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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Objective

To investigate the sensitivity for detecting subclinical synovitis of different reduced joint ultrasound (US) assessment models as compared with a comprehensive US assessment in rheumatoid arthritis (RA) patients in clinical remission.

Methods

Sixty-seven RA patients (50 women, 17 men) in clinical remission as judged by their consultant rheumatologist and treated with methotrexate were prospectively recruited. Patients were evaluated for disease activity according to the Disease Activity Score in 28 joints (DAS28) and the Simplified Disease Activity Index (SDAI) by the same investigator. Each patient underwent a 44-joint B-mode and power Doppler (PD) assessment by a rheumatologist blinded to the clinical and laboratory data. B-mode synovial hypertrophy (SH) and synovial PD signal were scored from 0–3 at each joint. Global indices for SH and PD signal were calculated for the 44-joint and different joint combination models for each patient.

Results

SH was detected in 87.8% of patients with a DAS28 <2.6 and in 81.8% of patients with an SDAI <3.3. Synovial PD signal was detected in 46.3% of patients with a DAS28 <2.6 and in 36.4% of patients with an SDAI <3.3. Wrist, second through fifth metacarpophalangeal (MCP), ankle, and second through fifth metatarsophalangeal (MTP) joint and 12-joint US assessments showed the highest correlations with the comprehensive US assessment. The wrist, MCP, ankle, and MTP joint US assessment showed the highest sensitivity for detecting SH and synovial PD signal in patients in remission according to the DAS28 and SDAI as compared to the comprehensive US assessment.

Conclusion

US assessment of the wrist, MCP, ankle, and MTP joints can be highly sensitive for detecting residual B-mode and Doppler joint inflammation in RA patients.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Over the last few years, remission has become the primary therapeutic goal in rheumatoid arthritis (RA) management. This has been possible due to early diagnosis and treatment, effective drugs (both old and new), tight clinical control, and the treat-to-target concept (1, 2). In this new scenario, therapeutic decisions should target remission in RA clinical trials and practice.

Remission can be measured and established by different instruments (e.g., the American College of Rheumatology [ACR] preliminary criteria, Disease Activity Score [DAS], DAS in 28 joints [DAS28], Simplified Disease Activity Index [SDAI], and Clinical Disease Activity Index), the latest being the new remission criteria in RA by the ACR and the European League Against Rheumatism (3). These instruments are either criteria or composite scores, which are combinations of clinical and laboratory parameter surrogates for inflammation. However, clinical assessment (e.g., tender and swollen joints) cannot accurately reflect real joint synovitis in patients with RA. Within the last decade, ultrasound (US) has shown added value over clinical assessment in the evaluation of patients with RA, based on the proven greater sensitivity of B-mode US compared to clinical examination for detecting synovitis in RA target joints (4–6). In addition, color Doppler and power Doppler (PD) modes are able to detect pathologic synovial blood flow, which reflects joint inflammatory activity (7–9).

Several recent studies have shown the capability of US to detect B-mode synovitis and synovial Doppler activity in a high percentage of RA patients in clinical remission treated with either synthetic or biologic disease-modifying antirheumatic drugs (10–18). US-detected synovitis, mainly synovial Doppler signal, has shown predictive value in relation to radiographic damage progression (12) and disease flare or relapse (13, 16, 18). In the above studies, US assessment has ranged from a reduced number of wrist and hand joints (10, 12, 14, 16–18) to a comprehensive examination of 42 (11, 15) or 44 joints (13). However, the optimal number and which joints should be assessed for a sensitive and feasible US assessment of synovitis in RA patients in clinical remission have not been investigated.

The purpose of the present study was to investigate the sensitivity for detecting subclinical synovitis of different reduced joint US assessment models as compared with a comprehensive US assessment in RA patients in clinical remission.

Significance & Innovations

  • Doppler ultrasound is able to detect joint synovitis in rheumatoid arthritis (RA) patients in clinical remission.

