Technical background

Ultrasound imaging is safe and noninvasive based on the mechanical transmission and reflection of ultrasound waves through the body . As the ultrasonic pulse passes through a medium, molecules within the body are reversibly perturbed from their equilibrium positions. Images are formed by sensitively detecting echoes of the pulse returned from interfaces or from scattering structures within the tissue. Ultrasonic transducers used to initiate and to detect ultrasonic pulses, and the electronics that accompany them are relatively low cost compared with the equipment necessary for most other imaging techniques.

The relative intensity of a returned echo is represented in terms of relative pixel brightness (from white to black) in the so-called “B mode” or “grey-scale”. The sound path’s orientation and the echo time-of-flight are used to map each echo intensity to a position in a reconstructed image of the structure under evaluation. Echo-based imaging speed is limited by the pulse’s travel time to and back from the deepest part of the imaged zone (in the order of 0.1 ms for an 8-cm depth).

The ultrasound evaluation provides real-time visualization. Movements within the structures can be observed as they occur, including the movement of blood flow (both velocity and direction) using the Doppler mode.

Management of RA by ultrasound

Because of safety and real-time evaluation, ultrasound has gained importance in the evaluation of musculoskeletal pathologies, including inflammatory arthritis, especially rheumatoid arthritis (RA). Over the last 20 years, an increasing number of studies have explored the value of ultrasound for the management of RA. All these published data support the importance of using ultrasound in addition to more established techniques such as conventional radiography (CR) or clinical and laboratory evaluation .

Detection of synovitis by ultrasound has shown to be an important outcome in both early and established RA .

Both Doppler and gray-scale (GS) ultrasound findings have shown to be predictive of later structural damage on CR. The potential use of ultrasound in the clinical management of RA has been outlined in a recent expert consensus-based publication .

In the following sections, recent data on the role of ultrasound for the diagnostic workup of RA, the monitoring of disease activity, and the added value for defining/monitoring remission are presented. The chapter focuses on the capability of ultrasound to detect inflammation at the synovial joint level (i.e., synovitis) with potential and established clinical implications, without focusing on the capability of ultrasound to detect inflammation at the tendon level (i.e., tenosynovitis) or to detect structural damage (i.e., bone erosions).

Ultrasound for the diagnostic workup of RA

Early diagnosis of RA and early initiation of disease-modifying anti-rheumatic drugs (DMARDs) have demonstrated to reduce inflammation and therefore limit disease progression and functional loss .

The American College of Rheumatology (ACR)/EULAR classification criteria have been developed for helping rheumatologists to classify earlier patients with potential RA on the basis of the presence of a minimal number of clinically inflamed joints (i.e., synovitis) or if bone erosions are detected on CR .

However, both clinical examination and CR can lack sensitivity and accuracy to detect early signs of joint inflammation and structural damage .

Ultrasound can detect minimal signs of synovitis and differentiate between intra-joint synovial inflammation and other causes of clinical swelling, such as tenosynovitis, bursitis, and other soft tissue lesions .

The use of ultrasound has been envisaged by the ACR/EULAR classification criteria to help in detecting synovitis in clinically unaffected joints, permitting to increase the number of involved joints needed to fulfill the criteria . In addition, several studies showed that patients assessed using ultrasound evaluation are likely to fulfill these criteria at an earlier stage of their disease than those assessed using conventional tools .

In patients at risk to develop RA (i.e., patients with arthralgia but without clinically detected synovitis or patients with rheumatoid factor (RF) or anti-citrullinated peptide antibodies (ACPA) positivity, without clinical signs of inflammation), ultrasound-detected abnormalities have shown to be a prognostic marker of RA development .

Which ultrasound findings have the best prognostic value? Both GS synovitis and Doppler signal seem to be predictive, but at different level. In a study by Van de Stadt and colleagues, the combination of GS synovitis and power Doppler abnormalities was the strongest predictor of arthritis (OR 12.9 and PPV 35%), at the joint level, but not at the patient level . On the contrary, in the study by Rakieh and colleagues, only power Doppler signal was an independent predictive factor of arthritis development at the patient level . This discrepancy may be explained by the different ultrasound procedures used, especially the number and the size of the joints scanned.

