Juvenile idiopathic arthritis (JIA) is the most common autoimmune systemic disease of the connective tissue affecting individuals at the developmental age. According to the definition of the International League of Associations for Rheumatology (ILAR), it is arthritis with the onset before the age of 16 and lasting for at least 6 weeks(1, 2).
Radiography, which was described in the first part of this publication, is the standard modality in the assessment of this condition(3). Ultrasound and magnetic resonance imaging enable early detection of the disease, which affects soft tissues: the synovial membrane of joints, sheaths and bursae, adipose tissue, as well as bones. Moreover, MRI enables the visualization of osteitis in the form of bone marrow edema. It is also applied for the diagnosis of inflammatory changes and complications in the spine, particularly in its cervical segment.
A US examination is conducted in patients with JIA for early diagnosis, treatment monitoring and determining remission. It presents early inflammatory lesions that precede joint destruction. A US picture is not specific for a definite disease entity but shows the spectrum of inflammatory and post-inflammatory changes.
US imaging is used to assess (Fig. 1, 2, 3, 4, 5, 6):
joint cavities, sheaths and bursae in order to visualize signs of synovitis: effusion, synovial thickening, hyper-vascularity and increased synovial echogenicity as signs of chronic inflammation or fibrosis;
intra- and extra-articular fat tissue in order to visualize signs of inflammation: increased echogenicity and increased blood flow;
hyaline cartilage, cartilaginous epiphyses and subchondral bone tissue in terms of damage (erosions, cysts, scars after injuries);
ligaments, tendons and entheses in terms of enthesopaties and tendinopathies (tenosynovitis, tendinitis secondary to tenosynovitis, tendon injuries, enthesitis).
US examination of the hand in a 3-year-old girl with JIA and thickening of the 3rd digit: A. effusion in the 3rd PIP joint (the PIP 4 joint seen on the right side of the image is normal); B. PIP 3 joint synovial thickening without hyperemia; C. thickening of the tenosynovium of that 3rd flexor digitorum tendon sheath without increased vascularity; D. no features of tenosynovitis of the 4th flexor digitorum tendons
US examination of the knee joint in a 2-year-old girl with JIA: effusion in the joint cavity, slightly thickened synovium with intense vascularity
US examination of the knee joints in a 7-year-old girl with JIA, a sagittal plane of the affected right knee (A) and a transverse plane of both knees (B): effussions, thickened and hypervascularised synovium, grade IV chondromalacia on the weight-bearing surface of the medial condyle of the right joint, hyaline cartilage of the left joint (right site of the image B) is normal
US examination of the wrist and knee in a 3-year-old boy with JIA: A. effusion, synovial thickening and hypervascularity in the radiocarpal and midcarpal joints; B. effusion, thickened and hypervascular synovium of the tendon sheath of the first carpal extensors compartment; C. effusion, thickened and hypertrophied synovium of the knee joint without signs of hypervascularity, sings of edema, no enhanced vascularity of the prefemoral fat pad; D. edema of the Hoffa's fat pad with articular synovial membrane bulging into the vertical fissure of the Hoffa's fat pad, no signs of increased vascularity
US imaging of the right Achilles tendon in a 17-year-old boy with suspected enthesitis: effusion, synovial thickening of the tendon bursa with signs of hypervascularity (bursitis). The calcaneal wall of the bursa is even, with no defects; the Achilles tendon at the level of the affected bursa shows no structural changes
US examination of the knee joint in a 13-year-old boy with JIA: tibial enthesitis of the iliotibial band with edema of the surrounding tissues (on the left); normal enthesis in the contralateral joint
The most common indication for an US examination is articular pain and edema or thickening and increased density of the joint soft tissues on plain radiography (see the first part of the publication on radiography)(4).
In the initial stage of JIA, its typical US features include: synovial thickening, its hypervascularity and effusion in the joint cavity, sheath and bursa. Moreover, enthesopathies(5) and intra- or extra-articular fat edema can be observed.