  • A reduced Doppler ultrasound assessment of the hand and foot joints can be highly sensitive for detecting residual B-mode and Doppler inflammation in RA patients.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Sixty-seven consecutive patients (50 women, 17 men) with RA according to the ACR 1987 criteria (19) and treated with methotrexate for at least 2 years were prospectively recruited from the outpatient rheumatology clinic for a period of 3 months. Inclusion criteria consisted of being in clinical remission judged by their usual consultant rheumatologist and having had neither disease flare nor changes in therapy, including corticosteroid and methotrexate doses, in the previous 6 months.

The study was conducted in accordance with the Declaration of Helsinki and was approved by the local ethics committee of the Hospital General Universitario Gregorio Marañón (Madrid, Spain). Informed consent was obtained from all patients before study enrollment.

Clinical and laboratory assessment.

Patient demographics and RA features, including the presence of rheumatoid factor (RF; by nephelometry, positive at >20 IU), anti–citrullinated protein antibodies (ACPAs; by second-generation commercial enzyme-linked immunosorbent assay [Immunoscan RA, Euro-Diagnostica], positive at >25 IU), and radiographic structural damage in the hands or feet, were recorded at study entry. Patients were evaluated for disease activity according to the DAS28 and SDAI criteria by the same investigator in each case (IDlT), who was blinded to previous clinical and laboratory data except the physician-determined remission status established as the inclusion criterion. In addition, functional ability was assessed with a self-assessment Spanish version of the Health Assessment Questionnaire (HAQ). Data on serum markers of inflammation (C-reactive protein level, normal range 0–0.5 mg/dl, and erythrocyte sedimentation rate, normal range 10–20 mm/hour) were obtained from laboratory tests performed on the day of the clinic visit. Clinical remission was defined by 2 criteria: either a DAS28 <2.6 (20) or an SDAI <3.3 (21).

US assessment.

Each patient underwent a B-mode and PD assessment by a rheumatologist experienced in musculoskeletal US (EN), blinded to the clinical, laboratory, and radiographic data, on the day of the clinic visit. To reduce the possibility of bias, the patients were asked not to talk about their clinical data to the US examiner. We maximized the level of darkness in the examination room.

The US assessment consisted of a systematic longitudinal and transverse multiplanar examination of 44 joints using a real-time scanner (Mylab 70 XVG, Esaote) equipped with 2 multifrequency linear array transducers, a 6–18-MHz transducer for superficial areas, and a 4–13-MHz transducer for deep areas.

The following bilateral joints were investigated for the presence of B-mode synovial hypertrophy (SH) and synovial PD signal: glenohumeral (i.e., posterior and axillary recesses and biceps sheath), elbow (i.e., anterior and posterior recesses), wrist (i.e., radiocarpal, midcarpal, distal radioulnar, and ulnar-carpal; dorsal recesses), second through fifth metacarpophalangeal (MCP; i.e., dorsal and palmar recesses), second through fifth proximal interphalangeal (PIP) of the hands (i.e., dorsal and palmar recesses), hip (i.e., anterior recess), knee (i.e., anterior and parapatellar recesses), ankle (i.e., tibiotalar, anterior recess, and subtalar, medial, and lateral recesses), and second through fifth metatarsophalangeal (MTP; i.e., dorsal recess). We considered the wrist SH or synovial PD signal positive if it was detected in the radiocarpal, midcarpal, distal radioulnar, or ulnar-carpal joints. We also considered the ankle SH or synovial PD signal positive if it was detected in either the tibiotalar or the subtalar joints.

B-mode and PD machine settings were optimized before the study and standardized for the entire study. These settings were as follows: B-mode frequency of 10–18 MHz, B-mode gain of 56–62%, Doppler frequency of 6.3–14.3 MHz, Doppler gain of 45–62%, low-wall filters, and pulse repetition frequency of 500–750 Hz, depending on the depth of the anatomic area.