The use of ultrasound appears even more important in ACPA-negative patients with arthralgia, especially in the absence of clinical and biological inflammatory markers. In this case, ultrasound helps to confirm the presence of joint inflammation before the appearance of a definite RA . In daily practice, the combined use of clinical, laboratory, and ultrasound findings may therefore improve the diagnostic management of RA. Which is the threshold of normality of ultrasound inflammatory findings at the joint level? And which joints are more frequently affected?

Witt and colleagues have suggested that in established RA, minimal GS findings in small joints are frequently detected in the absence of active disease, suggesting that a minimal GS score cannot be considered abnormal in such population .

In a recent ultrasound study performed in healthy subjects, Padovano and colleagues determined the prevalence of ultrasound inflammatory findings (i.e., effusion, synovial hypertrophy, and Doppler signal) in the small joints of hands and feet .

The author showed that at least one ultrasound abnormality can be detected in more than 80% of the subjects; however, the total number of the joints involved is very low (i.e., less than 6% of the total number of examined joints). The most frequently detected finding was effusion. The most frequently involved joints were the metatarsophalangeal (MTP) joints (especially the first and the second), followed by the wrist. These findings question the relevance of effusion as isolated inflammatory sign as well as the signification of isolated ultrasound abnormalities at the MTP 1 and 2 level or at the wrist level for diagnostic purposes.

Ultrasound for monitoring RA treatment

Published data have consistently shown that ultrasound is a sensitive tool for monitoring patients under treatment, either under conventional synthetic DMARDs (csDMARDs) or biological DMARDs (bDMARDs). By evaluating the actual presence of synovial inflammation and by excluding the other causes of joint pain (such as joint deformity or periarticular lesions), the use of ultrasound in assessing response to therapy can be of a great help in clinical practice.

Several studies have shown the sensitivity of ultrasound findings to change in RA-treated patients . Both GS and Doppler findings are as sensitive as clinical examination and laboratory markers in detecting changes in patients . A recent study has shown that an ultrasound response can be observed as fast as within 1 week. In this first multicenter international open-label therapeutic trial using ultrasound findings as primary outcome, a statistically significant decrease in Doppler findings and in a combined GS and Doppler score (PDUS combined score) was observed after 7 days of treatment. Synovial hypertrophy measured by GS alone showed a statistically significant change, as compared to baseline, after 2 weeks, and the effusion only after 1 month of treatment. This rapid response was observed independently of the number of joints scanned. This observation is very important as several reduced joint sets have been proposed for evaluating treatment response. At present, no consensus exists on the best-reduced number of joints to scan and on the modality to use for grading synovial inflammation at the joint level (GS, Doppler of both). Doppler appears very sensitive, although very dependent on the quality of the machine used. The more comprehensive the ultrasound evaluation, the more sensitive it is in detecting change . The inclusion of both small and large joints seems to ensure the best responsiveness .

Ultrasound in the evaluation of RA remission

Since sustained remission is the ultimate goal of the modern RA treatments, the definition of this state is highly important as flares predict erosive progression over time and functional disability .

Recent studies have shown that in patients in remission determined either by physician or by using various remission criteria, subclinical synovitis is present in both GS and Doppler in more than 30% of the patients whether the treatment used (csDMARDs or bDMARDs) .

The presence of an ultrasound-detected synovitis in patients on csDMARDs seems to be related to the development of structural damage on CR at both joint and patient levels . However, the role and the predictive value for the development of structural damage in patients under bDMARDs need to be further explored, as this detection does not seem to be related to radiographic damage .

Nevertheless, in RA patients in remission under both csDMARDs or bDMARDs, the presence of subclinical synovitis seems to predict flare. Saleem and colleagues have shown that the presence of subclinical synovitis with a positive Doppler signal increases the risk of flare in 30% of the RA patients in remission , whereas the absence of Doppler signal is the best predictor for not experiencing it .

The absence of subclinical synovitis seems to be associated with a better chance of no relapse when stopping or tapering bDMARDs. Patients with high ultrasound score on GS and Doppler are likely to have more risk to relapse than patients with low score . In addition, the detection of a decrease in Doppler inflammation at 3 months seems to be predictive of clinical response at 6 months .

