Role of ultrasonography in the diagnosis of rheumatic diseases in light of ACR/EULAR guidelines.

In the past years, ultrasound imaging has become an integral element of the diagnostic process in rheumatic diseases. It enables the identification of a range of inflammatory changes in joint cavities, sheaths and bursae, and allows their activity to be assessed. In 2012, experts of the European Society of Musculoskeletal Radiology prepared recommendations concerning the role of ultrasonography in the diagnosis of musculoskeletal diseases. Ultrasound was considered the method of choice in imaging peripheral synovitis. Moreover, ultrasound imaging has been popularized thanks to the new classification criteria for rheumatoid arthritis issued by the American College of Rheumatology and European League Against Rheumatism in 2010. They underline the role of ultrasound imaging in the detection of articular inflammatory changes that are difficult to assess unambiguously in the clinical examination. These criteria have become the basis for recommendations prepared by experts from the European League Against Rheumatism concerning medical imaging in rheumatoid arthritis. Nine of ten recommendations concern ultrasonography which is relevant in detecting diseases, predicting their progression and treatment response, monitoring disease activity and identifying remission. In the new criteria concerning polymyalgia rheumatica from 2012, an ultrasound scan of the shoulder and pelvic girdle was considered an alternative to clinical assessment. Moreover, the relevance of ultrasonography in the diagnosis and monitoring of peripheral spondyloarthropathies was widely discussed in 2014 during the meeting of the European League Against Rheumatism in Paris.

Introduction

Ultrasound imaging is currently a commonly acknowledged and widely used method in the diagnosis of rheumatic diseases. In the recent years, it has become an essential supplementation of physical examination in the rheumatologist practice. Modern equipment enables imaging of structures with the resolution up to 0.1 mm, which helps detect slight inflammatory foci and early joint damage. This examination is highly sensitive in detecting effusion and synovial hypertrophy. Additionally, Doppler modes (power Doppler, PD, and color Doppler, CD) help present evidence of enhanced vascularity in tissues affected by the inflammatory process. Moreover, ultrasound imaging is more sensitive in detecting rheumatoid erosions than conventional radiography; Wakefield et al. have demonstrated that US detects erosions 6.5 times more often than X-ray(. The PD mode enables the assessment of the activity of erosions. Furthermore, ultrasound imaging facilitates the detection of tenosynovitis, tendinitis, bursitis and enthesopathy(. The US image is non-specific, which means that it does not allow rheumatologic entities to be distinguished but merely assessed in terms of their nature, location and activity of inflammatory changes. Moreover, US imaging has also other limitations. It does not enable one to assess all articular surfaces due to limited access of an ultrasound transducer( and is highly dependent on the physician's experience in the diagnosis of motor organ diseases. Its result also depends on the quality of an ultrasound system.

In 2012, based on a literature review, experts of the European Society of Musculoskeletal Radiology (ESSR) prepared recommendations concerning the usage of ultrasonography in the diagnosis of musculoskeletal diseases. The following aspects were discussed for each peripheral joint: indications, level of research evidence (A – randomized clinical trials, cohort trials, B – retrospective cohort trials, case-control studies, C – case reports, D – expert opinions) as well as strength of clinical indications (0 – no indications, 1 – indicated if other techniques cannot be applied, 2 – comparable with other techniques, 3 – first choice examination, other techniques rarely provide additional information). For peripheral joint assessment, ultrasound imaging obtained the third, i.e. the highest level of recommendation, which has proven that this method is highly significant in assessing synovitis(.

This article discusses the role of ultrasound imaging in the diagnosis of rheumatic diseases, such as rheumatoid arthritis (RA), spondyloarthropathies (SpA) and polymyalgia rheumatica (PMR), based on the latest recommendations of ACR/EULAR (American College of Rheumatology/European League Against Rheumatism.