B-mode SH was identified according to the Outcome Measures in Rheumatology definitions as the presence of abnormal hypoechoic (relative to subdermal fat) intraarticular tissue that is nondisplaceable and poorly compressible (22). At each synovial recess, B-mode SH was scored semiquantitatively on a scale of 0–3 (where 0 = absent, 1 = mild, 2 = moderate, and 3 = marked). Synovial PD signal was also scored on a semiquantitative scale of 0–3 (where 0 = absent [no synovial flow], 1 = mild [≤3 PD signals], 2 = moderate [3 PD signals in less than half of the synovial area], and 3 = marked [>3 PD signals in more than half of the synovial area]) (23). Each joint was scored for B-mode SH and synovial PD signal on a scale from 0–3. These scores corresponded to the maximum score for SH and PD signal, respectively, obtained from any one of the synovial sites evaluated at each joint. The wrist and ankle SH and PD signal scores corresponded to the maximum score for these parameters, respectively, obtained from any of the joints evaluated at the above joint regions. A global index for B-mode SH (SHI; range 0–108) and a global index for synovial PD signal (PDI; range 0–108, the sum of the B-mode SH and synovial PD signal scores, respectively, obtained for each evaluated joint or joint region) were calculated for each patient (23–26). The time spent on the US assessment was 20–30 minutes.

We calculated the SHI and PDI for different models of joint combinations as follows: large joints (i.e., bilateral glenohumeral, elbow, wrist, hip, knee, and ankle joints), wrist and hand joints (i.e., bilateral wrist, MCP 2–5, and PIP joints 2–5), reduced wrist and hand joints (i.e., bilateral wrist and MCP joints 2–5), and wrist, MCP, ankle, and MTP joints (i.e., bilateral wrist, MCP 2–5, ankle, and MTP joints 2–5). In addition, we calculated the above scores for the 12-joint US assessment (i.e., bilateral elbow, wrist, MCP 2 and 3, knee, and ankle joints) (24), the 7-joint US assessment (i.e., wrist, MCP 2 and 3, PIP 2 and 3 of the clinically dominant hand, and MTP joints 2 and 5 of the clinically dominant foot) (25), and the 6-joint US assessment (i.e., bilateral wrist, MCP 2, and knee joints) (26), which had been previously validated in published studies on RA therapy monitoring.

Statistical analysis.

Statistical analysis was performed using SPSS, version 13.0. Quantitative variables are presented as the mean ± SD and range. Categorical variables are presented as absolute frequencies and percentages. Comparisons between independent means were analyzed using the Mann-Whitney test. Relationships between categorical variables were evaluated by the chi-square test. Correlations between quantitative variables were analyzed by Spearman's correlation coefficient. P values less than 0.05 were considered significant.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Demographics and clinical data.

Demographics and clinical and laboratory characteristics of the RA population are shown in Table 1. Of the 67 studied patients, the DAS28 remission criterion was fulfilled in 41 patients (61.2%) and the SDAI remission criterion was fulfilled in 22 patients (32.8%). There were no significant differences in demographics and RA features between the patients in remission and those not in remission according to both the DAS28 and the SDAI (data not shown).

Table 1. Demographics and clinical and laboratory characteristics of the 67 rheumatoid arthritis patients included in the study*
 Value
  • *

    Values are the mean ± SD (range) unless otherwise indicated. NSAIDs = nonsteroidal antiinflammatory drugs; RF = rheumatoid factor; ACPA = anti–citrullinated protein antibody; DAS28 = Disease Activity Score in 28 joints; SDAI = Simplified Disease Activity Index; HAQ = Health Assessment Questionnaire; ESR = erythrocyte sedimentation rate; CRP = C-reactive protein.