What is the role of using ultrasound in a treat-to-target (T2T) approach? Two recently published studies argue the added value of ultrasound for achieving a remission state in the context of a tight control in early RA .

Both studies showed that in an early population, both the clinical and the ultrasound tight controls permit to achieve remission without any superiority of an ultrasound approach. However, in both studies, the ultrasound arm seemed to produce a better structural outcome with a lower percentage of radiographic progression as compared to the clinical arm. Further studies, in more established RA populations and with a blinded design, are needed for answering this question.

Conclusions

The use of ultrasound in the management of RA patients has gained importance over the last few years. Ultrasound alone or in combination with other imaging and laboratory markers contributes to the improved management of RA.

Technical background

Ultrasound imaging is safe and noninvasive based on the mechanical transmission and reflection of ultrasound waves through the body . As the ultrasonic pulse passes through a medium, molecules within the body are reversibly perturbed from their equilibrium positions. Images are formed by sensitively detecting echoes of the pulse returned from interfaces or from scattering structures within the tissue. Ultrasonic transducers used to initiate and to detect ultrasonic pulses, and the electronics that accompany them are relatively low cost compared with the equipment necessary for most other imaging techniques.

The relative intensity of a returned echo is represented in terms of relative pixel brightness (from white to black) in the so-called “B mode” or “grey-scale”. The sound path’s orientation and the echo time-of-flight are used to map each echo intensity to a position in a reconstructed image of the structure under evaluation. Echo-based imaging speed is limited by the pulse’s travel time to and back from the deepest part of the imaged zone (in the order of 0.1 ms for an 8-cm depth).

The ultrasound evaluation provides real-time visualization. Movements within the structures can be observed as they occur, including the movement of blood flow (both velocity and direction) using the Doppler mode.

Management of RA by ultrasound

Because of safety and real-time evaluation, ultrasound has gained importance in the evaluation of musculoskeletal pathologies, including inflammatory arthritis, especially rheumatoid arthritis (RA). Over the last 20 years, an increasing number of studies have explored the value of ultrasound for the management of RA. All these published data support the importance of using ultrasound in addition to more established techniques such as conventional radiography (CR) or clinical and laboratory evaluation .

Detection of synovitis by ultrasound has shown to be an important outcome in both early and established RA .

Both Doppler and gray-scale (GS) ultrasound findings have shown to be predictive of later structural damage on CR. The potential use of ultrasound in the clinical management of RA has been outlined in a recent expert consensus-based publication .

In the following sections, recent data on the role of ultrasound for the diagnostic workup of RA, the monitoring of disease activity, and the added value for defining/monitoring remission are presented. The chapter focuses on the capability of ultrasound to detect inflammation at the synovial joint level (i.e., synovitis) with potential and established clinical implications, without focusing on the capability of ultrasound to detect inflammation at the tendon level (i.e., tenosynovitis) or to detect structural damage (i.e., bone erosions).

Ultrasound for the diagnostic workup of RA

Early diagnosis of RA and early initiation of disease-modifying anti-rheumatic drugs (DMARDs) have demonstrated to reduce inflammation and therefore limit disease progression and functional loss .

The American College of Rheumatology (ACR)/EULAR classification criteria have been developed for helping rheumatologists to classify earlier patients with potential RA on the basis of the presence of a minimal number of clinically inflamed joints (i.e., synovitis) or if bone erosions are detected on CR .

However, both clinical examination and CR can lack sensitivity and accuracy to detect early signs of joint inflammation and structural damage .

Ultrasound can detect minimal signs of synovitis and differentiate between intra-joint synovial inflammation and other causes of clinical swelling, such as tenosynovitis, bursitis, and other soft tissue lesions .

The use of ultrasound has been envisaged by the ACR/EULAR classification criteria to help in detecting synovitis in clinically unaffected joints, permitting to increase the number of involved joints needed to fulfill the criteria . In addition, several studies showed that patients assessed using ultrasound evaluation are likely to fulfill these criteria at an earlier stage of their disease than those assessed using conventional tools .

In patients at risk to develop RA (i.e., patients with arthralgia but without clinically detected synovitis or patients with rheumatoid factor (RF) or anti-citrullinated peptide antibodies (ACPA) positivity, without clinical signs of inflammation), ultrasound-detected abnormalities have shown to be a prognostic marker of RA development .