Rheumatoid arthritis

The role of medical imaging in the diagnosis of rheumatoid arthritis has become acknowledged, particularly in rheumatologic circles, after the new RA classification criteria were issued by ACR/EULAR in 2010 (Tab. 1)(. These criteria are used for early RA diagnosis and are applicable for patients diagnosed for the first time when clinical synovitis is identified in at least one joint (edema, tenderness), and its etiology cannot be explained by any other cause but RA. Medical history and clinical examination of peripheral joints are of major diagnostic importance in the ACR/EULAR criteria for RA. These principles enable many patients to be diagnosed and treated without the need for any additional examinations. In some cases, e.g. inflammation of low intensity, clinical assessment is not unequivocal. Moreover, a result of clinical examinantion largely depends on the physician's experience and patient's reaction to pain. That is why, according to ACR/EULAR, US examinations and MRI scans can be helpful not only to confirm arthritis, but also to detect inflammatory activity in subclinical patients. This way progression of undifferentiated inflammatory arthritis to erosional RA can be predicted(. Studies that compare sensitivity and specificity of RA detection by US vs physical examination have demonstrated a higher diagnostic value of ultrasonography. Of 104 patients with a suspicion of chronic arthritis, 41 met the 2010 ACR/EULAR criteria for RA and used methotrexate at baseline(. A US scan was performed in all patients prior to the observation. After a year, treatment indications were re-evaluated, and a follow-up US scan was conducted using a semi-quantitative scale proposed by Szkudlarek(. The best sensitivity to specificity ratio for the RA criterion was obtained for at least grade II in the gray-scale or at least grade I in the Doppler mode. According to the scale by Szkudlarek, grade 0 in the gray-scale ultrasound score (0ߝ3) denotes no inflammatory changes whereas changes in grades I–III (mild, moderate and marked synovial hypertrophy) occupy the consecutive third parts of maximum potential articular volume. As for the Doppler scale (0ߝ3), the grades denote as follows: 0 – no signs of synovial flow, grade I – isolated signals within hypertrophied synovium, grade II – vessels occupy <50% of the hypertrophied synovial area of a given compartment, grade III – marked signals occupying >50% of the hypertrophied synovial area. Current criteria do not include US findings in the identification of disease remission. According to ACR/EULAR, remission is identified when the following conditions are met: number of tender joints ≤1, number of swollen joints ≤1, CRP (C-reactive protein) ≤1 mg/dl, global patient-reported assessment of disease activity ≤1 (scale 0–10) or SDAI (simplified disease activity index) ≤3.3 (. The author's own practice (unpublished data) and published reports demonstrate that despite clinical remission, subclinical slight inflammatory activity persists in joint cavities or sheaths, leading to disease progression. Of 90 RA patients examined during the remission period, progression of destructive changes was identified in 19% of patients within a year of observation(. The most important risk factor was enhanced blood flow in the synovium of joint cavities seen in Doppler examinations.

Tab. 1

The 2010 ACR/EULAR classification criteria for rheumatoid arthritis (RA)*

A) Joint involvement
1 large joint	0 points
2–10 large joints	1 point
1-3 small joints (with or without involvement of large joints)	2 points
4–10 small joints	3 points
>10 joints (at least 1 small joint)	5 points
B) Serology
Negative rheumatoid factor (RF) and negative anti–citrullinated protein antibodies (ACPA)	0 points
Low-positive RF or low-positive ACPA	2 points
High-positive RF or high-positive ACPA	3 points
C) Acute-phase reactants
Normal CRP and ESR	0 points
Abnormal CRP or ESR	1 point
D) Duration of symptoms
<6 weeks	0 points
≥6 weeks	1 point

Confirmed RA – when the total score is at least 6

The crucial role in preventing joint damage belongs to early diagnosis and initiation of treatment modifying the course of the disease. That is why, in 2013, a group of 19 EULAR experts from 13 countries prepared recommendations concerning medical imaging in RA in order to make a diagnosis in patients with at least one joint bearing clinical signs of inflammation, detect structural joint damage, predict the course of the disease and treatment response, monitor progression and determine remission. Each of 10 recommendations has its specific strength (expressed in the visual analogue scale, VAS 0–10: 0 – not recommended at all, 10 – fully recommended) and evidence level (I – randomized controlled trials; II at least one controlled study without randomization; III non-experimental descriptive studies; IV, evidence from expert opinions). Although the level of evidence of the recommendations is III and IV, their strength is relatively high (7.8–9.4). Below, the said recommendations are listed(, nine of which concern the usage of ultrasonography as a recommended but not obligatory tool (Fig. 1 A, B).

Fig. 1

Grey-scale US (A) and color Doppler (B) of the wrist: effusion, synovial hypertrophy in the radiocarpal joint (synovitis) and tenosynovitis of the extensor carpi ulnaris

Recommendation 1. When there is diagnostic doubt, conventional radiography, ultrasound or MRI can be used (strength of recommendation: 9.1).

The influence of imaging on establishing a diagnosis was assessed on the basis of five observational studies (three with MRI and two with US). One study showed that the detection of synovitis improves the certainty of RA diagnosis from 42% to 53.2%(. In another study, ultrasound was superior to clinical examination in 75% of patients(.

Recommendation 2. The presence of inflammation seen with ultrasound or MRI can be used to predict the progression to clinical RA from so-called undifferentiated inflammatory arthritis (strength of recommendation: 7.9).