Age, years60.3 ± 15.0 (28–81)
Women, no. (%)50 (74.6)
Disease duration, years7.5 ± 5.8 (2 to >20)
Methotrexate dosage, mg/week12.1 ± 4.3 (7.5–20)
Oral prednisone, no. (%)38 (56.7)
Oral prednisone dosage, mg/day6.3 ± 2.2 (0–10)
NSAIDs, no. (%)18 (26.9)
Positive RF, no. (%)55 (82.1)
Positive ACPA, no. (%)50 (74.6)
DAS282.3 ± 1.1 (0.5–5.4)
SDAI7.5 ± 7.1 (0.0–37.0)
HAQ0.73 ± 0.77 (0–2.50)
ESR, mm/hour10.6 ± 7.6 (2–37)
CRP level, mg/dl0.8 ± 1.2 (0.1–6.5)
Erosive disease, no. (%)20 (29.9)

US findings.

B-mode SH was detected in 36 patients (87.8%) with a DAS28 <2.6 and in 26 patients (100%) with a DAS28 >2.6 (P = 0.078). Synovial PD signal was detected in 19 patients (46.3%) with a DAS28 <2.6 and in 16 patients (61.5%) with a DAS28 >2.6 (P = 0.168). B-mode SH was detected in 18 patients (81.8%) with an SDAI <3.3 and in 44 patients (97.8%) with an SDAI >3.3 (P = 0.037). Synovial PD signal was detected in 8 patients (36.4%) with an SDAI <3.3 and in 27 patients (60.0%) with an SDAI >3.3 (P = 0.059).

There were no significant differences in the mean ± SD SHI between patients with active and inactive disease according to the DAS28 criterion (10.54 ± 11.70 [range 1–55] versus 9.46 ± 9.82 [range 0–44]; P = 0.796), in the mean ± SD PDI between patients with active and inactive disease according to the DAS28 criterion (5.04 ± 8.51 [range 0–36] versus 3.27 ± 7.22 [range 0–38]; P = 0.249), and in the mean ± SD SHI between patients with active and inactive disease according to the SDAI criterion (11.04 ± 11.73 [range 0–55] versus 7.50 ± 7.10 [range 0–23]; P = 0.278). However, the mean ± SD PDI was significantly higher in patients with disease activity (5.04 ± 8.96 [range 0–38]) than in patients with inactive disease (1.73 ± 3.48 [range 0–13]) according to the SDAI criterion (P = 0.047).

The US indices were neither correlated with laboratory markers of inflammation or the HAQ, nor were they significantly different in RF-positive or ACPA-positive patients and patients negative for these parameters (data not shown). A representative US image of B-mode SH with PD signal in an RA patient in clinical remission is shown in Figure 1.

thumbnail image

Figure 1. Longitudinal ultrasound image of the dorsal aspect of a metacarpophalangeal joint that shows B-mode synovial hypertrophy with power Doppler signal in a rheumatoid arthritis patient in clinical remission. mc = metacarpal bone; pp = proximal phalanx.

Download figure to PowerPoint

Reduced US assessments versus comprehensive US assessment.

Tables 2 and 3 show the correlations between the 44-joint US indices and the reduced joint US indices in patients in remission according to the DAS28 and SDAI criteria. The wrist, MCP, ankle, and MTP joint and the 12-joint US assessments showed the highest correlations with the comprehensive US assessment for both B-mode SH and synovial PD signal in patients in remission according to the DAS28 criterion and the SDAI criterion. The other reduced joint models showed lower correlations with the comprehensive US assessment for both B-mode SH and synovial PD signal.

Table 2. Correlation coefficients between the SHI for the reduced joint US assessments and the 44-joint SHI in patients in remission according to the DAS28 and SDAI criteria*
Reduced joint US assessmentsDAS28 <2.6 (n = 41), 44-joint SHISDAI <3.3 (n = 22), 44-joint SHI
  • *

    SHI = index for B-mode synovial hypertrophy; US = ultrasound; DAS28 = Disease Activity Score in 28 joints; SDAI = Simplified Disease Activity Index; MCP = metacarpophalangeal; MTP = metatarsophalangeal.

  • P < 0.01.

  • P < 0.05.

