hypertrophy and hyperemia 1 week and 4 weeks after US-guided injection of corticosteroids
1 week post-injection
4 weeks post-injection
At the time of steroid injection, new systemic therapies were started in three of the patients: one of these children was previously untreated and was given methotrexate; one had previously received methotrexate and was switched to sulphasalazine; the third was receiving methotrexate as single therapy, and etanercept was added.
US follow-up of steroid injection
At clinical follow-up 1 week after injection, eight wrists were completely free from all signs of active arthritis (joint swelling or limitation in the range of joint movement accompanied by pain or tenderness), and seven wrists still exhibited clinically active arthritis. Four weeks after injection, normalization was achieved in 12 wrists, whereas three wrists had clinically active arthritis, two in a 13-year-old girl with ERA and one in a 6-year-old girl with poly JIA.
A 14-year-old girl with oligo JIA was the only patient with a recurrence of symptoms in an injected wrist compartment, and this was noted 7 months after the initial steroid injection. A relapse of synovitis was verified by Doppler-US, and the wrist was re-injected with steroids under US-guidance, which led to normalization of symptoms at the clinical follow-up 1 month later.
The only complication noted was local subcutaneous atrophy at the injected site (radio-carpal joint) in one patient, a 9-year-old girl. This represents a complication rate of 4.8%.
There are no validated US scoring systems for the assessment of inflammatory and joint damage abnormalities in JIA, and there is little knowledge of the normal US reference values of each joint at different developmental stages in children. In this study we used the OMERACT definitions for US pathology in adult RA , and the presence/absence of these signs of pathology were registered for each of the compartments examined. Recent investigations have demonstrated that clinical examination alone is inadequate to identify structures involved in JIA, and that subclinical synovitis is frequently detected by US [10, 11], particularly in the hands and feet [12, 13]. In the present US study, we were able to diagnose synovitis in such compartments, which are difficult to assess clinically [12, 13] (Table 3).
We conducted a descriptive investigation, which was not designed to compare the results of clinical and US assessments. In symptomatic wrists, the radio-carpal and midcarpal joints were often involved (in 87% and 53%, respectively). Diseased tendon sheaths were found in only one third of the wrists, which can be compared with such findings in 55% of the symptomatic ankles examined by Doppler-US in one of our previous studies . In contrast, our observation of synovial hyperemia in 88% of the diseased compartments (Table 3) is comparable to our findings in the ankle region (89%)  and to previous results showing hyperemia in 93% of symptomatic MCP joints  and 77% of symptomatic knees  in JIA patients. Effusion was infrequent in our patients, especially in the joint compartments.
Steroid injections constitute a major form of treatment in JIA, at disease onset or during the course of the disease . The clinical effect of such an injection depends on accurate placement of the steroid in the diseased compartment. Imaging-guidance can significantly improve the accuracy, and US is the best available technique for guided injections [18–24]. Indeed, in a number of studies significantly better results were obtained using imaging-guided injections, compared to palpation-guided injections, in treatment of adults with arthritis/osteoarthritis in large and small joints [18, 25] and of children with arthritis in the ankle region . Common clinical practice in JIA with wrist swelling has been to perform a palpation-guided injection in the radio-carpal joint, whereas injection of the midcarpal joints or tendon sheaths is done less frequently.
To our knowledge, our study is the first to describe US-guided steroid injections in the wrist region in JIA. Inasmuch as US-guidance of injections in this region is an established practice at the Pediatric Rheumatology Outpatient Clinic, Rigshospitalet, we considered it unethical to randomize patients to either palpation-guided or US-guided injections.
