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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Objective

More timely and effective therapy for rheumatoid arthritis (RA) has contributed to increasing rates of clinical remission. However, progression of structural damage may still occur in patients who have satisfied remission criteria, which suggests that there is ongoing disease activity. This questions the validity of current methods of assessing remission in RA. The purpose of this study was to test the hypothesis that modern joint imaging improves the accuracy of remission measurement in RA.

Methods

We studied 107 RA patients receiving disease-modifying antirheumatic drug therapy who were judged by their consultant rheumatologist to be in remission and 17 normal control subjects. Patients underwent clinical, laboratory, functional, and quality of life assessments. The Disease Activity Score 28-joint assessment and the American College of Rheumatology remission criteria, together with strict clinical definitions of remission, were applied. Imaging of the hands and wrists using standardized acquisition and scoring techniques with conventional 1.5T magnetic resonance imaging (MRI) and ultrasonography (US) were performed.

Results

Irrespective of which clinical criteria were applied to determine remission, the majority of patients continued to have evidence of active inflammation, as shown by findings on the imaging assessments. Even in asymptomatic patients with clinically normal joints, MRI showed that 96% had synovitis and 46% had bone marrow edema, and US showed that 73% had gray-scale synovial hypertrophy and 43% had increased power Doppler signal. Only mild synovial thickening was seen in 3 of the control subjects (18%), but no bone marrow edema.

Conclusion

Most RA patients who satisfied the remission criteria with normal findings on clinical and laboratory studies had imaging-detected synovitis. This subclinical inflammation may explain the observed discrepancy between disease activity and outcome in RA. Imaging assessment may be necessary for the accurate evaluation of disease status and, in particular, for the definition of true remission.

The treatment of rheumatoid arthritis (RA) is directed at suppressing inflammation, with the aim of eliminating synovitis and establishing a state of remission (1). Remission is regarded as the ideal therapeutic target for patients with RA, because further joint damage and disability should be prevented and function and quality of life maintained. Rates of remission are increasing with modern therapeutic strategies and more effective drug treatments (2–5). It is therefore important to ensure that our methods of assessing disease activity are accurate in order that correct management decisions can be made for the most favorable patient outcome.

Current methods used to evaluate remission in RA largely rely on composite scores based on clinical and laboratory assessments and include the American College of Rheumatology (ACR; formerly, the American Rheumatism Association) preliminary criteria for clinical remission in RA (6) and the Disease Activity Score (DAS) (7–9). Such measures have the disadvantage of not directly measuring inflammation at the primary site of pathology (10) and may be subject to confounding influences (11, 12). In addition, reports suggest a disparity between clinical status and outcome, with evidence of progression of joint damage despite apparent clinical remission (13, 14). This has been interpreted as evidence of a dissociation between synovitis and subsequent erosive joint damage (15) but could reflect the inadequate sensitivity of the traditional clinical approaches to the detection of synovitis.

Imaging techniques, such as ultrasonography (US) and magnetic resonance imaging (MRI), are capable of directly visualizing and objectively quantifying synovial inflammation. There are increasing data to support their validity as disease assessment tools as well as their superior sensitivity compared with clinical evaluation for detecting inflammation (16–25). Levels of imaging-detected synovitis have also been shown to correlate with subsequent bone damage and functional outcomes (26–31). Such modalities therefore offer the potential to provide a more accurate measure of disease activity than the established clinical methods and may be particularly useful in states where levels of inflammation may be low and assessment may be more challenging.

In the present study, we examined a large cohort of RA patients in clinical remission to test our hypothesis that objective evaluation of synovial inflammation using US and MRI may improve the accuracy of disease activity assessment.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patients.

In this prospective controlled cohort study, 107 patients attending rheumatology outpatient clinics at Leeds General Infirmary were studied. Ethical approval for the project was obtained from the Ethics Committee of the Leeds Teaching Hospitals National Health Service Trust. Written informed consent was obtained from all subjects prior to inclusion.

Inclusion criteria.

Using their clinical judgment, consultant rheumatologists identified patients from their outpatient clinics who they believed were in remission (physician-determined remission) using whatever assessments they thought necessary. In addition, all patients satisfied the following criteria: 1) RA classified according to the ACR criteria (32), 2) age >18 years, 3) at least 12 months' disease duration, 4) no disease flare within the preceding 6 months, 5) stable treatment for 6 months, and 6) no clinical indication for a change in treatment.

Controls.

A control group of 17 sex-matched normal subjects was also studied. Each had no previous history of joint disease or any musculoskeletal symptoms or signs at the time of evaluation. All underwent a clinical assessment and MRI scan of their dominant hand and wrist using a technique identical to that in the patient group, as outlined below.

Definitions of remission.

Three definitions of remission were applied in this study and used in the analyses. Physician-determined remission was defined as follows: RA deemed to be in remission in the clinical judgment of the consultant rheumatologist, using whatever assessments they considered necessary. This reflects stable, controlled disease, requiring no change in therapy (see inclusion criteria above). Established criteria for remission were defined as follows: patients satisfied the ACR (6) or the DAS28 (7–9) criteria for remission of RA. Complete clinical remission was defined as follows: asymptomatic patients, with no objective findings of disease activity on examination, as indicated by the absence of painful, tender, and swollen joints on formal metrology.

Study assessments.

ACR remission status (6) was determined at −2 months and at 0 months (baseline). Inclusion criteria were applied at both these time points by the patient's consultant rheumatologist. At baseline, the patients underwent complete clinical, laboratory, functional, quality of life, and imaging assessments.