Disease activity monitoring
Follow-up examinations are conducted to assess the activity of synovitis, tenosynovitis/tendovaginitis and bursitis (presence of effusion, vascularized or non-vascularized synovium) as well as the progression of joint destruction (hyaline cartilage and epiphyseal defects, chronic inflammatory changes in bursae in the form of erosions in their bony walls or secondary inflammatory changes in the neighboring tendons). Tendinopathies secondary to tenosynovitis, however, is seen rarely in children.
Information about the activity of the disease, in other words treatment efficacy, is of major importance for a clinician since persisting activity is a proven risk factor of articular destruction(6).
Kakati et al.(7) used ultrasonography to examine the knee joints of children with JIA before and after naproxen therapy. At baseline, synovial thickening was seen in 93.33% of joints in children with a clinically active disease, and in children with chronic inflammation (clinical findings: joint pain, slight or no edema), it was observed in 48.5% of joints. Effusion was found in 86.6% and 41.92% of joints, respectively. The differences were statistically significant. Ultrasound imaging was more sensitive than clinical assessment in the monitoring of treatment efficacy, which is confirmed by other authors(7, 8).
The assessment of disease activity is usually qualitative. Semi-quantitative scales are used rarely, mainly in adult patients with rheumatoid arthritis (RA)(9). No such scales have been developed for JIA. Spârchez et al.(6) demonstrated a correlation between power Doppler ultrasonography (PDUS) and clinical assessment using PhGA (physician global assessment of disease activity on visual analogue scale). PDUS occurred to be more sensitive than ESR and CRP levels in disease activity assessment (90.4% vs 57% and 28.5%, respectively). The authors concluded that US imaging can be of a greater practical value in the monitoring of JIA(6).
Moreover, systems for quantitative assessment of synovial vascularity are more and more often available in US equipment. As in MRI, they will probably enable more accurate monitoring of treatment efficacy (Fig. 7).
US examination of the knee joint with quantitative vascularity assessment (vascularity index); ROI in the region of the affected synovium of the suprapatellar recess
As in adult patients with RA, ultrasonography enables the detection of subclinical synovitis (i.e. synovitis that is not manifested clinically) in children with suspected JIA(6). Establishing the number of affected joints is of particular relevance since, according to the ILAR, JIA can be classified as either pauciarticular or polyarticular based on the number of inflamed joints (≤ or >4). Moreover, an active process in at least five joints necessitates the inclusion of the patient to clinical trials or initiation of biological treatment(9).
One of the first papers on ultrasound use in the assessment of subclinical synovitis was published by Wakefield et al. in 2004(8). The authors examined 644 painful joints (both with and without clinical synovitis) in 80 children with JIA. In patients with clinically suspected arthritis, synovitis was confirmed by ultrasound in 79% of joints. In the remaining patients with clinically diagnosed arthritis, US revealed tenosynovitis or excluded the presence of inflammatory signs. Approximately 2/3 of children presented subclinical disease and about 1/3 of patients with oligoarthritis were re-classified to the group with polyarthritis(8).
Magni-Manzoni et al.(9) carried out US examinations of 52 joints in 32 children with JIA. Subclinical synovitis was detected in 10% of joints, which resulted in the re-classification of 5 cases from oligo- to polyarthritis.
Breton et al.(10) assessed the 2nd–5th MCP joints and 1st–5th MTP joints in 31 children with JIA and in 41 controls. Features of synovitis (defined as synovial thickening with or without effusion and hypervascularity) were detected in 7% of joints in children with JIA without clinical signs of inflammation. The disease usually involved the first MTP and the second and third MCP joints. Epiphyseal cartilage vascularization was observed in 4.2% of control joints and in 8.7% of children with JIA. Children with JIA presented effusion with no other evident synovial pathology in merely 1.9% of cases. Effusion, synovial swelling or hyper-vascularity were not found in any child from the control group(9, 10).
Our own observations (not published) indicate that slight effusion with no other synovial pathology is quite common in healthy individuals (adults, children and adolescents), particularly in the MCP, MTP and PIP joints. Effusion in joints without JIA was also observed by other authors(10). Such knowledge indicates that conclusions based on US findings should be made carefully and proves that the value of imaging in JIA requires further systematic research taking into account the whole spectrum of inflammatory features (synovitis, tenosynovitis and tendinitis, panniculitis, bursitis, assessment of erosions and cysts as well as enthesopathies) and the determination of threshold values which would accurately indicate the presence of the disease (e.g. acceptable volume of the synovial fluid in a joint without JIA).