Which ultrasound findings have the best prognostic value? Both GS synovitis and Doppler signal seem to be predictive, but at different level. In a study by Van de Stadt and colleagues, the combination of GS synovitis and power Doppler abnormalities was the strongest predictor of arthritis (OR 12.9 and PPV 35%), at the joint level, but not at the patient level . On the contrary, in the study by Rakieh and colleagues, only power Doppler signal was an independent predictive factor of arthritis development at the patient level . This discrepancy may be explained by the different ultrasound procedures used, especially the number and the size of the joints scanned.

The use of ultrasound appears even more important in ACPA-negative patients with arthralgia, especially in the absence of clinical and biological inflammatory markers. In this case, ultrasound helps to confirm the presence of joint inflammation before the appearance of a definite RA . In daily practice, the combined use of clinical, laboratory, and ultrasound findings may therefore improve the diagnostic management of RA. Which is the threshold of normality of ultrasound inflammatory findings at the joint level? And which joints are more frequently affected?

Witt and colleagues have suggested that in established RA, minimal GS findings in small joints are frequently detected in the absence of active disease, suggesting that a minimal GS score cannot be considered abnormal in such population .

In a recent ultrasound study performed in healthy subjects, Padovano and colleagues determined the prevalence of ultrasound inflammatory findings (i.e., effusion, synovial hypertrophy, and Doppler signal) in the small joints of hands and feet .

The author showed that at least one ultrasound abnormality can be detected in more than 80% of the subjects; however, the total number of the joints involved is very low (i.e., less than 6% of the total number of examined joints). The most frequently detected finding was effusion. The most frequently involved joints were the metatarsophalangeal (MTP) joints (especially the first and the second), followed by the wrist. These findings question the relevance of effusion as isolated inflammatory sign as well as the signification of isolated ultrasound abnormalities at the MTP 1 and 2 level or at the wrist level for diagnostic purposes.

Ultrasound for monitoring RA treatment

Published data have consistently shown that ultrasound is a sensitive tool for monitoring patients under treatment, either under conventional synthetic DMARDs (csDMARDs) or biological DMARDs (bDMARDs). By evaluating the actual presence of synovial inflammation and by excluding the other causes of joint pain (such as joint deformity or periarticular lesions), the use of ultrasound in assessing response to therapy can be of a great help in clinical practice.

Several studies have shown the sensitivity of ultrasound findings to change in RA-treated patients . Both GS and Doppler findings are as sensitive as clinical examination and laboratory markers in detecting changes in patients . A recent study has shown that an ultrasound response can be observed as fast as within 1 week. In this first multicenter international open-label therapeutic trial using ultrasound findings as primary outcome, a statistically significant decrease in Doppler findings and in a combined GS and Doppler score (PDUS combined score) was observed after 7 days of treatment. Synovial hypertrophy measured by GS alone showed a statistically significant change, as compared to baseline, after 2 weeks, and the effusion only after 1 month of treatment. This rapid response was observed independently of the number of joints scanned. This observation is very important as several reduced joint sets have been proposed for evaluating treatment response. At present, no consensus exists on the best-reduced number of joints to scan and on the modality to use for grading synovial inflammation at the joint level (GS, Doppler of both). Doppler appears very sensitive, although very dependent on the quality of the machine used. The more comprehensive the ultrasound evaluation, the more sensitive it is in detecting change . The inclusion of both small and large joints seems to ensure the best responsiveness .

Ultrasound in the evaluation of RA remission

Since sustained remission is the ultimate goal of the modern RA treatments, the definition of this state is highly important as flares predict erosive progression over time and functional disability .

Recent studies have shown that in patients in remission determined either by physician or by using various remission criteria, subclinical synovitis is present in both GS and Doppler in more than 30% of the patients whether the treatment used (csDMARDs or bDMARDs) .

The presence of an ultrasound-detected synovitis in patients on csDMARDs seems to be related to the development of structural damage on CR at both joint and patient levels . However, the role and the predictive value for the development of structural damage in patients under bDMARDs need to be further explored, as this detection does not seem to be related to radiographic damage .