Assessments of demographic and clinical characteristics.

The following demographic and clinical characteristics were recorded at baseline: age, sex, ethnicity, marital status, presenting history of RA, presence of rheumatoid factor, extraarticular features of RA, current and previous use of disease-modifying antirheumatic drugs (DMARDs) and other therapies, duration of current remission, and other medical and occupational history. Clinical data included the duration of morning stiffness; Likert scale and visual analog scale (VAS) assessments of fatigue, joint pain, and physician's assessment of disease activity, as well as VAS assessment for the patient's global impression of health and disease activity; and the number of painful, tender, and swollen joints, as assessed by an independent trained metrologist. The Health Assessment Questionnaire (HAQ) (33) and the RA Quality of Life (RAQoL) questionnaire (34, 35) were completed, and the scores were calculated. Remission and disease activity scores were calculated using the ACR remission criteria (6) and the DAS28 (9).

Laboratory assessments.

A complete blood cell count, erythrocyte sedimentation rate, plasma viscosity, C-reactive protein level, and rheumatoid factor were measured at baseline. HLA typing was performed to assess the presence of RA susceptibility (shared epitope) alleles.

Radiographic assessments.

Standard posteroanterior radiographs of the hands, wrists, and feet were obtained. Radiographic damage was scored according to the Genant scoring method (36, 37) by a single experienced reader (CGP) who was blinded to all other imaging and clinical findings.

Ultrasonography.

Each patient underwent US assessment of the dominant hand and wrist joints, using gray-scale and power Doppler techniques. Eight joint regions were imaged with US: the second through the fifth metacarpophalangeal (MCP) joints and the radiocarpal, ulnar-carpal, distal radioulnar, and intercarpal compartments of the wrist. US was performed by a single experienced sonographer (ZK) who was blinded to all other study findings. An ATL HDI 3000 US machine (ATL, Bothell, WA) with a 10–5-MHz linear-array “hockey-stick” transducer was used, and the US examination was performed according to the European League Against Rheumatism (EULAR) guidelines (38).

The presence and location of any synovial hypertrophy and tenosynovitis was recorded with reference to the Outcome Measures in Rheumatology Clinical Trials (OMERACT)/EULAR definitions of pathology (39). Synovial hypertrophy was graded on gray-scale images, using a semiquantitative scoring method (the Leeds Score) (19, 20), which consists of a 0–3 scale, where 0 = no synovial hypertrophy, 1 = mild hypertrophy, 2 = moderate hypertrophy, and 3 = severe hypertrophy. The maximal area of enhancement on power Doppler was recorded using a previously described semiquantitative technique (40), which consists of a 0–3 scale, where 0 = normal/minimal vascularity, 1 = mild hyperemia, 2 = moderate hyperemia, and 3 = marked hyperemia. Tenosynovitis was recorded as either present or absent.

Each patient evaluation took ∼30 minutes, and representative images were archived. Interobserver reliability was determined by comparing the findings of 2 independent experienced rheumatologist ultrasonographers (ZK and AKB) who performed US examinations of 120 joint regions in a random subset of 15 patients. Each examiner performed the US assessments independently and sequentially while blinded to all other study data. Intraobserver reliability was assessed by blinded rescoring of the archived US images in the same subset ∼12 months after the original US assessment.

Magnetic resonance imaging.

MRI of the dominant hand and wrist was performed using a conventional 1.5T Phillips MRI scanner (Philips, Mahwah, NJ). The same joint regions were imaged by MRI as for US. The subjects were positioned in a supine position with the arm to be imaged placed in an outstretched “superman” position. A dual-coil approach was used in order to image the hand and wrist in a single sitting. T1-weighted and T1 spectral presaturation with inversion recovery (a method of fat-suppression) sequences were recorded after intravenous administration of gadolinium, in axial and coronal planes. All images were archived.

Synovitis and bone marrow edema were defined according to the OMERACT guidelines (41–44). Images were graded using the OMERACT RA MRI Scoring (RAMRIS) system (41–44), by a single experienced reader (PGC) who was blinded to all other imaging and clinical findings. Synovitis was scored on a 0–3 semiquantitative scale, where 0 = normal, 1 = mild, 2 = moderate, and 3 = severe, with each point representing one-third of the maximum volume of enhancing tissue in the synovial compartment. A similar method was used to score bone marrow edema, corresponding to the proportion of each bone that contained edema (0–3 scale, where 0 = no edema, 1 = 1–33% of the bone was edematous, 2 = 34–66% of the bone was edematous, and 3 = 67–100% of the bone was edematous). Tenosynovitis was recorded as either present or absent.

The acquisition of each MRI scan took ∼50 minutes, and interpretation and scoring took ∼20 minutes, per patient. Intraobserver reliability was assessed by blinded rescoring of all archived MRI images for each patient ∼6–12 months after the original assessment.

Statistical analysis.

Data evaluation and statistical analysis were performed using SPSS version 11.5 software (SPSS, Chicago, IL). Normally distributed continuous data were analyzed using parametric tests (independent t-test, analysis of variance [ANOVA]) and were summarized with means and standard deviations. Non-normally distributed and ordinal data were analyzed using nonparametric tests (Mann-Whitney U test, Kruskal-Wallis test) and were summarized with medians and ranges. Categorical data were analyzed using chi-square tests. Holm's correction (45) was used to correct for multiple comparisons on a family-wise basis. Critical P for testing at the 5% level of significance was set at P = 0.003 for the chi-square test, Mann-Whitney U test, and Kruskal-Wallis test, and at P = 0.005 for the independent t-test and ANOVA. Interobserver and intraobserver agreement was calculated by overall agreement (percentage of observed exact agreement), intraclass correlation coefficients (ICC), and kappa statistics (unweighted for dichotomous scoring [e.g., presence/absence of synovitis]; weighted for semiquantitative scoring).