Large joints, SHI0.690.68
Wrist and hand joints, SHI0.740.70
Reduced wrist and hand joints, SHI0.730.65
Wrist, MCP 2–5, ankle, and MTP joints 2–5, SHI0.950.92
12 joints, SHI0.890.89
7 joints, SHI0.660.55
6 joints, SHI0.750.71
Table 3. Correlation coefficients between the PDI for the reduced joint US assessments and the 44-joint PDI in patients in remission according to the DAS28 and SDAI criteria*
Reduced joint US assessmentsDAS28 <2.6 (n = 41), 44-joint PDISDAI <3.3 (n = 22), 44-joint PDI
  • *

    PDI = index for synovial power Doppler signal; US = ultrasound; DAS28 = Disease Activity Score in 28 joints; SDAI = Simplified Disease Activity Index; MCP = metacarpophalangeal; MTP = metatarsophalangeal.

  • P < 0.01.

  • P < 0.05.

Large joints, PDI0.460.52
Wrist and hand joints, PDI0.850.70
Reduced wrist and hand joints, PDI0.740.67
Wrist, MCP 2–5, ankle, and MTP joints 2–5, PDI0.991.00
12 joints, PDI0.930.89
7 joints, PDI0.830.76
6 joints, PDI0.860.67

Tables 4 and 5 show the proportion of patients with SHI >0 and PDI >0 detected by the reduced joint US assessments in both populations: patients in remission according to the DAS28 criterion (Table 3) and the SDAI criterion (Table 4). The wrist, MCP, ankle, and MTP joint US assessment detected 97.2% of patients with SHI >0 (i.e., 1 patient was lost) and 100% of patients with PDI >0 in the population in remission according to the DAS28 criterion. The above reduced US assessment detected 94.4% of patients with SHI >0 (i.e., 1 patient was lost) and 100% of patients with PDI >0 in the population in remission according to the SDAI criterion. The 12-joint US assessment detected 94.4% of patients with SHI >0 (i.e., 2 patients were lost) and 94.7% of patients with PDI >0 (i.e., 1 patient was lost) in the population in remission according to the DAS28 criterion. This reduced US assessment detected 88.9% of patients with SHI >0 (i.e., 2 patients were lost) and 87.5% of patients with PDI >0 (i.e., 1 patient was lost) in the population in remission according to the SDAI criterion. The other reduced joint models yielded lower sensitivity for detecting patients with B-mode SH and synovial PD signal in patients in DAS28 and SDAI remission.

Table 4. Sensitivity for detecting B-mode SH and synovial PD signal of the reduced joint US assessments in patients in remission according to the Disease Activity Score in 28 joints criterion*
Reduced joint US assessmentsSHI >0 (n = 36)PDI >0 (n = 19)
  • *

    Values are the percentage (number) of patients. SH = synovial hypertrophy; PD = power Doppler; US = ultrasound; SHI = index for B-mode SH; PDI = index for synovial PD signal; MCP = metacarpophalangeal; MTP = metatarsophalangeal.

Large joints77.8 (28)21.1 (4)
Wrist and hand joints75 (27)84.2 (16)
Reduced wrist and hand joints72.2 (26)84.2 (16)
Wrist, MCP 2–5, ankle, and MTP joints 2–597.2 (35)100 (19)
12 joints94.4 (34)94.7 (18)
7 joints63.8 (23)68.4 (13)
6 joints83.3 (30)89.4 (17)
Table 5. Sensitivity for detecting B-mode SH and synovial PD signal of the reduced joint US assessments in patients in remission according to the Simplified Disease Activity Index criterion*
Reduced joint US assessmentsSHI >0 (n = 18)PDI >0 (n = 8)
  • *

    Values are the percentage (number) of patients. SH = synovial hypertrophy; PD = power Doppler; US = ultrasound; SHI = index for B-mode SH; PDI = index for synovial PD signal; MCP = metacarpophalangeal; MTP = metatarsophalangeal.