Nevertheless, in RA patients in remission under both csDMARDs or bDMARDs, the presence of subclinical synovitis seems to predict flare. Saleem and colleagues have shown that the presence of subclinical synovitis with a positive Doppler signal increases the risk of flare in 30% of the RA patients in remission , whereas the absence of Doppler signal is the best predictor for not experiencing it .

The absence of subclinical synovitis seems to be associated with a better chance of no relapse when stopping or tapering bDMARDs. Patients with high ultrasound score on GS and Doppler are likely to have more risk to relapse than patients with low score . In addition, the detection of a decrease in Doppler inflammation at 3 months seems to be predictive of clinical response at 6 months .

What is the role of using ultrasound in a treat-to-target (T2T) approach? Two recently published studies argue the added value of ultrasound for achieving a remission state in the context of a tight control in early RA .

Both studies showed that in an early population, both the clinical and the ultrasound tight controls permit to achieve remission without any superiority of an ultrasound approach. However, in both studies, the ultrasound arm seemed to produce a better structural outcome with a lower percentage of radiographic progression as compared to the clinical arm. Further studies, in more established RA populations and with a blinded design, are needed for answering this question.

Conclusions

The use of ultrasound in the management of RA patients has gained importance over the last few years. Ultrasound alone or in combination with other imaging and laboratory markers contributes to the improved management of RA.

Technical background

Magnetic resonance imaging (MRI) is a noninvasive imaging modality yielding cross-sectional images of the body in any plane without morphologic distortion or magnification. The projectional superimposition, a problem with conventional radiography (CR), can be avoided with MRI because of its multiplanar capabilities. MRI allows simultaneous assessment of the entire diarthrodial joint, including the primary inflammatory lesions in RA, including synovitis, tenosynovitis, bone marrow edema (BME) (or osteitis), as well as articular cartilage and bone. MRI does not use ionizing radiation and has few adverse effects. The introduction of potent, but expensive, biologic therapies in RA has highlighted the need for reliable prognostic markers and outcome measures to monitor treatment effect and disease activity to better tailor treatment options and strategies to the individual patient . Prompt treatment after diagnosis has been shown to reduce inflammation and limit joint destruction . The potential role of MRI in diagnosing and monitoring RA disease activity and progression is discussed in the following sections.

Technical aspects and sequences

The human body contains a large amount of water molecules in almost all tissues. Each water molecule contains two hydrogen nuclei or protons. MRI generates an image of an anatomic region by detecting protons that have been exposed to a powerful magnetic field, causing the magnetic moments of these protons to align with the direction of the field. Nuclear magnetic resonance is a physical phenomenon in which nuclei in a magnetic field absorb radio waves of a certain frequency and then re-emit electromagnetic radiation. In MRI, spatial information is obtained from this signal and transformed into a three-dimensional image. An MRI sequence is a number of radiofrequency pulses and gradients that result in a set of images with certain appearances of particular tissues to optimize the contrast and signal-to-noise ratio, while limiting artifacts. Certain contrast media, usually gadolinium-based, are used to improve the visibility of protons inside tissues via interactions with the contrast agent.

The OMERACT MRI in RA group recommends a core set of basic sequences to evaluate inflammatory and destructive changes in RA joints, which at least should include the following :

• •
  

  Imaging in two planes with T1-weighted images before and after intravenous gadolinium contrast

  
  
• •
  

  A T2-weighted fat saturated sequence or, if the latter is not available, a STIR (short tau inversion recovery) sequence

Imaging in two planes can be substituted by a three-dimensional sequence with isometrical voxels in one plane allowing reconstruction in other planes.

Recently, recommendations from the European Society of Musculoskeletal Radiology Arthritis Subcommittee regarding the standards of the use of MRI in the diagnosis of musculoskeletal rheumatic diseases were published . These emphasize the use of intravenous contrast for detection of tenosynovitis and synovitis, and that isotropic 3D imaging can be very useful for the hands and feet, especially for follow-up imaging. A detailed overview of recommended MRI scanning protocols has been provided .