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patients and controls.

A total of 107 patients who satisfied the inclusion criteria for physician-determined remission of RA and 17 normal control subjects were studied. All study subjects provided written consent prior to taking part in the evaluation.

Demographic and clinical features of the RA patients.

The study population was predominantly female (66%) with a mean age of 56 years (Table 1). The control group was also predominantly female (71%) with a mean age of 38 years. Sixty-four percent of the patients were rheumatoid factor positive and 61% were shared epitope positive (Table 1). The mean disease duration was 7 years, and the median period of remission was almost 2 years. Eighty-one percent of the patients had radiographic evidence of erosions in the hands or feet. Ninety-nine percent of the patients had received DMARD therapy during the course of their disease, and the majority had received more than 1 drug. Ninety-two percent of the cohort were currently taking DMARD therapy, with oral methotrexate and sulfasalazine being the most commonly used medications; 24% were taking combination therapies, 5 patients were currently receiving biologic drugs either as monotherapy or combination therapy, and 4 patients had previously received therapy with biologic agents. Forty percent of the patients were currently receiving a nonsteroidal antiinflammatory drug, and 2% were taking oral prednisolone (≤5 mg).

Table 1. Demographic and clinical characteristics of the 107 RA patients in the study cohort*
VariableResult
  • *

    RA = rheumatoid arthritis; RF = rheumatoid factor; JSN = joint space narrowing; DMARDs = disease-modifying antirheumatic drugs; MTX = methotrexate; SSZ = sulfasalazine; HCQ = hydroxychloroquine; NSAIDs = nonsteroidal antiinflammatory drugs.

  • Most patients had previously taken MTX or SSZ monotherapy/combination therapy; 3% had taken biologic agents.

Age, mean (range) years56 (23–81)
% female/male66/34
Duration of RA, median (range) years7 (2–38)
% RF positive at a titer >40 IU (mean titer)64 (249)
% shared epitope positive61
 % homozygotes15
 % heterozygotes46
Duration of remission, median (range) months22 (6–144)
% with radiographic erosions in the hands and/or feet81
Radiographic scoring (n = 94) 
 Hands/wrists 
  % of patients with erosions69
  Erosion score, median (range)4 (0–51)
  JSN score, median (range)2 (0–39)
  Total score, median (range)6.5 (0–90)
 Feet 
  % of patients with erosions65
  Erosion score, median (range)2 (0–24)
  JSN score, median (range)1 (0–32)
  Total score, median (range)2.25 (0–48)
% currently taking DMARDs (median 1; range 0–3) 
 No DMARDs8
 1 DMARD (% taking each drug indicated)68 (38 oral MTX; 21 SSZ; 1 biologics)
 2 DMARDs (% taking the combination indicated)18 (9 SSZ/MTX; 4 biologics/MTX)
 3 DMARDs (% taking the combination indicated)6 (5 SSZ/MTX/HCQ)
% who had previously taken DMARDs (median 1; range 0–4) 
 No DMARDs46
 1 DMARD32
 2 DMARDs13
 3 DMARDs8
 4 DMARDs2
% currently taking NSAIDs40
% currently taking oral steroids2 (all taking ≤5 mg/day)

Findings of the clinical, laboratory, function, and quality of life assessments.

Results of clinical and laboratory measures of disease activity were all low, as indicated by the Likert scale and VAS scores, the duration of morning stiffness, the formal joint counts, and the markers of acute-phase reactants (Table 2). The group had generally low levels of functional impairment and disability, as assessed by the HAQ, and only mild quality of life impairment, as measured by the RAQoL questionnaire.

Table 2. Assessments of clinical, laboratory, function, and quality of life in the study cohort*
  • *

    VAS = visual analog scale; NA = not applicable; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; HAQ = Health Assessment Questionnaire; RAQoL = Rheumatoid Arthritis Quality of Life; ACR = American College of Rheumatology; DAS28 = Disease Activity Score 28-joint assessment.

Fatigue 
 Likert scale (%) 
  None89
  Mild3
  Moderate7
  Severe1
 VAS score, median (range), 0–100-mm scale20 (0–81)
Joint pain 
 Likert scale (%) 
  None79
  Mild15
  Moderate6
  Severe0
 VAS score, median (range), 0–100-mm scale14 (0–81)
Patient's global assessment 
 Likert scale (%)NA
 VAS score, median (range), 0–100-mm scale14 (0–71)
Physician's global assessment 
 Likert scale (%) 
  None38
  Mild62
  Moderate0
  Severe0
 VAS score, median (range), 0–100-mm scale10 (0–30)
Morning stiffness, median (range) minutes0 (0–120)
Joint counts, median (range) 
 Painful (80 assessed)0 (0–22)
 Tender (28 assessed)0 (0–15)
 Swollen (28 assessed)1 (0–13)
Laboratory assessments 
 CRP, median (range) mg/liter5 (0–30)
 ESR, median (range) mm/hour10 (1–57)
 Plasma viscosity, mean ± SD mPa/second1.64 ± 0.09
Function, median (range) 
 HAQ Disability Index score, 0–3 scale0.38 (0–2.5)
Quality of life, median (range) 
 RAQoL, 0–30 scale3 (0–23)
ACR remission, no. (%) 
 Yes59 (55)
 No48 (45)
DAS28 disease activity, no. (%) 
 Remission, scores <2.661 (57)
 Low disease activity, scores ≥2.6 but <3.221 (20)
 Moderate disease activity, scores ≥3.2 but <5.124 (22)
 High disease activity, scores ≥5.11 (1)

Fulfillment of established criteria for remission.

