Abstract
Juvenile idiopathic arthritis (JIA) is a heterogeneous group of arthritides characterized by chronic synovial inflammation that can lead to structural damage. The main objective of JIA therapies is to induce disease control to avoid disability in childhood. The advances in therapeutic effectiveness have created a need to search for imaging tools that describe more precisely disease activity in children with JIA. Musculoskeletal ultrasound and magnetic resonance imaging have demonstrated to be more sensitive than clinical examination in early detection of synovitis. These modalities can detect both inflammatory and destructive changes. The unique characteristics of the growing skeleton and a scarce validation of imaging in children result in important challenges in evaluating paediatric population. This review describes indications and limitations of these imaging techniques and suggests some advices for a rational use in the management of JIA in clinical practice.
Introduction
Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children . JIA includes a group of clinically heterogeneous arthritis that develop before the age of 16 years, persist for at least 6 weeks and have no identifiable cause. It is characterized by a chronic inflammatory process of the synovium and periarticular tissue that can lead to structural damage and growth abnormalities. The International League of Association for Rheumatology proposed the current classification for JIA that aims to enable the identification of homogeneous groups of children suitable for etiopathogenetic studies . JIA could affect the appendicular skeleton and the axial skeleton. The presence of joint involvement in JIA may be expressed by some imaging findings such as synovial proliferation, effusion, cartilage thinning and bone erosions.
Historically, conventional radiography (CR) was a mainstay for the evaluation of children with suspected JIA, because it allows to easily rule out traumas and some tumours ; moreover, it shows the irreversible structural damage that occurs late in the disease course. The availability of therapeutic agents to prevent joint destruction, especially when treatment is initiated promptly, highlights the importance of early detection of inflammation and initial signs of damage . As a result, the management of JIA has evolved to include greater use of imaging techniques such as high-frequency ultrasound (US) and magnetic resonance imaging (MRI). In the last few years, a considerable amount of evidence has shown that these imaging modalities are sensitive in detecting inflammatory lesions and monitoring disease progression, thus playing an important role in the assessment of juvenile arthritis . However, there are hardly any studies that focussed on demonstrating the real validity of these techniques in children . Furthermore, the peculiarities of the growing skeleton, which include age-related variations in the thickness of the articular cartilage and incomplete ossification, make the evaluation of children’s joints a real challenge.
In the present article, we will discuss utility of the most modern imaging modalities (US and MRI) integrated in practice for the management of children with known or suspected JIA and further applications of these modalities.
Plain radiography, US or MRI in JIA; which, when and for what purpose?
The imaging approach to JIA has radically changed over the last decades, and new imaging modalities such as musculoskeletal US and MRI are increasingly overtaking plain radiography for the assessment of children with JIA. As reported in Table 1 , there are strengths and weaknesses for each imaging technique that should be considered by clinicians when choosing the best imaging modality for the assessment of JIA. Furthermore, choosing wisely, the question ‘why is imaging required’ cannot be ignored. Answering this question (for what purpose?) will also allow us to delineate a timeline scheduled workflow for imaging JIA (when?).
| Imaging technique | Advantages | Limitations |
|---|---|---|
| Plain radiography | Useful for the initial diagnostic workout. Current reference for monitoring damage progression. Suitable for the visualisation of growth disturbances. Suitable for the assessment of joint deformities. | Exposure to ionizing radiation. Not sensitive to detect soft tissue inflammation. It shows erosive changes to the joint late in the disease course. |
| Ultrasonography | High patient acceptability, non-invasive. Can be performed at the bedside. Widely available. Ability to scan multiple joints at once. Does not entail sedation or ionising radiation. It can detect synovitis in peripheral joints. More sensitive than clinical evaluation for revealing joint inflammation. It is suitable in detecting tendon involvement. Potential for guiding intra-articular steroid injection. | Strict dependence on the physician’s skills and on the type of equipment used. Not all joints are accessible. Reproducibility is variable. Lack of standardization and validated scoring system for the assessment of disease activity and damage. Acoustic shadowing from overlying bones. |
| Magnetic resonance imaging | Absence of ionising radiation exposure. High image resolution and multiplanar tomographic imaging. Sensitive in detecting periarticular soft tissue inflammation and early erosive changes. Visualisation of bone marrow changes. Provides information on cartilage integrity. Suitable for the assessment of axial skeleton and temporomandibular joints. Semiquantitative scoring system is available. | MRI remains relatively expensive. Long examination time and the timing of the contrast restrict the number of joints that can be assessed. Risks associated with intravenous administration of contrast medium (nephrogenic systemic fibrosis can occur in patients with severe renal impairment). General anaesthesia is required in younger children. Limited availability worldwide. |
Plain radiography imaging
Until 15 years ago, imaging for JIA was largely confined to plain radiography, which is however insensitive for the detection of active arthritis and rarely shows erosive changes to the joint until late in the disease course . Despite these limitations, plain radiography should not be considered obsolete because it has still much to offer to clinicians. Doubtless, it is a useful imaging modality in diagnosis, especially to rule out trauma, osteochondroses, bone tumours and congenital dysplasias that may mimic JIA. Localised hyperaemia around joints can initially cause epiphyseal enlargement ( Fig. 1 ) and advancement of bone maturation, while in the later stages, accelerated bone maturation promotes premature fusion of the physis . These growth disturbances, which are distinctive of JIA, are well visualised by plain radiography. Of note, this technique remains the current reference for the assessment of structural damage to the joints, which traditionally manifests itself as joint space narrowing, bone erosions or other abnormalities such as bone deformities . Over the last decades, new radiographic scoring systems have been devised, and adult radiographic scores have been adapted for use in JIA . Their use in non-controlled clinical studies has clearly demonstrated that a standardized assessment of radiographic progression in children with JIA is feasible , suggesting that quantitative measurement of radiographic damage should be included in the evaluation of treatment efficacy . Finally, late in the disease course, plain radiography has a pivotal role in the assessment of joint deformities such as joint subluxation, dislocation and flexion/extension defects, which are associated with severe impaired physical function .