Most studies concern the prognostic value of MRI, but certain studies on Doppler examination indicate the likelihood of progression of undifferentiated inflammatory arthritis to RA with OR 9.9 if one joint is involved and OR 48.7 if inflammation is detected in at least four other joints (OR – odds ratio, which is a ratio of odds that a given event will occur in an investigated sample to its occurrence in another group).

Recommendation 3. US and MRI are superior to clinical examination in the assessment of joint inflammation; these techniques should be considered for improved detection of inflammation in joints (strength of recommendation: 8.7).

This recommendation is a result of the analysis of 51 studies comparing imaging and clinical examination in the detection of inflammation in various joints. Twenty-nine studies concerned US, 16 – MRI, 14 – scintigraphy, and 2 – positron emission tomography (PET). Ultrasound and MRI detected joint inflammation twice as frequently as clinical examination. The diagnostic value of scintigraphy and PET only slightly exceeded that of clinical examination.

Recommendation 4. Conventional radiography of the hands and feet should be the initial imaging technique to detect damage (erosions). However, ultrasound or MRI should be considered for earlier detection of erosions or if radiography is negative (strength of recommendation: 9.0).

In this recommendation, the role of ultrasound in detect ing RA and its superiority to conventional radiography in terms of sensitivity in identifying erosions is emphasized again.

Recommendation 5. MRI bone edema is a strong independent predictor of subsequent radiographic progression in early RA and should be considered for use as a prognostic indicator. Early joint inflammation detected by MRI or US as well as joint damage detected by conventional radiography, MRI or US can also be considered for the prediction of further joint damage (strength of recommendation: 8.4).

This recommendation was prepared on the basis of 48 studies assessing the predictive value of joint damage in individual imaging techniques. The predictive value of ultrasound synovitis for erosive progression detected by MRI occurred superior to MRI synovitis (likelihood ratios of 1.75 and 1.45, respectively).

Recommendation 6. Inflammation seen on imaging may be more predictive of a therapeutic response than clinical features of disease activity (strength of recommendation: 7.8).

Two prospective cohort studies have compared clinical measures with imaging in predicting the efficacy of TNF inhibitors. Ellegaard et al. measured inflammatory activity by Doppler ultrasound (CF assessment, color fraction) and clinical parameters, such as the number of tender and swollen joints, CRP, DAS28 (disease activity score) and HAQ (health assessment questionnaire) at baseline and after a year of TNF inhibitor therapy ((tumor necrosis factor). CF assessment occurred to be the only effective tool for predicting a therapeutic response(.

Recommendation 7. Since MRI and US are more effective than clinical examination in detecting inflammation, they may be useful in monitoring disease activity (strength of recommendation: 8.3).

According to the authors of the recommendation, there are no published data describing how imaging should be used to monitor disease activity. However, there is evidence( that US, together with DAS28, is capable of detecting even slight changes in synovial inflammatory activity during treatment.

Recommendation 8. The periodic use of radiography of the hands and feet should be considered for joint damage monitoring. MRI (and possibly ultrasound), being more sensitive, can also be used to monitor disease progression (strength of recommendation: 7.8).

As in the previous recommendation, there are no data on the frequency of imaging applied for the monitoring of progressive joint damage.

Recommendation 9. If cervical spine is suspected of being involved, it should be periodically evaluated for functional instability by lateral radiograph obtained in the neutral position, maximum flexion and extension. When the radiograph is positive or specific neurological symptoms and signs are present, MRI should be performed (strength of recommendation: 9.4).

Recommendation 9 is the only recommendation that does not concern US; only radiography and MRI are mentioned.

Recommendation 10. MRI and US can detect inflammation that predicts subsequent joint damage, even when clinical remission is present. These methods can be used to assess persistent inflammation (strength of recommendation: 8.8).

There is good evidence that despite clinical remission shown by imaging, signs of ongoing inflammation persist in even 15–62% of patients in remission according to DAS28, ACR or SDAI. The presence of persistent inflammation has an undisputed effect on disease progression to joint damage. The presence of synovial hypertrophy, power Doppler inflammatory activity and MRI bone marrow edema in clinical remission are an indicator of the risk of structural and radiological progression in clinically asymptomatic joints, even within one year. Moreover, US inflammation in patients who meet the clinical criteria of remission is predictive of a disease flare within 12 months: a disease flare is observed within this period of time in 20% of patients with no PD inflammatory activity at baseline compared with 47% with baseline power Doppler activity(.

Polymyalgia rheumatica

Polymyalgia rheumatica (PMR) is a disease entity manifested by pain and stiffness in the neck as well as shoulder or pelvic girdle. Its etiology is unknown.