Of the 107 study patients who were in physician-determined remission, 55% fulfilled the ACR criteria for remission and 57% satisfied the DAS28 criteria for remission (DAS28 score <2.6) (Table 2). The mean ± SD DAS28 score was 2.5 ± 0.96 (range 0.64–5.42).

Findings of ultrasonography.

In the entire cohort of RA patients, 84.9% had evidence of synovial hypertrophy on gray-scale US, and 60.4% had increased power Doppler signal (Table 3). The presence of power Doppler signal confirms active synovitis (Figure 1).

thumbnail image

Figure 1. Top, Axial section of a T1 spectral presaturation with inversion recovery, postgadolinium magnetic resonance imaging scan of the metacarpophalangeal (MCP) joints of the right hand of a patient with rheumatoid arthritis (RA) in clinical remission, demonstrating synovitis in the second MCP joint, flexor tenosynovitis of the third flexor tendon, and extensor tenosynovitis of the third and fourth extensor tendons (Arrow is an artifact of the archived image from which the figure was taken). L = left. Bottom, Longitudinal section of an ultrasonography scan of the second MCP joint of the right hand of a patient with RA in clinical remission, demonstrating gray-scale changes of synovial hypertrophy.

Download figure to PowerPoint

Table 3. Imaging assessments in the study cohort*
VariableUltrasonographyMRI
  • *

    MRI = magnetic resonance imaging; NA = not applicable; MCP = metacarpophalangeal; CMC = carpometacarpal.

  • A total of 106 and 94 patients were evaluated by ultrasonography and MRI, respectively.

  • A total of 106 patients were evaluated by ultrasonography.

  • §

    A total of 96 patients were evaluated by MRI.

  • A total of 106 and 91 patients were evaluated by ultrasonography and MRI, respectively.

Patients with imaging-detected pathology, no. (%)  
 Synovial inflammation90 (84.9)87 (92.6)
 Increased power Doppler signal64 (60.4)NA
 Bone marrow edema§NA53 (55.2)
 Tenosynovitis40 (37.7)34 (37.4)
Frequency of imaging-detected pathology, % of patients  
 MCP2 joint  
  Synovial inflammation67.967.7
  Power Doppler13.2NA
  Bone marrow edemaNA15.1
 MCP3 joint  
  Synovial inflammation64.254.8
  Power Doppler14.2NA
  Bone marrow edemaNA4.3
 MCP4 joint  
  Synovial inflammation44.326.9
  Power Doppler3.8NA
  Bone marrow edemaNA2.2
 MCP5 joint  
  Synovial inflammation33.032.3
  Power Doppler1.9NA
  Bone marrow edemaNA2.2
 Radiocarpal joint  
  Synovial inflammation38.186.2
  Power Doppler34.3NA
  Bone marrow edemaNARadius 8.4
 Ulnar-carpal joint  
  Synovial inflammation39.067.7
  Power Doppler18.1NA
  Bone marrow edemaNAUlna 5.3
 Distal radioulnar joint  
  Synovial inflammation18.342.9
  Power Doppler5.8NA
  Bone marrow edemaNANA
 Intercarpal joint  
  Synovial inflammation30.569.2
  Power Doppler18.1NA
  Bone marrow edemaNACarpus 8.6
 Bone marrow edema  
  CMC12.1
  CMC25.3
  CMC33.2
  CMC40
  CMC50
  Hamate7.4
  Capitate14.7
  Trapezoid10.5
  Trapezium9.5
  Triquetrum9.5
  Pisiform2.1
  Lunate24.5
  Scaphoid23.4

In all of the RA patients, 843 joint regions in the hand and wrist were examined by US (Table 3). Of these joint regions, 86% (n = 725) had no clinical synovitis (swollen joint count score of 0). Of these, 36% (n = 263) had synovial hypertrophy detected by US, despite normal clinical findings. Of the 354 joints with synovial hypertrophy on US, 82% (n = 291) were graded as mild, 16% (n = 57) as moderate, and 2% (n = 6) as severe. Increased power Doppler signal was demonstrated in one-third of these joints. Tenosynovitis was uncommon but was more likely to be detected at the wrist.

The reliability of US imaging was calculated. The interobserver reliability assessment showed an exact agreement of 91% and 92% for the presence/absence of synovial hypertrophy and for the power Doppler signal, respectively, with κ = 0.60 for the presence/absence of synovial hypertrophy. Using the semiquantitative grading system, the exact agreement was 38% and 92% for synovial hypertrophy and for the power Doppler signal, respectively, with weighted κ = 0.53 and ICC 0.57 for synovial hypertrophy. The intraobserver reliability assessment showed an exact agreement of 82% and 90%, with κ = 0.60 and κ = 0.62 for the presence/absence of synovial hypertrophy and for the power Doppler signal, respectively. Using the semiquantitative grading system, exact agreement was 66% and 60%, with weighted κ = 0.55 and weighted κ = 0.59 and ICC 0.54 and ICC 0.38, for synovial hypertrophy and for the power Doppler signal, respectively.