According to the current criteria(9), remission of JIA (and of other rheumatic diseases) is determined on the basis of a clinical examination. Numerous studies indicate that, in certain patients, joint destruction progresses due to persisting subclinical disease, which can be detected in US and MR imaging. As far as the identification of the inflammatory process in clinically silent cases does not pose any problem for ultrasonography, confirming remission might be problematic. In our opinion, it is currently impossible to confirm that even slight persisting effusion or synovial thickening without hypervascularity are an evidence of remission and not a sign of chronic inflammation(11, 12). The remission criteria for US imaging have still not been established(11).
Karmazyn et al.(13) found ultrasound signs of arthritis, tenosynovitis or joint damage (erosions, cartilage thinning) in 25% of children with JIA with no clinical evidence of the disease.
Cellerini et al.(14) examined knee joints in children with oligoarticular JIA in its active phase and in remission. Effusion and synovial thickening were found in 70% of clinically asymptomatic patients. Such findings could correspond either to post-inflammatory changes or to chronic inflammation. In dynamic MRI (see below), Malattia et al.(15) observed no correlation between synovial thickness and dynamic parameters of synovium vascularity. Moreover, Gylys-Morin et al.(16) confirmed that maximum synovial thickness ≥3 mm or synovial volume ≥3 ml is a sensitive and specific criterion of active synovitis in the knee joint.
Doria et al.(17) conducted contrast-enhanced US examinations of the knee joint (using Levovist) in children with JIA and in controls. In non-contrast and in contrast-enhanced US, they distinguished three groups of patients: with active JIA, with chronic JIA and in remission. These authors found no significant differences between the groups in terms of the peak enhancement ratio. The usage of the contrast agent enhanced the signal in the two first groups of patients. The effect was not that obvious in the third group, and no enhancement occurred in healthy controls.
Magnetic resonance imaging
Magnetic resonance imaging is conducted to assess the inflammatory process occurring in soft tissues and bone marrow. A contrast-enhanced examination enables assessment of the activity of synovitis and confirms the presence of inflammation in the subchondral bone tissue.
MRI is more sensitive than physical examination and conventional radiography. Additionally, in many cases, it surpasses ultrasonography in the assessment of inflammatory and degenerative changes in JIA(18). Optimized MRI protocols make it possible to scan children, usually older than 5 years of age, without the need for sedation or anesthesia(18).
The evaluation of inflammatory signs in MRI in children differs from that in adults in many aspects and still remains a challenge(18).
The basic indications for MRI in children with JIA include:
Assessment of inflammatory changes in peripheral joints and tendon sheaths. In initial stages, the disease is manifested by effusions and synovial thickening with post-contrast ehancement (synovitis, tenosynovitis) (Fig. 8). In later stages, one can observe gradual damage to the articular hyaline tissue by the pannus, which leads to bony erosions, cartilage thinning and, finally, deformation of joint surfaces. Tenosynovitis can be complicated with tendinitis, followed by tendon damage. Moreover, MRI is a method of choice in the diagnosis of early inflammatory changes in the temporomandibular joints (65% of cases)(11). Using ultrasonography for this purpose is a mistake. Furthermore, MRI is the method of choice in diagnosing early stages of osteonecrosis (more common in children with JIA due to steroid therapy).
Assessment of inflammatory changes in the bone marrow (Fig. 9). MRI-detected bone marrow edema (BME) corresponds to inflammatory infiltrates (osteitis), which are identical to those observed in the synovium. Bone marrow edema leads to inflammatory cysts (geodes) which will develop into erosions when they have crossed the cortical bone layer. BME regresses upon treatment.
Search for inflammatory lesions in whole-body MRI, particularly when the clinical picture is unclear (Fig. 10).
Assessment of the spine and spinal cord in order to detect synovitis, BME and spondylodiscitis as well as to assess their activity, location, progression (e.g. in the atlantoaxial region), and complications (spinal canal stenosis, subluxations, usually anterior and vertical) (Fig. 11).