With the current emphasis on early intervention in the inflammatory arthritides, the detection of early synovitis and preradiographic joint damage has become a priority.
Musculoskeletal US imaging
US has a striking role in documenting early signs of arthritis, wherein it can detect joint effusion and synovial hyperplasia in the peripheral joints ( Fig. 2 ) . Colour and power Doppler may be used to assess increased vascularisation, a marker of active inflammation, and to differentiate between active and quiescent disease . Caution, however, is needed in interpreting any juxta-articular Doppler signals as a sign of active synovitis, owing to the physiologically enhanced blood flow of the growing skeleton . US is more sensitive than clinical evaluation for revealing joint inflammation in children with recent-onset JIA . Several studies have reported that a proportion of patients diagnosed to have oligoarticular JIA were reclassified as having polyarthritis after US examination, with relevant implications for treatment strategy. US represents a valuable imaging support for clinicians to precisely identify the site of inflammation and to differentiate between synovial, tendinous, and enthesal inflammation, especially for joints with anatomical complexity such as wrist and ankle ( Fig. 3 ) . Rooney et al. found a poor agreement between clinical and US evaluation in the assessment of tenosynovitis of the ankle in patients with JIA . Furthermore, around 40% of patients with JIA with ankle active arthritis based on clinical ground had tenosynovitis alone on US examination , thus enhancing the role of this imaging modality in detecting tendon involvement. The value of US in the assessment of enthesitis, a peculiar feature of enthesitis-related arthritis (ERA) subtype, remains debatable ( Fig. 4 ). In particular, the significance of power Doppler signals in clinically silent apparent enthesitis remains to be clarified . The capability to evaluate joint dynamically and on several planes makes US a valuable tool to detect bone erosions in JIA ( Fig. 5 ). However, it remains a real challenge to differentiate between physiological irregular appearance of some ossification centres and bony erosions caused by the disease progression . Another advantage of US is that it enables direct visualization of nonossified epiphysis and the secondary ossification nucleus long before it becomes visible radiographically . An acceptable agreement between US and MRI in the measurement of cartilage thickness in different joints has been recently reported . In contrast to adults, it is difficult to reliably determine cartilage loss in children because cartilage width normally decreases with skeletal maturity. Of note, age- and sex-related normal standards for cartilage thickness in different joints have been recently established . Finally, US is indicated to guide steroid injections in joints and tendon sheaths, thus reducing the risk of side effects due to delivery of the steroid preparation out of the joint space and maximizing treatment efficacy of the procedure .