Findings of MRI.

In the entire cohort of RA patients, 92.6% had evidence of synovitis on MRI (Figure 1). Bone marrow edema was observed in 55.2% of patients and was most common in the lunate and scaphoid bones. MRI detected a greater frequency of synovitis at the wrist than did US (Table 3), although most patients had detectable inflammation in both the hand and wrist.

In all of the RA patients, 741 joint regions in the hand and wrist were examined by MRI (Table 3). Of these joint regions, 85% (n = 627) had no clinical synovitis (swollen joint count score of 0). Of these, 52% (n = 327) had synovitis detected by MRI, despite normal clinical findings. Of the 414 joints with synovitis on MRI, 69% (n = 287) were graded as mild, 24% (n = 99) as moderate, and 7% (n = 28) as severe. Tenosynovitis was seen infrequently but, as with US, was more common at the wrist.

Intraobserver reliability was calculated for MRI and showed an exact agreement of 84% and 97% for the presence/absence of synovitis and for bone marrow edema, respectively, with κ = 0.69 and κ = 0.79, respectively. Using the semiquantitative grading system, the exact agreement was 79% and 97% for synovitis and for bone marrow edema, respectively, with weighted κ = 0.69 and weighted κ = 0.78 and ICC 0.83 and ICC 0.84 for synovitis and for bone marrow edema, respectively.

Findings in the control group.

All control subjects had normal clinical findings. Three control subjects (18%) had evidence of synovitis on MRI. This consisted of a total of 4 joints (3%), all of which were graded as mild. Bone marrow edema was not seen in any joints. One subject had evidence of tenosynovitis in 2 palmar flexor tendons.

Established criteria for remission (ACR criteria and DAS28 scores) compared with imaging measures of disease activity.

Of the RA patients who were in remission according to the ACR criteria, 96.1% had synovitis detectable on MRI, and 81.0% had synovial hypertrophy on US (Table 4). Similarly, 96.2% of the RA patients who were in remission according to the DAS28 criteria had synovitis demonstrable on MRI, and 84.2% had synovial hypertrophy on US. There were no statistically significant differences between the number of patients with synovial pathology detectable on MRI or US and their DAS28 or ACR remission status. Patients who did not satisfy the ACR or DAS28 remission criteria were more likely to have a significantly greater number of joints with US-detected synovial hypertrophy.

Table 4. Clinical, laboratory, and imaging measures of disease activity, by DAS28 disease activity category and ACR remission status*
VariableDAS28 disease activity categoryACR remission status
RemissionLowModerateHighPRemissionNo remissionP
  • *

    Since only 1 patient had a high level of disease activity on the Disease Activity Score 28-joint assessment (DAS28), that patient was excluded from the statistical analyses. Wrist compartments assessed were the radiocarpal, ulnar-carpal, distal radioulnar, and intercarpal joints. ACR = American College of Rheumatology; NA = not applicable; KW = Kruskal-Wallis test; MWU = Mann-Whitney U test; CS = chi-square test; VAS = visual analog scale; HAQ = Health Assessment Questionnaire; RAQoL = Rheumatoid Arthritis Quality of Life; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; ANOVA = analysis of variance; MCP = metacarpophalangeal; PD = power Doppler.

  • Statistically significant difference.

  • The trend toward a significant difference was not significant after correction for multiple comparisons.

  • §

    A total of 58, 20, 23, and 1 patient in the respective DAS28 groups, and 59 and 48 patients in the respective ACR groups were evaluated.

  • A total of 57, 21, 24, and 1 patient in the respective DAS28 groups, and 58 and 48 patients in the respective ACR groups were evaluated.

  • #

    A total of 57, 20, 24, and 1 patient in the respective DAS28 groups, and 58 and 48 patients in the respective ACR groups were evaluated.

  • **

    A total of 60, 21, 24, and 1 patient in the respective DAS28 groups, and 58 and 48 patients in the respective ACR groups were evaluated.

  • ††

    A total of 53, 20, 20, and 1 patient in the respective DAS28 groups, and 51 and 43 patients in the respective ACR groups were evaluated.

  • ‡‡

    A total of 54, 21, 20, and 1 patient in the respective DAS28 groups, and 53 and 43 patients in the respective ACR groups were evaluated.

  • §§

    A total of 50, 20, 20, and 1 patient in the respective DAS28 groups, and 48 and 43 patients in the respective ACR groups were evaluated.