Feasibility, selection of joints, and assessment of RA pathology

MRI has certain limitations that are common to both research settings and clinical practice. The examination of MRI is time-consuming, and a whole-body MRI unit may require the patient to lie in an uncomfortable position for a prolonged time. The MRI equipment requires a substantial financial investment, and individual examination is also costly. Consequently, there can be substantial waiting time to obtain an MRI scan at many centers. Assessment of inflammation on MRI preferentially involves intravenous contrast, which is contraindicated in patients with severe impaired renal function. To minimize scanning time, MRI can only cover a small proportion of affected joints in RA. This limited anatomical coverage may restrict the use of MRI in RA, compared to the broad coverage of anatomical sites by clinical examination or imaging by conventional radiographs. The wrist and/or the metacarpophalangeal (MCP) joints are often chosen for MRI examination as these joints are thought to be the most representative of the overall RA activity. No significant differences were found between MRI of “few” joints (unilateral wrist and 2nd to 5th MCPs) and “many” joints (bilateral wrists and 2nd to 5th MCPs, unilateral 1st to 5th MTP joints) with regard to the detection of progressive joint damage, while both MRI methods were more responsive than CR of hands and feet . In RA, scanning of both hands would be optimal, but is often not feasible with adequate image quality. In clinical practice, usually the most symptomatic hand or the dominant hand is examined . The use of MRI for the assessment of RA pathology has been facilitated by the rheumatoid arthritis magnetic resonance imaging score (RAMRIS) scoring system developed by the OMERACT MRI in RA task force . It has been developed since 2000, focusing on validity and reliability to evaluate inflammatory and destructive changes in RA of hands and wrists . RAMRIS consists of MRI definitions of important joint pathologies, a core set of MRI sequences (as described above) and a semi-quantitative scoring system for erosions, BME, and synovitis . In 2000, EULAR and OMERACT in collaboration published an atlas of reference images for the RAMRIS score, which provides readers with a tool for the standardized assessment of RA joints . A feasible and reliable scoring system for wrist tenosynovitis is also available . In light of the technical improvement of MRI, the OMERACT group in 2011 also published a preliminary MRI joint space narrowing score, which further adds to the RAMRIS . However, the use of the RAMRIS system in clinical practice is limited by the long time needed to perform the scoring.

MRI in the diagnosis of RA

Evidence from several studies supports the notion of a “window of opportunity” in early RA, during which initiating DMARD treatment maximizes improvement in long-term outcomes and increases the chance of reaching sustained remission . Because diagnostic criteria for RA do not exist, a clinical diagnosis should be established by the rheumatologist; thus, classification criteria are helpful in defining homogeneous treatment populations for study purposes and might be a guide to establish a clinical diagnosis. In 2010, a joint working group from ACR and EULAR developed new classification criteria to facilitate the classification at an early stage of the disease . The criteria are based on joint involvement, serology, acute-phase reactants, and duration of symptoms. The joint involvement includes both swelling and tenderness on clinical examination that is indicative of active synovitis. Additional evidence of joint inflammation from imaging techniques such as MRI or ultrasound may be used for the confirmation of joint involvement . A number of studies have confirmed that MRI is superior to clinical examination in the detection of joint inflammation . Several studies have described the impact of MRI on confirming a diagnosis of RA when conventional methods were inconclusive; the presence of MRI synovitis increases the sensitivity and specificity of a diagnosis of RA, and in one study, MRI findings were considered to be more important than ACPA status in the absence of RF . These findings are also reflected in recent EULAR recommendations for the use of imaging of the joints in the clinical management of RA, stating that when there is diagnostic doubt, imaging can be used to improve the certainty of a diagnosis of RA over and above clinical criteria alone . In addition, the presence of inflammation visualized by ultrasound or MRI can be used to predict the progression to clinical RA from undifferentiated arthritis .