MR imaging
MRI allows the simultaneous assessment of all relevant structures involved in inflammatory arthritis and is regarded as the most attractive imaging modality for the investigation of this condition in both clinical and research settings . A variety of sequences are available for the assessment of different joint components. The basic sequences for an accurate assessment of inflammatory arthritis include anatomy-defining sequences (e.g. T1-weighted images) for the assessment of destructive changes, fluid-sensitive sequences (e.g. T2-weighted or short-tau inversion recovery sequences) for detecting synovial effusion and bone marrow changes, and gadolinium-enhanced T1-weighted images for reliably differentiating the active hypervascular pannus from the inactive fibrotic pannus ( Fig. 6 ). Accurate detection and quantification of synovial inflammation is crucial for monitoring disease course and assessing treatment efficacy. The semiquantitative rheumatoid arthritis (RA) MRI synovitis score, which has been recently validated for the use in JIA , was found to be a promising imaging biomarker for measuring therapeutic response in a recent study comparing the American College of Rheumatology paediatric criteria with MRI . Of note, only patients who achieved the highest level of clinical response (ACR 90) showed a significant decrease in MRI synovitis score, thus highlighting the need for higher levels of clinical response to assess drug efficacy and enhancing the potentiality of MRI as a primary efficacy outcome . In this perspective, it is worth mentioning that quantitative methods to assess synovial changes are available. Dynamic contrast-enhanced MRI enables a quantitative assessment of inflammation by analysing the time-dependent synovial tissue contrast uptake , which is strictly dependent on the cytokine-mediated hypervascularisation and on the permeability of the synovial vessels. By using a pharmacokinetic model, it is possible to analyse the transfer of contrast medium between intravascular and extravascular spaces and to provide an objective follow-up measure of therapeutic efficacy in patients with JIA . Malattia et al. showed that MRI-computerised automated measurement of inflamed synovial volume of the wrist was more accurate than the semiquantitative approach to assess treatment efficacy and to predict progressive joint destruction . Automation of the reading and computer guidance in image analysis allows for high reproducibility of the results; furthermore, quantifying changes in synovial inflammation on a continuous scale is more sensitive to change of therapeutic intervention, with the potential to improve patients care by tailoring the exposure time to anti-rheumatic drugs. The major limitation of the quantitative methods lies in the requirements of post-processing analysis and specific software, which are currently not accessible to all centres.
The multiplanar approach and high spatial resolution of MRI enable clinicians to detect bone erosions long before erosive changes are visible on plain radiographs or on US . A thorough understanding of normal physiological changes in the growing skeleton and a sound knowledge of the wide spectrum of normal variants are required for an accurate assessment of bone damage in JIA . Bony depression, in fact, may represent vascular channels, interosseous ligamentous attachments or simply the normal surface irregularities of the growing carpal bones. In an MRI study on 88 healthy children, bony depressions resembling erosions were found in the carpal bones of most of the individuals , thus hindering the use of MRI as a damage endpoint in JIA. Unexpectedly, MRI was less sensitive than CR in evaluating structural damage progression . The lack of inclusion of cartilage domain, the hallmark of erosive process in JIA, in the wrist MR score might explain this result. An increasing number of cartilage-specific sequences to assess cartilaginous damage have recently been developed and included in the MRI protocol for the assessment of JIA . Finally, MRI is the only imaging modality that can visualize bone marrow oedema (BMO) ( Fig. 7 ), the most important independent predictor of radiographic progression and functional impairment in RA. Care should be taken before considering BMO as a prognostic indicator in JIA, because long-term studies investigating whether the presence of bone marrow changes predates the development of bone erosions in JIA also are currently lacking. Furthermore, signal changes resembling BMO have been reported in carpal and tarsal bones of healthy children. It has been hypothesised that these patchy areas of high signal could represent ‘islands’ of residual red marrow or marrow changes due to ‘microtrauma’ . Studies in healthy adults did not show the same phenomenon, thus emphasising the peculiarities of the growing skeleton and enhancing the need to include healthy subjects in MRI studies on JIA.
Plain radiography, US or MRI in JIA; which, when and for what purpose?
The imaging approach to JIA has radically changed over the last decades, and new imaging modalities such as musculoskeletal US and MRI are increasingly overtaking plain radiography for the assessment of children with JIA. As reported in Table 1 , there are strengths and weaknesses for each imaging technique that should be considered by clinicians when choosing the best imaging modality for the assessment of JIA. Furthermore, choosing wisely, the question ‘why is imaging required’ cannot be ignored. Answering this question (for what purpose?) will also allow us to delineate a timeline scheduled workflow for imaging JIA (when?).