Large joints77.8 (14)25 (2)
Wrist and hand joints66.7 (12)62.5 (5)
Reduced wrist and hand joints61.1 (11)62.5 (5)
Wrist, MCP 2–5, ankle, and MTP joints 2–594.4 (17)100 (8)
12 joints88.9 (16)87.5 (7)
7 joints44.4 (8)62.5 (5)
6 joints77.7 (14)75 (6)

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Over the last decade, there has been increasing use of musculoskeletal US in the diagnosis and monitoring of joint inflammatory activity in patients with RA (27–29). A variety of comprehensive or reduced joint counts have been used for scoring B-mode and Doppler synovitis at the patient level (30). Some studies have shown reduced US assessments as surrogates for comprehensive US assessment for monitoring (24–26) or diagnosing RA (31). To the best of our knowledge, this is the first study that has compared different reduced models of US assessment with a comprehensive 44-joint US assessment in RA patients in clinical remission.

In accordance with previously published data, the SDAI remission criterion was fulfilled by fewer patients than the DAS28 remission criterion (10, 15, 17, 18). However, we detected B-mode SH in the majority of patients in clinical remission according to both the DAS28 or SDAI and the synovial PD signal in almost half of them. These findings were comparable to those of previously published studies on RA patients in clinical remission according to different criteria (10–18). As previously reported, there were no significant differences in either the SHI or the PDI between patients in DAS28 remission and those not in DAS28 remission (10, 15, 17). However, there were significantly fewer patients with B-mode SH and the mean PDI was significantly lower in patients in remission as compared with patients not in RA remission according to the SDAI. These findings were in agreement with the results of Balsa et al (15), who also performed a comprehensive US assessment (i.e., 42 joints) in RA patients in clinical remission, suggesting that the SDAI can perform better than the DAS28 in capturing residual active joint inflammation (15, 21). Consistent with the findings of previous studies, there was no relationship between the US indices and laboratory markers of inflammation, HAQ values, or the presence of RF or ACPAs (14, 15).

The combination of bilateral wrist, MCP 2–5, ankle, and MTP joints 2–5 as well as the 12-joint assessment, which is also a combination of small and large joints, showed the highest correlations with the comprehensive 44-joint US assessment for both the SHI and PDI in RA patients in remission according to either the DAS28 or SDAI criterion. However, the wrist, MCP, ankle, and MTP joint assessment yielded the highest sensitivity for detecting patients in clinical remission with B-mode SH and synovial PD signal as compared to the comprehensive US assessment.

Some limitations in our study should be noted. The population size, particularly the population in remission determined by the SDAI, was relatively small. However, we decided to analyze separately the patients in remission according to the DAS28 and SDAI criteria to obtain US data on homogeneous populations. In addition, the type of study, being cross-sectional, limited any analysis of the predictive value of the reduced US assessments.

In conclusion, the results of this cross-sectional study suggest that US assessment of wrist, MCP, ankle, and MTP joints can be highly sensitive for detecting B-mode and Doppler joint inflammation in RA patients in clinical remission. Nevertheless, our results should be confirmed in other RA populations in clinical remission. In addition, further longitudinal studies should address the predictive value in relation to relevant outcomes in RA of reduced versus comprehensive US assessments of residual synovitis.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Naredo had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Naredo, Valor, De la Torre.

Acquisition of data. Naredo, Valor, De la Torre, Martínez-Barrio, Hinojosa, Aramburu, Ovalles-Bonilla, Hernández, Montoro, González, López-Longo, Monteagudo.