Follow-up of treatment efficacy in arthritis patients is based on clinical examination and imaging. US follow-up after steroid injection or other treatments in rheumatology has been scrutinized in several studies of adults but only a few investigations of children [27–30]. Moreover, all JIA studies thus far have focused on the knee and hip. Doppler-US is widely used for follow-up in adult rheumatology, whereas the literature contains only three JIA studies in which this technique was used to evaluate treatment efficacy after steroid injections in the ankle region  or in knee synovitis after systemic corticosteroids  and NSAIDs . Our study is the first to describe Doppler-US for follow-up of steroid injections in the wrist region in JIA patients. Table 4 illustrates the effect of US-guided steroid injections on synovial hypertrophy and hyperemia. In joints, normalization of hyperemia was faster than normalization of synovial hypertrophy. In tendon sheaths, complete normalization of both synovial hyperemia and hypertrophy, appeared already 1 week after steroid injection. Previous studies of JIA have shown that US and Doppler-US are more sensitive than clinical examination alone [10–13]. In the present investigation, Doppler-US revealed persistent synovitis in injected compartments in two wrists (two patients) at 4-week follow-up, and one of those wrists did not exhibit any clinical signs of active arthritis. At the same time point, results of US examination were completely normal for one of the three wrists with clinically active arthritis. Most compartments that did not receive steroid injections showed normalization 4 weeks after treatment, with the exception of one midcarpal joint. Arthrographic studies of the wrist region in children are lacking, and thus it is uncertain whether the mentioned beneficial effects were due to the existence of anatomical communications between joint compartments and tendon sheaths, or to systemic absorption of steroid. Furthermore, a number of patients received pharmacological treatments with a potential impact on the course of the disease and some received concomitant steroid injections in other joints, which might have biased the follow-up of steroid injections.
Subcutaneous atrophy is a well-recognized adverse effect of intra-articular steroid injection in pediatric patients, and it occurs most likely in small or complex joints such as the wrist or ankle in children under 4 years of age  or when a larger injection volume is used . When employing US-guidance, as in our study, the needle tip is always correctly localized before injection, which minimizes extravasation of steroid into the subcutaneous tissue. Despite the precautions taken (see methods section for details), subcutaneous atrophy did occur in one of our patients.
US is suitable for examination of children of all ages and has certain advantages over MRI in that it is cheaper, mobile, quickly accessible bedside, easy to combine with clinical assessment (interactivity), and non-invasive. It does not require sedation, which facilitates repeated examinations for follow-up. Assessment of multiple locations is possible during a single session. Agitation of the patient is rarely a problem, and young children can be seated on a parent's lap or play while being examined. Modern high-frequency US transducers provide unsurpassed resolution of the superficial musculoskeletal structures in children. Doppler-US adds further information by depicting articular and para-articular soft tissue hyperemia [10, 31]. The Doppler signal reflects disease activity in RA, correlating to clinical and laboratory data , MRI results , and histology . Even though only a few studies have considered the use of Doppler-US for evaluation of synovial hyperemia in JIA, four investigations have demonstrated a correlation between a high synovial Doppler signal and clinical activity [8, 15, 16, 37]. Various systems, involving quantitative or semi-quantitative methods, are used to grade the Doppler flow. In a recent US study, synovial vascularization was absent in healthy controls, and Doppler flow of any grade was significantly associated with clinical synovitis in JIA . In the current study, we assessed synovial vascularization based on the presence or absence of color Doppler flow.
A weakness of the present study is that the US assessments, were evaluated for accuracy by only one experienced musculoskeletal radiologist. Furthermore, our US examination protocol did not include the radio-ulnar joint, and hence we cannot rule out any synovitis in this compartment. Accordingly, in the future we will use a revised and more appropriate scanning protocol for juvenile arthritis that includes the radio-ulnar joint.
Our results highlight the value of US in pediatric rheumatology. US provided information on the exact anatomical location of inflamed structures in the wrist region, and disease was frequently found in compartments that are difficult to evaluate clinically. Also, US enabled exact guidance of steroid injections with a low rate of subcutaneous atrophy, and it was well suited for follow-up examinations. Furthermore, normalization of synovial hypertrophy and hyperemia was achieved in most cases and with few relapses, which suggests that US assessment prior to steroid injection and US-guidance of injections in this complex region have the potential to improve treatment efficacy.
The authors are grateful to the Wilhelm and Martina Lundgren Research Foundation for financial support and to Wyeth Denmark for providing the US equipment.