In 2012, new diagnostic criteria were established which have completely changed the attitude to this disease entity (Tab. 2). It was demonstrated that PMR is an inflammatory disease of the neck, shoulders and hips. The role of ultrasound in the imaging of affected structures was emphasized, particularly in the context of poorly severe inflammation in clinical examination. The previous diagnostic criteria were based on a 6-score clinical scale. The new criteria include the clinical picture and an 8-score ultrasound scale. They enable PMR to be differentiated from non-inflammatory pathology of the shoulder and hip, such as post-traumatic changes, overload pathology or degenerative lesions, which frequently are asymmetrical. However, this disease entity cannot be differentiated from RA since the ultrasound image of inflammation that symmetrically affects the joints can be similar. The score of at least 4 of 6 on the scale of these clinical criteria enables the disease to be diagnosed with the sensitivity of 68% and specificity of 78%. However, the score of 5 on the 8-score ultrasound scale allows PMR to be detected with the sensitivity of 81% and specificity of 66%. It seems, therefore, that US plays a particularly important role in the event of doubts( (Fig. 2).

Tab. 2

The 2012 ACR/EULAR classification criteria for polymyalgia rheumatica (PMR)

PMR can be identified if three required criteria are met: age 50 years or older; bilateral shoulder aching; abnormal CRP and/or ESR; and if a score of 4 of 6 is obtained in the algorithm without US and a score of 5 of 8 is obtained in the algorithm with US.
	Points without US (0–6)	Points with US (0–8)
1. Morning stiffness duration >45 min	2	2
2. Hip pain or limited range of motion	1	1
3. Absence of rheumatoid factor (RF) and negative anti–citrullinated protein antibodies (ACPA)	2	2
4. No involvement of joints other than shoulder and hip	1	1
5. At least 1 shoulder with subacromial-subdeltoid bursitis and/or long head of biceps tenosynovitis and/or glenohumeral synovitis AND at least one hip with synovitis or greater trochanteric bursitis	-	1
6. Bilateral subacromial-subdeltoid bursitis, long head of biceps tenosynovitis or glenohumeral synovitis	-	1

Fig. 2

US of the wrist: synovial hypertrophy with poorly enhanced synovial vascularity in the distal radioulnar joint (synovitis)

Spondyloarthropathies

The role of imaging in the detection of spondyloarthropathies (SpA) was discussed in 2014 during the latest EULAR congress in Paris. Twenty-one members of the League (rheumatologists and radiologists from 11 countries) worked on 10 recommendations concerning axial and peripheral SpA. Conventional radiography and MRI are the most important imaging tools. They are followed by US and computed tomography. In the clinical practice, imaging is significant in detecting changes, monitoring disease activity and structural progression, determining prognosis and predicting treatment outcome. As for axial SpA, the first choice examination is sacroiliac joint radiography. In cases with a short duration of the disease or in young patients, MRI is the method of choice(. This examination enables one to detect early active inflammatory changes, mainly bone marrow edema, and structural changes, such as erosions, sclerosis or fatty transformation of the bone marrow. In peripheral SpA, the leading diagnostic methods are MRI and US. They enable to detect and monitor joint synovitis, tenosynovitis and bursitis as well as to identify enthesopathy( (Fig. 3 A, B).

Fig. 3

MRI of the sacroiliac joints, TIRM sequence (turbo inversion recovery magnitude) (A) and T1FS sequence (T1 fat-suppressed sequence) after contrast agent administration (B): bilateral bone marrow edema in the subchondral layer of the iliac and sacral bone with changes prevailing on the left side undergoes contrast enhancement; and (B) bilateral inflammation of the anterior joint capsule and synovitis

Conclusion

The past several years have brought more information confirming the necessity to support clinical assessment with imaging for early disease detection, its monitoring (treatment efficacy) and identification of complications (joint damage)(. The recommendations presented above were created by experts, mostly rheumatologists. They have greatly contributed to the popularization of imaging in rheumatology.

It seems, however, that we are only starting the journey. Among these criteria and disease entities, the spectrum of pathological changes is incomplete (the recommendations concerning RA lack the aspect of tenosynovitis and bursitis). There are few reports concerning the attempts of using quantitative methods for the detection and monitoring of rheumatic diseases, whilst still imperfect, poorly reproducible semi-quantitative systems are being promoted. We still have no knowledge of the frequency with which imaging examinations should be performed for joint damage monitoring. These are only few areas that still require investigation.

Nevertheless, more and more common usage of ultrasonography is an optimistic sign. In ESSR recommendations from 2012, it was considered the leading method in peripheral synovitis imaging, irrespective of the disease entity. However, as has already been mentioned, the limitations of this method should be borne in mind(.