Analysis and interpretation of data. Naredo, Valor, De la Torre, Carreño.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  • 1
    Smolen JS, Aletaha D, Bijlsma JW, Breedveld FC, Boumpas D, Burmester G, et al. Treating rheumatoid arthritis to target: recommendations of an international task force. Ann Rheum Dis 2010; 69: 6317.
  • 2
    Smolen JS, Landewe R, Breedveld FC, Dougados M, Emery P, Gaujoux-Viala C, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis 2010; 69: 96475.
  • 3
    Felson DT, Smolen JS, Wells G, Zhang B, van Tuyl LH, Funovits J, et al. American College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Arthritis Rheum 2011; 63: 57386.
  • 4
    Backhaus M, Burmester GR, Sandrock D, Loreck D, Hess D, Scholz A, et al. Prospective two year follow up study comparing novel and conventional imaging procedures in patients with arthritic finger joints. Ann Rheum Dis 2002; 61: 895904.
  • 5
    Wakefield RJ, Green MJ, Marzo-Ortega H, Conaghan PG, Gibbon WW, McGonagle D, et al. Should oligoarthritis be reclassified? Ultrasound reveals a high prevalence of subclinical disease. Ann Rheum Dis 2004; 63: 3825.
  • 6
    Naredo E, Bonilla G, Gamero F, Uson J, Carmona L, Laffon A. Assessment of inflammatory activity in rheumatoid arthritis: a comparative study of clinical evaluation with grey-scale and power Doppler ultrasonography. Ann Rheum Dis 2005; 64: 37581.
  • 7
    Walther M, Harms H, Krenn V, Radke S, Faehndrich TP, Gohlke F. Correlation of power Doppler sonography with vascularity of the synovial tissue of the knee joint in patients with osteoarthritis and rheumatoid arthritis. Arthritis Rheum 2001; 44: 3318.
  • 8
    Szkudlarek M, Court-Payen M, Strandberg C, Klarlund M, Klausen T, Ostergaard M. Power Doppler ultrasonography for assessment of synovitis in the metacarpophalangeal joints of patients with rheumatoid arthritis: a comparison with dynamic magnetic resonance imaging. Arthritis Rheum 2001; 44: 201823.
  • 9
    Terslev L, Torp-Pedersen S, Savnik A, von der Recke O, Qvistgaard E, Danneskiold-Samsoe B, et al. Doppler ultrasound and magnetic resonance imaging of synovial inflammation of the hand in rheumatoid arthritis: a comparative study. Arthritis Rheum 2003; 48: 243441.
  • 10
    Brown AK, Quinn MA, Karim Z, Conaghan PG, Peterfy CG, Hensor E, et al. Presence of significant synovitis in rheumatoid arthritis patients with disease-modifying antirheumatic drug–induced clinical remission: evidence from an imaging study may explain structural progression. Arthritis Rheum 2006; 54: 376173.
  • 11
    Wakefield RJ, Freeston JE, Hensor EM, Bryer D, Quinn MA, Emery P. Delay in imaging versus clinical response: a rationale for prolonged treatment with anti–tumor necrosis factor medication in early rheumatoid arthritis. Arthritis Rheum 2007; 57: 15647.
  • 12
    Brown AK, Conaghan PG, Karim Z, Quinn MA, Ikeda K, Peterfy CG, et al. An explanation for the apparent dissociation between clinical remission and continued structural deterioration in rheumatoid arthritis. Arthritis Rheum 2008; 58: 295867.
  • 13
    Scire CA, Montecucco C, Codullo V, Epis O, Todoerti M, Caporali R. Ultrasonographic evaluation of joint involvement in early rheumatoid arthritis in clinical remission: power Doppler signal predicts short-term relapse. Rheumatology (Oxford) 2009; 48: 10927.
  • 14
    Saleem B, Brown AK, Keen H, Nizam S, Freeston J, Karim Z, et al. Disease remission state in patients treated with the combination of tumor necrosis factor blockade and methotrexate or with disease-modifying antirheumatic drugs: a clinical and imaging comparative study. Arthritis Rheum 2009; 60: 191522.
  • 15