- Nieuwenhuis MK, van der Net J, Keessen W, Kuis W, Helders JM: Pathokinesiology of wrist deformity in juvenile chronic arthritis: state of the art. Physiotherapy Therapy and Practice. 1996, 12: 15-25. 10.3109/09593989609036414.View ArticleGoogle Scholar
- Ansell BM, Kent PA: Radiological changes in Juvenile Chronic Polyarthritis. Skeletal Radiol. 1977, 1: 129-144. 10.1007/BF00347138.View ArticleGoogle Scholar
- Ravelli A, Martini A: Early predictors of outcome in juvenile idiopathic arthritis. Clin Exp Rheumatol. 2003, 21: S89-93.PubMedGoogle Scholar
- Chaplin D, Pulkki T, Saarimaa A, Vainio K: Wrist and finger deformities in juvenile rheumatoid arthritis. Acta Rheumatol Scand. 1969, 15: 206-223.View ArticlePubMedGoogle Scholar
- Hyrich KL, Lal SD, Foster HE, Thornton J, Adib N, Baildam E, Gardner-Medwin J, Wedderburn LR, Chieng A, Davidson J, Thomson W: Disease activity and disability in children with juvenile idiopathic arthritis one year following presentation to paediatric rheumatology. Results from the Childhood Arthritis Prospective Study. Rheumatology (Oxford). 2010, 49: 116-122. 10.1093/rheumatology/kep352.View ArticleGoogle Scholar
- Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J, He X, Maldonado-Cocco J, Orozco-Alcala J, Prieur AM: International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004, 31: 390-392.PubMedGoogle Scholar
- Wakefield RJ, Balint PV, Szkudlarek M, Filippucci E, Backhaus M, D'Agostino MA, Sanchez EN, Iagnocco A, Schmidt WA, Bruyn GA: Musculoskeletal ultrasound including definitions for ultrasonographic pathology. J Rheumatol. 2005, 32: 2485-2487.PubMedGoogle Scholar
- Breton S, Jousse-Joulin S, Cangemi C, de Parscau L, Colin D, Bressolette L, Saraux A, Devauchelle-Pensec V: Comparison of Clinical and Ultrasonographic Evaluations for Peripheral Synovitis in Juvenile Idiopathic Arthritis. Semin Arthritis Rheum. 2011, 41: 272-278. 10.1016/j.semarthrit.2010.12.005.View ArticlePubMedGoogle Scholar
- Lanni S, Bertamino M, Consolaro A, Pistorio A, Magni-Manzoni S, Galasso R, Lattanzi B, Calvo-Aranda E, Martini A, Ravelli A: Outcome and predicting factors of single and multiple intra-articular corticosteroid injections in children with juvenile idiopathic arthritis. Rheumatology (Oxford). 2011, 50: 1627-1634. 10.1093/rheumatology/ker165.View ArticleGoogle Scholar
- Magni-Manzoni S, Epis O, Ravelli A, Klersy C, Veisconti C, Lanni S, Muratore V, Scire CA, Rossi S, Montecucco C: Comparison of clinical versus ultrasound-determined synovitis in juvenile idiopathic arthritis. Arthritis Rheum. 2009, 61: 1497-1504. 10.1002/art.24823.View ArticlePubMedGoogle Scholar
- Filippou G, Cantarini L, Bertoldi I, Picerno V, Frediani B, Galeazzi M: Ultrasonography vs. clinical examination in children with suspected arthritis. Does it make sense to use poliarticular ultrasonographic screening?. Clin Exp Rheumatol. 2011, 29: 345-350.PubMedGoogle Scholar
- Haslam KE, McCann LJ, Wyatt S, Wakefield RJ: The detection of subclinical synovitis by ultrasound in oligoarticular juvenile idiopathic arthritis: a pilot study. Rheumatology (Oxford). 2010, 49: 123-127. 10.1093/rheumatology/kep339.View ArticleGoogle Scholar