MRI of the ankle joint, sagittal T1 TSE CM image. Inflammatory features in the form of edema and contrast enhancement of the bone marrow in the anterior aspect of the talus bone and calcaneus; effusion, thickened and enhancing synovium in the talonavicular and talocalcaneal joints
MRI of the foot, PD TSE. Bone marrow edema in the tarsal bones; the greatest changes can be seen in the medial cuneiform and navicular bones
Whole-body MRI, coronal T2 TIRM image. Bone marrow edema within the distal femoral epiphyses; no other pathologies are detected
MRI of the cervical spine, sagittal T1 TSE CM image. Effusion, thickened and enhancing synovium of the C1/C2 articulation, bone marrow edema of the odontoid process
In practice, MRI of the peripheral joints and entheses is usually the third examination, after radiography and ultrasonography. As for the assessment of the axial spine, it is usually the method of the second choice (after radiography).
Magnetic resonance imaging is used for early diagnosis, treatment monitoring, confirming remission and assessing complications. MRI assessment is usually qualitative in terms of signal characteristics, presence, quantity, size and location of inflammatory changes typical of synovitis, tenosynovitis and tendinitis, BME, erosions, geodes etc. Moreover, changes visible in MRI of the knee joint can be evaluated semi-quantitatively using the validated Juvenile Arthritis MRI Scoring (JAMRIS)(18). Also, it is attempted to develop similar scoring systems for small joints of the hands and wrists as well as the temporomandibular joints(18). The simplified semi-quantitative scoring system used to assess the wrist and metacarpophalangeal joints in children, called OMERACT (Outcome Measures in Rheumatology Clinical Trials), is used to assess erosions, BME and synovitis. Whereas in adults the assessment of the size of erosions is burdened with a considerable error, erosions in children are assessed with the use of a 4-grade system depending on the surface of damaged bone (0 – no erosions, 1 – 25%, 2 – 26–50%, 3 – 51–75%, 4 – 76–100%). Synovitis and osteitis are assessed in 15 sites: wrist bones, metacarpal bases and distal radial and ulnar epiphyses(2), and the manner of semi-quantitative assessment is identical as in RA patients.
It seems that broader usage of quantitative examinations (dynamic contrast-enhanced magnetic resonance imaging, DCE-MRI) is needed in rheumatology and in JIA. They would enable more accurate assessment of disease activity and treatment monitoring compared with semi-quantitative systems(18). In DCE-MRI, a series of images are acquired every several seconds after an intravenous bolus of a contrast agent. This makes it possible to assess contrast enhancement, including a range of indicators (maximum, moderate, minimum enhancement or the shape of the enhancement curve). It has been demonstrated that the volume of enhancing synovium can reflect the size of cellular infiltration as well as synovial proliferation and hypertrophy, and be a measure of inflammatory activity(12). Moreover, a relationship between the intensity of enhancement and inflammatory activity has been observed(12). Despite certain discrepancies between reported values of DCE-MRI and clinical parameters of JIA, dynamic MRI scans may be useful in the monitoring of treatment efficacy(19).
The rate of synovial enhancement (RE) in DCE-MRI depends on tissue vascularity and capillary permeability. It is believed that both these factors should reflect the degree of inflammatory activity. It has been shown that RE is an important parameter in the assessment of disease activity, responsiveness to treatment and predicting progression to erosions in adults with RA(15). Malattia et al.(15) performed DCE-MRI in children with JIA with clinical manifestations of the disease in the writs and hip. They measured the following parameters of contrast enhancement: rate of early enhancement (REE), maximum rate of enhancement (MV) and maximum absolute enhancement (ME). In wrist assessment, REE exhibited a strong correlation with ESR and wrist edema (p < 0.02) as well as a moderate correlation with pain and mobility limitation. None of the parameters correlated with clinical damage indicators, such as wrist mobility restriction. As for hip examination, ME correlated with clinical indicators of joint mobility restriction. This is a valuable piece of information for a clinician since clinical assessment of the hip is difficult, and the risk of progression in this joint, despite patient's good clinical condition, is high in children.