No. (%) of patients61 (57.0)21 (19.6)24 (22.4)1 (0.9)NA59 (55.1)48 (44.9)NA
Morning stiffness, median (range)  minutes0 (0–30)0 (0–60)0 (0–120)0 (–)KW 0.0120 (0–10)0 (0–120)MWU <0.001
Joint pain, no. (%)        
 Mild6 (9.8)2 (9.5)8 (33.3)0 (0)CS 0.0042 (3.4)14 (29.2)CS <0.001
 Moderate1 (1.6)2 (9.5)2 (8.3)1 (100)0 (0)6 (12.5)
Fatigue, no. (%)        
 Mild2 (3.3)0 (0)1 (4.2)0 (0) 2 (3.4)1 (2.1) 
 Moderate3 (4.9)0 (0)3 (12.5)1 (100)CS 0.5411 (1.7)6 (12.5)CS 0.131
 Severe1 (1.6)0 (0)0 (0)0 (0) 1 (1.7)0 (0) 
VAS assessments, median (range),  0–100-mm scale        
 Fatigue20.0 (0–66)23 (0–62)22 (0–81)30 (–)KW 0.68020 (0–66)24.5 (0–81)MWU 0.230
 Joint pain11.0 (0–41)20 (0–81)21.5 (0–52)63 (–)KW 0.00210.0 (0–35)24 (0–81)MWU <0.001
 Patient's global assessment13 (0–47)13 (0–46)22.5 (2–71)35 (–)KW 0.00212 (0–47)23.5 (0–71)MWU <0.001
 Physician's global assessment8 (0–22)10 (0–27)15.5 (2–30)28 (–)KW <0.0017.0 (0–22)14 (0–30)MWU <0.001
Likert scale assessment, no. (%)        
 Physician's global assessment:  mild25 (41.0)19 (90.5)21 (87.5)1 (100)CS <0.00122 (37.3)44 (91.7)CS <0.001
Joint count, median (range)        
 Painful0 (0–6)0 (0–16)2 (0–22)11 (–)KW <0.0010 (0–16)1 (0–22)MWU <0.001
 Swollen0 (0–8)2 (0–9)4 (0–13)12 (–)KW <0.0010 (0–13)2 (0–12)MWU <0.001
 Tender0 (0–2)1 (0–7)2.5 (0–15)15 (–)KW <0.0010 (0–7)1.5 (0–15)MWU <0.001
HAQ Disability Index score,  median (range)0.25 (0–2.50)0.5 (0–2.0)0.81 (0–2.25)2 (–)KW 0.0030.25 (0–2.5)0.75 (0–2.25)MWU 0.001
RAQoL score, median (range)2 (0–16)4 (0–19)6.5 (0–20)23 (–)KW 0.0052 (0–16)5 (0–23)MWU 0.002
Laboratory assessments at  baseline        
 CRP, median (range) mg/liter§0 (0–24)5 (0–19)7.5 (0–30)0 (–)KW 0.0340 (0–24)6 (0–30)MWU 0.019
 ESR, median (range) mm/hour¶7 (1–23)13 (4–43)18 (3–57)13 (–)KW <0.0018 (2–36)12.5 (1–57)MWU 0.056
 Plasma viscosity, mean ± SD  mPa/second1.62 ± 0.091.6 ± 0.081.69 ± 0.101.66ANOVA 0.0101.64 ± 0.091.64 ± 0.10T 0.090
ACR remission, no. (%)51 (83.6)7 (33.3)1 (4.2)0 (0)CS <0.001NANANA
DAS28 disease activity category,  no. (%)        
 RemissionNANANANANA51 (86.4)10 (20.8)CS <0.001
 LowNANANANANA7 (11.9)14 (29.2)
 ModerateNANANANANA1 (1.7)23 (47.9)
 HighNANANANANA0 (0)1 (2.1)
Ultrasonography        
 Patients with synovial  hypertrophy, no. (%)48 (84.2)18 (85.7)23 (95.8)1 (100)CS 0.34547 (81.0)43 (89.6)CS 0.264
 Joints with synovial hypertrophy,   median (range)        
  MCP joints2 (0–4)3 (0–4)3 (0–4)2 (–) 2 (0–4)2.5 (0–4) 
  Wrist compartments0 (0–4)1 (0–4)2 (0–4)1 (–)KW <0.0010 (0–4)1 (0–4)MWU 0.003
  Total3 (0–8)4 (0–8)5 (0–8)3 (–) 3 (0–7)4 (0–8) 
 Patients with increased PD  signal, no. (%)#29 (50.9)14 (70.0)20 (83.3)1 (100)CS 0.04032 (55.2)32 (66.7)CS 0.285
 Patients with tenosynovitis, no.  (%)**15 (25.0)11 (52.4)14 (58.3)0 (0)CS 0.01216 (27.6)24 (50.0)CS 0.018
Magnetic resonance imaging        
 Patients with synovitis, no.   (%)††51 (96.2)17 (85.0)19 (95.0)0 (0)CS 0.60049 (96.1)38 (88.4)CS 0.156
 Joints with synovitis, median   (range)        
  MCP joints (4 assessed)1 (0–4)2 (0–4)2 (0–4)0 (–) 1 (0–4)2 (0–4) 
  Wrist compartments (4   assessed)3 (0–4)3 (0–4)4 (0–4)0 (–)KW 0.6563 (0–4)3 (0–4)MWU 0.243
  Total (8 assessed)4.5 (0–8)5 (0–8)5 (0–8)0 (–) 4 (0–8)5 (0–8) 
 Patients with bone marrow  edema, no. (%)‡‡28 (51.9)9 (42.9)15 (75.0)1 (100)CS 0.13725 (47.2)28 (65.1)CS 0.080
 Patients with tenosynovitis, no.  (%)§§13 (26.0)10 (50.0)11 (55.0)0 (0)CS 0.06110 (20.8)24 (55.8)CS 0.001

Criteria for complete clinical remission compared with imaging measures of disease activity.

Despite a total absence of joint symptoms and signs, 96.2% of patients who were in complete clinical remission continued to demonstrate synovitis on MRI (Table 5). Bone marrow edema was identified by MRI in 46.4% of patients. Synovial hypertrophy was identified by US in 73.3% of patients, with associated power Doppler flow in 43.3%.