    Balsa A, de Miguel E, Castillo C, Peiteado D, Martin-Mola E. Superiority of SDAI over DAS-28 in assessment of remission in rheumatoid arthritis patients using power Doppler ultrasonography as a gold standard. Rheumatology (Oxford) 2010; 49: 68390.
  • 16
    Peluso G, Michelutti A, Bosello S, Gremese E, Tolusso B, Ferraccioli G. Clinical and ultrasonographic remission determines different chances of relapse in early and long standing rheumatoid arthritis. Ann Rheum Dis 2011; 70: 1725.
  • 17
    Saleem B, Brown AK, Keen H, Nizam S, Freeston J, Wakefield R, et al. Should imaging be a component of rheumatoid arthritis remission criteria? A comparison between traditional and modified composite remission scores and imaging assessments. Ann Rheum Dis 2011; 70: 7928.
  • 18
    Saleem B, Brown AJ, Quinn M, Karim Z, Hensor EM, Conaghan P, et al. Can flare be predicted in DMARD treated RA patients in remission, and is it important? A cohort study. Ann Rheum Dis 2012; 71: 131621.
  • 19
    Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31: 31524.
  • 20
    Prevoo ML, van Gestel AM, van 't Hof MA, van Rijswijk MH, van de Putte LB, van Riel PL. Remission in a prospective study of patients with rheumatoid arthritis: American Rheumatism Association preliminary remission criteria in relation to the disease activity score. Br J Rheumatol 1996; 35: 11015.
  • 21
    Aletaha D, Ward MM, Machold KP, Nell VP, Stamm T, Smolen JS. Remission and active disease in rheumatoid arthritis: defining criteria for disease activity states. Arthritis Rheum 2005; 52: 262536.
  • 22
    Wakefield RJ, Balint PV, Szkudlarek M, Filippucci E, Backhaus M, D'Agostino MA, et al. Musculoskeletal ultrasound including definitions for ultrasonographic pathology. J Rheumatol 2005; 32: 24857.
  • 23
    Naredo E, Moller I, Cruz A, Carmona L, Garrido J. Power Doppler ultrasonographic monitoring of response to anti–tumor necrosis factor therapy in patients with rheumatoid arthritis. Arthritis Rheum 2008; 58: 224856.
  • 24
    Naredo E, Rodriguez M, Campos C, Rodriguez-Heredia JM, Medina JA, Giner E, et al, for the Ultrasound Group of the Spanish Society of Rheumatology. Validity, reproducibility, and responsiveness of a twelve-joint simplified power Doppler ultrasonographic assessment of joint inflammation in rheumatoid arthritis. Arthritis Rheum 2008; 59: 51522.
  • 25
    Backhaus M, Ohrndorf S, Kellner H, Strunk J, Backhaus TM, Hartung W, et al. Evaluation of a novel 7-joint ultrasound score in daily rheumatologic practice: a pilot project. Arthritis Rheum 2009; 61: 1194201.
  • 26
    Perricone C, Ceccarelli F, Modesti M, Vavala C, Di Franco M, Valesini G, et al. The 6-joint ultrasonographic assessment: a valid, sensitive-to-change and feasible method for evaluating joint inflammation in RA. Rheumatology (Oxford) 2012; 51: 86673.
  • 27
    Schmidt WA. Value of sonography in diagnosis of rheumatoid arthritis. Lancet 2001; 357: 10567.
  • 28
    Wakefield RJ, Brown AK, O'Connor PJ, Emery P. Power Doppler sonography: improving disease activity assessment in inflammatory musculoskeletal disease [editorial]. Arthritis Rheum 2003; 48: 2858.
  • 29
    Wakefield RJ, D'Agostino MA, Naredo E, Buch MH, Iagnocco A, Terslev L, et al. After treat-to-target: can a targeted ultrasound initiative (TUI) improve RA outcomes? Ann Rheum Dis 2012; 71: 799803.
  • 30
    Mandl P, Naredo E, Wakefield RJ, Conaghan PG, D'Agostino MA, for the OMERACT Ultrasound Task Force. A systematic literature review analysis of ultrasound joint count and scoring systems used to assess synovitis in rheumatoid arthritis, according to the OMERACT filter. J Rheumatol 2011; 38: 205562.
  • 31
    Filer A, de Pablo P, Allen G, Nightingale P, Jordan A, Jobanputra P, et al. Utility of ultrasound joint counts in the prediction of rheumatoid arthritis in patients with very early synovitis. Ann Rheum Dis 2011; 70: 5007.