Contrast-enhanced MRI is superior in visualizing epiphyseal cartilage defects. Several cartilage vascularity patterns have been identified: peculiar, striated and linear. They can represent vascularity in response to ongoing inflammation(19). In the material of Hérve-Somma, MRI without contrast enhancement presented normal cartilage in most children with JIA(20). Following contrast injection, however, grade 1–3 cartilage defects were detected in numerous children(20). Moreover, atrophic or hypoplastic menisci covered with the synovium were found(20). One study has revealed that cartilage defects regressed after intraarticular administration of a steroid, which might suggests that cartilaginous defects in JIA, at least in initial stages, correspond to inflammatory infiltrations, rather than actual joint destruction(19).
Local differences in water concentration and orientation of collagen fibers produce differences in the mobility of water particles in cartilage, which can be measured by differences in T2 relaxation time in MRI. It has been demonstrated that increased cartilage water content is an early feature of its degeneration. Moreover, the proteoglycan matrix also undergoes degradation which is followed by damage and inhibition of proteoglycan synthesis, which increases T2 relaxation time(21). This evidence indicates that early cartilage degeneration, caused by increased water content of articular cartilage and decreased collagen content, is manifested by increased cartilage T2 relaxation time(21). Kight et al.(21) observed a T2 relaxation time increase in the cartilage of the distal femoral epiphysis in girls with JIA compared with healthy girls at a similar age. This can confirm the presence of microstructural differences in JIA and makes it possible to map cartilage for early diagnosis of its degeneration(19).
In contrast to adolescents, young children rarely present erosions in the subchondral bone. Cartilage destruction can begin both from the side of the joint cavity, as a result of its destruction by the pannus, and as a consequence of subchondral tissue resorption. In the latter case, MRI presents BME enhancing upon contrast injection(16). Malattia et al.(2) compared the detectability of erosions in the wrist in radiography, US and MRI. Thanks to three imaging planes, enabling access to all articular surfaces, MRI helped detect twice as many erosions as radiographs and US. Ejberg et al.(22) demonstrated that erosions on radiographs are identified with delay associated with the needed destruction of an appropriate amount of bone tissue. This was confirmed by Malattia et al.(2), who found X-ray-invisible erosions in MRI in patients with shorter disease duration.
Despite high sensitivity, the specificity of MRI is a subject of debate. McQueen et al.(23) demonstrated that merely ¼ of all “erosions” detected by MRI develop into X-ray-detectable erosions within 2 years. Moreover, McQueen(24) described the spectrum of wrist changes that can be mistaken for erosions. Ejberg et al.(25), in turn, stated that slight erosions observed in MRI can also be found in healthy individuals, usually in the capitate and lunate bones. These opinions are contradicted by histological findings, computed tomography and mini-arthroscopy, which confirm that MRI-detected erosions are indeed bony defects(2). This issue remains open. It is constantly addressed in the literature and requires further investigations. In the study conducted by Malattia et al.(2), the value of US and radiography in detecting erosions was comparable. In other studies mentioned in this publication, more erosions were detected in US than on radiographs, or the other way round. The problem in radiography is the fact that tissues in AP or PA and even in oblique views overlap. In US, however, there is no access to all articular surfaces(2). In MRI all erosions are visible, but their image must be discriminated from nutritional channels and numerous midcarpal ligaments.
Despite a range of advantages, MRI is not free from limitations. The examination is long and requires a motionless position. Children at the age of several years can conform to this requirement, but younger, agitated and non-compliant ones with additional pain require sedation. Moreover, the assessment involves one joint or a group of joints (e.g. the hand) with no possibility of comparing the contralateral side or performing a dynamic examination.