MRI in the prognosis of RA

Several factors are known to predict prognosis in RA, including ACPA status, RF status, age, gender, genetic factors, inflammatory markers, and erosions on conventional radiography . In the last two decades, MRI has also proven to be an important prognostic marker in RA, and several studies have confirmed the predictive value of MRI findings for future erosive progression of conventional radiographic damage. These studies have different follow-up time, ranging from 1 year and up to 10 years . In an inception cohort of 84 early RA patients, MRI BME was an independent predictor of structural progression on CR and MRI . Similar results were found in the randomized controlled CIMESTRA trial of 130 RA patients, where baseline BME was the strongest independent predictor of radiographic progression in hands, wrists, and forefeet after 2 years . The 5-year follow-up of these patients confirmed a long-term predictive ability of BME . Bøyesen et al. reported that both baseline and 1-year cumulative measures of MRI synovitis and osteitis independently predicted 3-year radiographic progression . These findings are reflected in the EULAR recommendations, which emphasize that MRI BME is a strong predictor of subsequent radiographic progression in early RA and should be considered for use as a prognostic indicator . Further, other MRI features, including synovitis and erosions at baseline, can be considered for the prediction of further joint damage .

MRI in monitoring disease activity in RA

Given the high sensitivity to detect both inflammation and structural joint damage, MRI may be useful in monitoring disease activity . Recently, MRI assessments of inflammatory activity (synovitis, tenosynovitis and BME) and joint damage (bone erosions and joint space narrowing) are increasingly used in RA clinical trials . MRI is a highly responsive imaging modality in terms of measuring changes in joint inflammation. In a study of RA patients receiving anti-TNF therapy, a MRI composite measure of inflammation comprising synovitis, tenosynovitis, and BME was more responsive than conventional measures of disease activity . However, it remains unclear how physicians might use MRI measures in routine clinical care and the potential impact of MRI findings on clinical decision-making. It is also unclear if the use of MRI in clinical practice would be cost-effective. Still, in certain clinical settings, the use of MRI is warranted, and one such practical application of MRI is in RA patients with clinical suspicion of cervical involvement, where MRI of the spine should be performed if specific neurological symptoms and signs are present .

MRI in the assessment of RA patients in clinical remission

Structural joint damage is one of the main outcomes in RA, and in the development of the 2011 ACR/EULAR remission criteria, candidate criteria were tested for their ability to predict a good future radiographic and functional outcome; in patients fulfilling the final Boolean criteria, 23% of patients experienced progression of joint damage . A study in an observational cohort of established RA found similar results . Several studies have demonstrated that MRI findings of inflammation are a frequent finding in RA patients in clinical remission . In a multicenter study coordinated by the OMERACT MRI group, data from six cohorts were collected, including RA patients in clinical remission or low disease activity, and MRI inflammatory activity in the wrist and/or MCP joints was present in most of the patients . In further longitudinal analyses of the same data set, the OMERACT MRI group demonstrated that RF-positive RA patients with a synovitis score below an “MRI inflammatory activity acceptable state” were at low risk of radiographic progression. This risk stratification may be clinically important in patients in remission where the rheumatologist considers the option of tapering biologic therapy. The concept of “imaging remission,” that is, clinical remission without inflammation detected by sensitive imaging methods, may be an attractive treatment target to reduce the risk of progression of joint damage . In the 2013 EULAR recommendations for the use of imaging in clinical management of RA, the recommendation regarding imaging in clinical remission states that “MRI can detect inflammation that predicts subsequent joint damage, even when clinical remission is present and can be used to assess persistent inflammation” . However, it still needs to be shown that an imaging-guided treatment strategy involving therapeutic adjustments will improve outcomes over and above a treatment strategy based on clinical and laboratory assessments , and at least one study is currently examining the target of no MRI-detected BME . This study will clarify the value of applying MRI in RA patients who are in clinical remission.

Nuclear imaging technique

Feasibility studies of F-18-FDG-PET in clinically active RA

Most PET studies in RA have been performed with the tracer [ ¹⁸ F] fluorodeoxyglucose ([ ¹⁸ F]FDG). This clinically available tracer accumulates in metabolically active tissue as inflammation. In 1995, first clinical proof of principle [ ¹⁸ F]FDG PET studies in active, established RA patients were performed. Increased [ ¹⁸ F]FDG uptake was found in clinically inflamed wrist joints. The quantitative uptake of [ ¹⁸ F]FDG (Standardized Uptake Value (SUV)) correlated with clinical assessments of tenderness and swelling . These findings were later confirmed by other researchers for the correlation between PET data and disease activity score 28 (DAS28) and for simple disease activity index (SDAI) and disease duration . Kubota et al. and Goerres et al. found that simple visual semi-quantitative scoring of [ ¹⁸ F]FDG uptake in joints on whole body PET scans, that is, grading 0–4 , also reflected the inflammatory activity and clinical symptoms of the RA joints ( Fig. 1 ). Simple scoring systems can make the technique more accessible in routine clinical practice without the need to determine the quantified tracer uptake in joints.