| Imaging technique | Advantages | Limitations |
|---|---|---|
| Plain radiography | Useful for the initial diagnostic workout. Current reference for monitoring damage progression. Suitable for the visualisation of growth disturbances. Suitable for the assessment of joint deformities. | Exposure to ionizing radiation. Not sensitive to detect soft tissue inflammation. It shows erosive changes to the joint late in the disease course. |
| Ultrasonography | High patient acceptability, non-invasive. Can be performed at the bedside. Widely available. Ability to scan multiple joints at once. Does not entail sedation or ionising radiation. It can detect synovitis in peripheral joints. More sensitive than clinical evaluation for revealing joint inflammation. It is suitable in detecting tendon involvement. Potential for guiding intra-articular steroid injection. | Strict dependence on the physician’s skills and on the type of equipment used. Not all joints are accessible. Reproducibility is variable. Lack of standardization and validated scoring system for the assessment of disease activity and damage. Acoustic shadowing from overlying bones. |
| Magnetic resonance imaging | Absence of ionising radiation exposure. High image resolution and multiplanar tomographic imaging. Sensitive in detecting periarticular soft tissue inflammation and early erosive changes. Visualisation of bone marrow changes. Provides information on cartilage integrity. Suitable for the assessment of axial skeleton and temporomandibular joints. Semiquantitative scoring system is available. | MRI remains relatively expensive. Long examination time and the timing of the contrast restrict the number of joints that can be assessed. Risks associated with intravenous administration of contrast medium (nephrogenic systemic fibrosis can occur in patients with severe renal impairment). General anaesthesia is required in younger children. Limited availability worldwide. |
Plain radiography imaging
Until 15 years ago, imaging for JIA was largely confined to plain radiography, which is however insensitive for the detection of active arthritis and rarely shows erosive changes to the joint until late in the disease course . Despite these limitations, plain radiography should not be considered obsolete because it has still much to offer to clinicians. Doubtless, it is a useful imaging modality in diagnosis, especially to rule out trauma, osteochondroses, bone tumours and congenital dysplasias that may mimic JIA. Localised hyperaemia around joints can initially cause epiphyseal enlargement ( Fig. 1 ) and advancement of bone maturation, while in the later stages, accelerated bone maturation promotes premature fusion of the physis . These growth disturbances, which are distinctive of JIA, are well visualised by plain radiography. Of note, this technique remains the current reference for the assessment of structural damage to the joints, which traditionally manifests itself as joint space narrowing, bone erosions or other abnormalities such as bone deformities . Over the last decades, new radiographic scoring systems have been devised, and adult radiographic scores have been adapted for use in JIA . Their use in non-controlled clinical studies has clearly demonstrated that a standardized assessment of radiographic progression in children with JIA is feasible , suggesting that quantitative measurement of radiographic damage should be included in the evaluation of treatment efficacy . Finally, late in the disease course, plain radiography has a pivotal role in the assessment of joint deformities such as joint subluxation, dislocation and flexion/extension defects, which are associated with severe impaired physical function .
With the current emphasis on early intervention in the inflammatory arthritides, the detection of early synovitis and preradiographic joint damage has become a priority.
Musculoskeletal US imaging
US has a striking role in documenting early signs of arthritis, wherein it can detect joint effusion and synovial hyperplasia in the peripheral joints ( Fig. 2 ) . Colour and power Doppler may be used to assess increased vascularisation, a marker of active inflammation, and to differentiate between active and quiescent disease . Caution, however, is needed in interpreting any juxta-articular Doppler signals as a sign of active synovitis, owing to the physiologically enhanced blood flow of the growing skeleton . US is more sensitive than clinical evaluation for revealing joint inflammation in children with recent-onset JIA . Several studies have reported that a proportion of patients diagnosed to have oligoarticular JIA were reclassified as having polyarthritis after US examination, with relevant implications for treatment strategy. US represents a valuable imaging support for clinicians to precisely identify the site of inflammation and to differentiate between synovial, tendinous, and enthesal inflammation, especially for joints with anatomical complexity such as wrist and ankle ( Fig. 3 ) . Rooney et al. found a poor agreement between clinical and US evaluation in the assessment of tenosynovitis of the ankle in patients with JIA . Furthermore, around 40% of patients with JIA with ankle active arthritis based on clinical ground had tenosynovitis alone on US examination , thus enhancing the role of this imaging modality in detecting tendon involvement. The value of US in the assessment of enthesitis, a peculiar feature of enthesitis-related arthritis (ERA) subtype, remains debatable ( Fig. 4 ). In particular, the significance of power Doppler signals in clinically silent apparent enthesitis remains to be clarified . The capability to evaluate joint dynamically and on several planes makes US a valuable tool to detect bone erosions in JIA ( Fig. 5 ). However, it remains a real challenge to differentiate between physiological irregular appearance of some ossification centres and bony erosions caused by the disease progression . Another advantage of US is that it enables direct visualization of nonossified epiphysis and the secondary ossification nucleus long before it becomes visible radiographically . An acceptable agreement between US and MRI in the measurement of cartilage thickness in different joints has been recently reported . In contrast to adults, it is difficult to reliably determine cartilage loss in children because cartilage width normally decreases with skeletal maturity. Of note, age- and sex-related normal standards for cartilage thickness in different joints have been recently established . Finally, US is indicated to guide steroid injections in joints and tendon sheaths, thus reducing the risk of side effects due to delivery of the steroid preparation out of the joint space and maximizing treatment efficacy of the procedure .
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