Table 5. Clinical, laboratory, and imaging measures of disease activity, by the number of painful, tender, or swollen joints*
VariablePainful, tender, or swollen jointsP
0>0
  • *

    Patients with no painful, tender, or swollen joints were considered to be in complete clinical remission. Wrist compartments assessed were the radiocarpal, ulnar-carpal, distal radioulnar, and intercarpal joints. NA = not applicable; MWU = Mann-Whitney U test; CS = chi-square test; VAS = visual analog scale; HAQ = Health Assessment Questionnaire; RAQoL = Rheumatoid Arthritis Quality of Life; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; IT = independent t-test; ACR = American College of Rheumatology; DAS28 = Disease Activity Score 28-joint assessment; MCP = metacarpophalangeal; PD = power Doppler.

  • The trend toward a significant difference was not significant after correction for multiple comparisons.

  • Statistically significant difference.

  • §

    A total of 31 and 74 patients in the 0 and >0 painful, tender, or swollen joints groups, respectively, were evaluated.

  • A total of 30 and 76 patients in the 0 and >0 painful, tender, or swollen joints groups, respectively, were evaluated.

  • #

    A total of 25 and 66 patients in the 0 and >0 painful, tender, or swollen joints groups, respectively, were evaluated.

  • **

    A total of 26 and 68 patients in the 0 and >0 painful, tender, or swollen joints groups, respectively, were evaluated.

  • ††

    A total of 28 and 68 patients in the 0 and >0 painful, tender, or swollen joints groups, respectively, were evaluated.

  • ‡‡

    A total of 25 and 66 patients in the 0 and >0 painful, tender, or swollen joints groups, respectively, were evaluated.

No. (%) of patients31 (29.0)76 (71.0)NA
Morning stiffness, median (range) minutes0 (0–60)0 (0–120)MWU 0.032
Joint pain, no. (%)   
 None26 (83.9)70 (92.1)CS 0.059
 Mild2 (6.5)1 (1.3)
 Moderate2 (6.5)5 (6.6)
 Severe1 (3.2)0 (0)
Fatigue, no. (%)   
 None26 (83.9)70 (92.1)CS 0.196
 Mild2 (6.5)1 (1.3)
 Moderate2 (6.5)5 (6.6)
 Severe1 (3.2)0 (0)
VAS assessments, median (range), 0–100-mm scale   
 Fatigue22.0 (0–66)20.0 (0–81)MWU 0.706
 Joint pain11.0 (0–28)18.0 (0–81)MWU 0.012
 Patient's global assessment12.0 (0–47)16.5 (0–71)MWU 0.052
 Physician's global assessment8.0 (0–22)11 (0–30)MWU 0.010
Likert scale assessment, no. (%)   
 Physician's global assessment: asymptomatic18 (58.1)23 (30.3)CS 0.007
 Physician's global assessment: mild13 (41.9)53 (69.7)
Joint count, median (range)   
 Painful0 (0–0)0 (0–22)MWU <0.001
 Swollen0 (0–0)2 (0–13)MWU <0.001
 Tender0 (0–0)1 (0–15)MWU <0.001
HAQ Disability Index score, median (range)0.25 (0–2.5)0.44 (0–2.25)MWU 0.062
RAQoL score, median (range)3 (0–17)3 (0–23)MWU 0.288
Laboratory assessments   
 CRP, median (range) mg/liter§0 (0–15)5 (0–23)MWU 0.515
 ESR, median (range) mm/hour9 (2–34)9.5 (2–52)MWU 0.514
 Plasma viscosity, mean ± SD mPa/second#1.60 ± 0.071.63 ± 0.10IT 0.068
ACR remission, no. (%)29 (93.5)30 (39.5)CS <0.001
DAS28 disease activity category, no. (%)   
 Remission29 (93.5)30 (39.5)CS <0.001
 Low2 (6.5)19 (25.0)
 Moderate0 (0)24 (31.6)
 High0 (0)0 (0)
Ultrasonography   
 Patients with synovial hypertrophy, no. (%)22 (73.3)68 (89.5)CS 0.037
 Joints with synovial hypertrophy, median (range)   
  MCP joints1 (0–4)3 (0–4) 
  Wrist compartments0 (0–3)1 (0–4)MWU <0.001
  Total2 (0–6)4 (0–8) 
 Patients with increased PD signal, no. (%)13 (43.3)50 (65.8)CS 0.210
 Patients with tenosynovitis, no. (%)7 (23.3)33 (43.4)CS 0.055
Magnetic resonance imaging   
 Patients with synovitis, no. (%)**25 (96.2)62 (91.2)CS 0.411
 Joints with synovitis, median (range)   
  MCP joints (4 assessed)1 (0–4)2 (0–4) 
  Wrist compartments (4 assessed)3 (0–4)3 (0–4)MWU 0.477
  Total (8 assessed)4 (0–8)5 (0–8) 
 Patients with bone marrow edema, no. (%)††13 (46.4)40 (58.8)CS 0.267
 Patients with tenosynovitis, no. (%)‡‡2 (8.0)32 (48.5)CS <0.001

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

We identified 107 RA patients as being in remission, based on clinical assessments by their consultant rheumatologist (physician-determined remission). Such an evaluation accurately reflects the pragmatic clinical judgments that are made every day in routine rheumatology practice. Objectively, all of these patients had clinical and laboratory findings that confirmed low levels of inflammation. Applying the established criteria for remission, the cohort was divided into 2 roughly equal groups of ACR and DAS28 remission and non-remission. In addition, using our definition of complete clinical remission, one-third of the patients had a total absence of painful, swollen, or tender joints. However, when disease activity was assessed with sensitive imaging technologies at the primary site of inflammation, the majority of patients had ongoing active synovitis demonstrable on both MRI and US, irrespective of which criteria were used to define remission. Furthermore, there were no significant differences in the number of patients with imaging-detected inflammation and their remission status, as determined by either the ACR or the DAS28 classification system or by joint count metrology. Therefore, these observations provide evidence that current methods of assessing remission (unlike the classic oncology concept of remission) do not necessarily correlate with an absence of disease, and so, they may be inaccurate measures of true RA remission.