Whole body [ ¹⁸ F]FDG-PET scan of an RA patient demonstrating arthritis activity in multiple joints reflected by local uptake of the tracer in the inflamed joints.

Sourced from Kubota K et al., Ann Nucl Med 2009; 23:783–791.

Although sample sizes of performed feasibility studies were small, an impression of the diagnostic test values of [ ¹⁸ F]FDG PET for imaging of arthritis can be obtained from some published studies. Sensitivity levels up to 90% were obtained by Beckers et al. in a study evaluating 356 joints of 21 established RA patients . With regard to specificity, [ ¹⁸ F]FDG PET allows excellent differentiation between inflamed RA joints and healthy joints, and joints of patients without inflammatory joint disease, with the latter two groups of joints not showing any tracer uptake . However, absolute joint uptake of [ ¹⁸ F]FDG does not allow distinction between RA and osteoarthritis (OA), despite a higher number of PET positive joints in RA than in OA patients . Other researchers confirmed [ ¹⁸ F]FDG uptake in OA joints .

Despite this limitation in specificity of uptake, the pattern of uptake of [ ¹⁸ F]FDG in joints or whole body distribution may aid in differential diagnosis. The biodistribution patterns on whole body [ ¹⁸ F]FDG PET scans and distribution within the joint allowed distinction between RA and spondylarthropathy (SpA) , and between multiarticular types of collagen vascular diseases-associated arthritis depicting more active synovitis than nonmultiarticular type .

Addition of anatomical information to the PET signal may further specify the anatomical source of the PET signal. First images produced with [ ¹⁸ F]FDG-PET-MRI underline the high potential for imaging of arthritis .

Development of specific tracers for RA imaging

Improvement of the specificity of PET for the detection of arthritis in RA can contribute to early diagnosis and development of individualized imaging guided treatment strategies. This stimulated the development of more specific tracers targeting molecular pathways specifically associated with rheumatoid synovitis.

In the last few years, an increasing number of potential specific tracers for RA imaging has been explored. One of the first investigated more specific tracers was [ ¹¹ C]choline. This tracer targets proliferative changes in rheumatoid synovitis as choline is a precursor for the synthesis of phospholipids, an essential component of cell membranes . This study evaluated 10 patients with inflammatory joint disease (among which n = 2 RA) and showed that [ ¹¹ C]choline uptake rates were eightfold faster than [ ¹⁸ F]FDG.

Another interesting target for visualization of RA disease activity is the macrophage, since (activated) macrophages infiltrate in the synovial tissue as soon as RA develops and play a central role in more established RA. Moreover, histological studies have shown that the macrophage is an important biomarker for the prediction of therapeutic outcome in RA . Targeting translocator protein (TSPO), formally known as peripheral benzodiazepine receptors particularly expressed on activated macrophages, with [ ¹¹ C]PK11195 has been successful to visualize clinical arthritis in patients with established RA. [ ¹¹ C]PK11195 joint uptake on PET correlated with clinical synovial swelling and macrophage infiltration in the synovial tissue (immunohistochemistry) ( Fig. 2 ). A disadvantage of [ ¹¹ C]PK11195 is the relatively high periarticular nonspecific background uptake that limits its use for the detection of more subtle arthritis activity, which is relevant for early diagnosis and for image-guided therapy monitoring. Therefore, new generation TSPO tracers, [ ¹¹ C]DPA713, and [ ¹⁸ F]DPA714 have been investigated preclinically in animal models of arthritis with promising superior characteristics for imaging of arthritis as compared to [ ¹¹ C]PK11195 . Another promising target is the folate receptor β (FR-β), which is expressed on activated macrophages in RA synovial tissue . This target has clearly therapeutic potential as well, since methotrexate as an anti-folate agent is the anchor drug of RA treatment. The feasibility of using the FR-β target for nuclear imaging of RA has been demonstrated both in preclinical and clinical studies (see Fig. 3 ).

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