- Pascoli L, Wright S, McAllister C, Rooney M: Prospective evaluation of clinical and ultrasound findings in ankle disease in juvenile idiopathic arthritis: importance of ankle ultrasound. J Rheumatol. 2010, 37: 2409-2414. 10.3899/jrheum.091262.View ArticlePubMedGoogle Scholar
- Laurell L, Court-Payen M, Nielsen S, Zak M, Boesen M, Fasth A: Ultrasonography and color Doppler in juvenile idiopathic arthritis: diagnosis and follow-up of ultrasound-guided steroid injection in the ankle region. A descriptive interventional study. Pediatr Rheumatol Online J. 2011, 9: 4-10.1186/1546-0096-9-4.PubMed CentralView ArticlePubMedGoogle Scholar
- Karmazyn B, Bowyer SL, Schmidt KM, Ballinger SH, Buckwalter K, Beam TT, Ying J: US findings of metacarpophalangeal joints in children with idiopathic juvenile arthritis. Pediatr Radiol. 2007, 37: 475-482. 10.1007/s00247-007-0438-9.View ArticlePubMedGoogle Scholar
- Shahin AA, el-Mofty SA, el-Sheikh EA, Hafez HA, Ragab OM: Power Doppler sonography in the evaluation and follow-up of knee involvement in patients with juvenile idiopathic arthritis. Z Rheumatol. 2001, 60: 148-155. 10.1007/s003930170063.View ArticlePubMedGoogle Scholar
- Bloom BJ, Alario AJ, Miller LC: Intra-articular corticosteroid therapy for juvenile idiopathic arthritis: report of an experiential cohort and literature review. Rheumatol Int. 2011, 31: 749-756. 10.1007/s00296-010-1365-x.View ArticlePubMedGoogle Scholar
- Cunnington J, Marshall N, Hide G, Bracewell C, Isaacs J, Platt P, Kane D: A randomized, double-blind, controlled study of ultrasound-guided corticosteroid injection into the joint of patients with inflammatory arthritis. Arthritis Rheum. 2010, 62: 1862-1869.PubMedGoogle Scholar
- Laurell L, Court-Payen M, Nielsen S, Zak M, Thomsen C, Boesen M, Fasth A: The role of ultrasonography in juvenile idiopathic arthritis (in French). In Actualités en échographie de l'appareil locomoteur. Edited by: Brasseur J, Zeitoun-Eiss D, Renoux J, Grenier P. 2008, Paris: Sauramps médical, 73-97.Google Scholar
- Balint PV, Kane D, Sturrock RD: Modern patient management in rheumatology: interventional musculoskeletal ultrasonography. Osteoarthr Cartil. 2001, 9: 509-511. 10.1053/joca.2001.0430.View ArticlePubMedGoogle Scholar
- Qvistgaard E, Kristoffersen H, Terslev L, Danneskiold-Samsoe B, Torp-Pedersen S, Bliddal H: Guidance by ultrasound of intra-articular injections in the knee and hip joints. Osteoarthr Cartil. 2001, 9: 512-517. 10.1053/joca.2001.0433.View ArticlePubMedGoogle Scholar
- Grassi W, Lamanna G, Farina A, Cervini C: Synovitis of small joints: sonographic guided diagnostic and therapeutic approach. Ann Rheum Dis. 1999, 58: 595-597. 10.1136/ard.58.10.595.PubMed CentralView ArticlePubMedGoogle Scholar
- Holm HH, Skjoldbye B: Interventional ultrasound. Ultrasound Med Biol. 1996, 22: 773-789. 10.1016/0301-5629(96)00086-5.View ArticlePubMedGoogle Scholar
- Christensen RA, Van Sonnenberg E, Casola G, Wittich GR: Interventional ultrasound in the musculoskeletal system. Radiol Clin North Am. 1988, 26: 145-156.PubMedGoogle Scholar
- Sibbitt WL, Peisajovich A, Michael AA, Park KS, Sibbitt RR, Band PA, Bankhurst AD: Does sonographic needle guidance affect the clinical outcome of intraarticular injections?. J Rheumatol. 2009, 36: 1892-1902. 10.3899/jrheum.090013.View ArticlePubMedGoogle Scholar