JIA treatment monitoring and prognosis
The course of JIA is difficult to predict. In certain children, progressive joint degeneration is observed(2). The success of treatment depends on close monitoring of the disease activity(13). Biological therapy, introduced in the recent years, has considerably improved the efficacy of JIA treatment. However, it is important to identify risk factors of poor prognosis in order to implement such treatment early. Moreover, markers helpful in early diagnosis and prognosis as well as indicators to intensify treatment in JIA patients are being continuously searched for. Anti-citrullinated peptide antibodies (ACPA), which are very specific in adults with RA, are rarely found in JIA (1.8–14%). They are mainly observed in children with polyarthritis, and do not carry such a prognostic value as in adult patients with polyarticular-onset RA, with considerable joint destruction or with a significant risk of destruction. It must be emphasized that, because of the very individual course of the disease, the factor that determines it the most (taking into account joint destruction) is the clinical form of JIA and location of joint changes.
Imaging plays a significant role in making a prognosis concerning the course of JIA and in follow-up. The most numerous reports concern radiographic monitoring of the wrist, which is one of the most commonly involved joints in JIA(2, 26). In most children, the wrist becomes involved within the first year from the onset(26). Moreover, wrist involvement is associated with more severe JIA, worse functional outcome and higher probability of the lack of long-term response to treatment(2, 26). Additionally, the wrist is the most common location of erosions(2). Their early detection means a higher risk of progression and indicates poor prognosis(2). As the disease develops, the second wrist becomes involved in most patients with JIA(26).
Flato et al.(27) identified the following factors of poor prognosis: young age of onset, presence of HLA-DRBI*08, positive rheumatoid factor, elevated ESR persisting for a long time and a considerable number of affected joints within the first 6 months from the onset. Al-Matar et al.(28) concluded that symmetrical joint involvement and arthritis in the ankle or wrist were predictors of erosions in oligoarthritis(28). Furthermore, Ravelli et al. and Al-Matar et al.(28, 29) enumerate the following predictors of poor treatment outcomes and disease progression: considerable advancement of changes at the onset (number of affected joints, severity of symptoms), symmetrical joint involvement, hip or wrist involvement, positive rheumatoid factor, long-lasting active disease, onset at a young age, elevated ESR, late medical consultation and late implementation of disease-modifying antirheumatic drugs (DMARDs).
Persisting clinical sings of JIA or their exacerbation is an indication for treatment modification and is associated with poor prognosis(10). However, the response to treatment in JIA has not been standardized. There are several evaluation methods, but few of them are reproducible(30). The clinical examination is the mainstay in patient follow-up. Joints are evaluated in terms of edema, restricted mobility and pain. This assessment is subjective and characterized by considerable interobserver variability(30). From the radiologist's viewpoint, the dilemmas mentioned by the authors of the publication are surprising, namely whether treatment efficacy should be assessed by considering the number of joints with active inflammation, number of swollen joints or number of joints with mobility limitation.
In patients followed for 10 years, the percentage of destructive changes in joints reached: 63–75% in systemic JIA, 8–27% in oligoarthritis and 35–67% in polyarthritis, including 39% of polyarticular RF-negative JIA and 79% of polyarticular RF-positive JIA(29). In the study conducted by Al-Matar et al.(28) among children followed for over 5 years, the progression from oligoarticular to a more advanced form (>4 involved joints) of the disease was observed in 39.5% of patients.
The current criteria for the diagnosis of JIA, disease activity monitoring and identification of remission are based on the clinical examination and laboratory tests. The clinical assessment is difficult and burdened with a risk of errors. Extending the diagnostic work-up and including US and MR imaging makes it possible to optimize the diagnosis and treatment of patients with JIA. The identification of children with the highest risk of progression at the stage of initial diagnosis could enable their optimal treatment and discrimination from the remaining patients who do not require such intensive management.
Based on the review presented above, several research directions on JIA imaging can be distinguished:
developing more sensitive and specific imaging methods and indicators that would enable early diagnosis of pathologies in JIA and identification of patients at a higher risk of rapid progression, requiring optimal therapy(2);
determining the value of US and MR imaging in the identification of patients likely to develop an aggressive and destructive disease in order to establish an optimal therapeutic strategy(31);
specifying remission criteria in US and MR imaging;
determining the usefulness of MRI in the assessment of small joints, the involvement of which is associated with poor prognosis;
assessment of the prognostic value of BME seen in MRI in children. Probably, as in adults with RA, bone marrow edema marks a pre-degenerative phase that requires intensive treatment(11).