- Remedios D, Martin K, Kaplan G, Mitchell R, Woo P, Rooney M: Juvenile chronic arthritis: diagnosis and management of tibio-talar and sub-talar disease. Br J Rheumatol. 1997, 36: 1214-1217. 10.1093/rheumatology/36.11.1214.View ArticlePubMedGoogle Scholar
- Kakati P, Sodhi KS, Sandhu MS, Singh S, Katariya S, Khandelwal N: Clinical and ultrasound assessment of the knee in children with juvenile rheumatoid arthritis. Indian J Pediatr. 2007, 74: 831-836. 10.1007/s12098-007-0148-1.View ArticlePubMedGoogle Scholar
- Cellerini M, Salti S, Trapani S, D'Elia G, Falcini F, Villari N: Correlation between clinical and ultrasound assessment of the knee in children with mono-articular or pauci-articular juvenile rheumatoid arthritis. Pediatr Radiol. 1999, 29: 117-123. 10.1007/s002470050554.View ArticlePubMedGoogle Scholar
- Eich GF, Halle F, Hodler J, Seger R, Willi UV: Juvenile chronic arthritis: imaging of the knees and hips before and after intraarticular steroid injection. Pediatr Radiol. 1994, 24: 558-563. 10.1007/BF02012732.View ArticlePubMedGoogle Scholar
- Sureda D, Quiroga S, Arnal C, Boronat M, Andreu J, Casas L: Juvenile rheumatoid arthritis of the knee: evaluation with US. Radiology. 1994, 190: 403-406.View ArticlePubMedGoogle Scholar
- Shanmugavel C, Sodhi KS, Sandhu MS, Sidhu R, Singh S, Katariya S, Khandelwal N: Role of Power Doppler sonography in evaluation of therapeutic response of the knee in juvenile rheumatoid arthritis. Rheumatol Int. 2008, 28: 573-578. 10.1007/s00296-007-0482-7.View ArticlePubMedGoogle Scholar
- Job-Deslandre C, Menkes CJ: Complications of intra-articular injections of triamcinolone hexacetonide in chronic arthritis in children. Clin Exp Rheumatol. 1990, 8: 413-416.PubMedGoogle Scholar
- Beukelman T, Arabshahi B, Cahill AM, Kaye RD, Cron RQ: Benefit of intraarticular corticosteroid injection under fluoroscopic guidance for subtalar arthritis in juvenile idiopathic arthritis. J Rheumatol. 2006, 33: 2330-2336.PubMedGoogle Scholar
- Naredo E, Bonilla G, Gamero F, Uson J, Carmona L, Laffon A: Assessment of inflammatory activity in rheumatoid arthritis: a comparative study of clinical evaluation with grey scale and power Doppler ultrasonography. Ann Rheum Dis. 2005, 64: 375-381.PubMed CentralView ArticlePubMedGoogle Scholar
- Szkudlarek M, Court-Payen M, Strandberg C, Klarlund M, Klausen T, Ostergaard M: Power Doppler ultrasonography for assessment of synovitis in the metacarpophalangeal joints of patients with rheumatoid arthritis: a comparison with dynamic magnetic resonance imaging. Arthritis Rheum. 2001, 44: 2018-2023. 10.1002/1529-0131(200109)44:9<2018::AID-ART350>3.0.CO;2-C.View ArticlePubMedGoogle Scholar
- Walther M, Harms H, Krenn V, Radke S, Faehndrich TP, Gohlke F: Correlation of power Doppler sonography with vascularity of the synovial tissue of the knee joint in patients with osteoarthritis and rheumatoid arthritis. Arthritis Rheum. 2001, 44: 331-338. 10.1002/1529-0131(200102)44:2<331::AID-ANR50>3.0.CO;2-0.View ArticlePubMedGoogle Scholar
- Sparchez M, Fodor D, Miu N: The role of Power Doppler ultrasonography in comparison with biological markers in the evaluation of disease activity in Juvenile Idiopathic Arthritis. Med Ultrason. 2010, 12: 97-103.PubMedGoogle Scholar
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