The validity of these imaging findings is strengthened by the data in the control subjects. Only 18% of the control group (3 subjects) had evidence of synovial thickening on MRI, and this was confined to 4 joints (3%), all of which were graded as mild, and none was associated with bone marrow edema. In contrast, the RA patient population had a much greater frequency of MRI-detected synovitis (92.6% of patients), with 287 joints (69%) graded as mild, but unlike the control population, an additional 127 joints (31%) demonstrated more active inflammatory disease, as reflected by grades of moderate and severe synovitis. Furthermore, 55.2% of patients had detectable bone marrow edema.

The findings from this study may have a number of important pathophysiologic implications. These data provide a possible pathologic explanation for the paradoxical observation that patients in apparent remission may experience progression of joint damage (13, 14). The primacy of synovitis in RA and a direct link between inflammation and structural damage have been established (26, 46). It is also recognized that even relatively small amounts of imaging-detected synovial inflammation, and particularly bone marrow edema, may be sufficient to cause the development of new erosions (27–29) and that bone damage is unlikely to occur in the absence of inflammation (26). Given this evidence, one may predict that the synovitis identified in this cohort may result in subsequent structural damage. Therefore, the persistence of active synovial inflammation (synovitis) may be the explanation for adverse outcome despite patients achieving remission according to the ACR criteria and the DAS28 scores.

There are increasing data to support the validity and clinical utility of imaging techniques such as US and MRI in the evaluation of patients with inflammatory arthritis, with evidence demonstrating clinical and pathologic correlation (16–25). We applied these imaging techniques to a large cohort of RA patients in clinical remission and identified ongoing synovitis. The advantage of joint imaging over clinical examination was also demonstrated. Approximately one-half of clinically normal joints had evidence of ongoing synovitis on MRI and one-third had persistent synovial hypertrophy on US. This reflects the superior sensitivity of MRI and US in the detection of synovial inflammation as compared with clinical examination. Ninety-two percent of patients in this cohort were currently receiving DMARD therapy with almost exclusively traditional nonbiologic agents. It may be that such therapies are not sufficiently potent to completely suppress inflammation. Therefore, one may hypothesize that the application of imaging as an assessment tool to accurately quantify levels of synovitis in patients with stable disease may provide additional objective information with which to direct therapy decisions, such as initiation of new treatment in states of persistent inflammation or reduction or discontinuation of therapy in states of true remission. This may be confirmed with longitudinal evaluation.

Although this study was not designed to directly compare US and MRI, it is possible to make some interpretations as to their relative capabilities in identifying pathology when applied to assessments of inflammatory disease activity. Gray-scale US primarily detects synovial hypertrophy, which although it is reversible in early RA, may not be so in established disease when the synovial membrane may become chronically thickened and fibrotic. For this reason, gray-scale changes alone may not necessarily reflect active inflammation (i.e., synovitis). The presence of increased power Doppler signal signifies increased vascularity associated with active inflammation and may be more representative of true synovitis and, therefore, particularly useful in established RA. Consequently, the specificity of US for synovitis may be improved by performing a simultaneous gray-scale and power Doppler assessment. Gadolinium-enhanced MRI provides information relating to both synovial thickness and enhancement (vascularity) and, as such, may be a more precise marker of synovitis than gray-scale US alone. Bone marrow edema is an important determinant of structural and functional outcome (29, 30). Therefore, the detection of MRI synovitis together with bone marrow edema and increased power Doppler signal confirms the presence of active synovitis in this patient group and supports the validity of our findings. We have also shown that US and MRI are reproducible methods of assessing joint inflammation, with consistent scoring by individual readers and good levels of agreement between different readers, even at relatively low levels of disease activity. This is consistent with published data (43, 44, 47, 48) from studies of patients with increased levels of synovitis.

The results of the present study should be interpreted in consideration of certain limitations. Although a relationship has been demonstrated between imaging-detected inflammation and subsequent adverse structural and functional outcome (26–31), further work specific to this clinical remission cohort is required to precisely evaluate the long-term significance of our findings. The effect of suppression of subclinical inflammation with additional therapy, particularly alternative agents to traditional DMARDs, such as biologic agents, and the results of reducing or stopping therapy based on imaging measures of inflammation merit further study. Supplementary control group data may also be useful, particularly in an older population in order to evaluate the incidence of US and MRI evidence of synovitis in association with degenerative joint disease. However, age-related changes on MRI in normal controls occur infrequently and are predominantly ligamentous, which is quite different from those seen in our study, and characteristic MRI changes of osteoarthritis tend to only be present in joints with clinical symptoms or signs (49). Therefore, age-related osteoarthritic changes are unlikely to explain our findings. The application of additional state-of-the-art imaging technologies, including contrast-enhanced power Doppler, may increase the sensitivity of the US assessment. Correlation of histopathology in patients in clinical remission may also provide further insights.

This study demonstrates that the majority of patients achieving ACR and DAS28 remission status, as well as asymptomatic patients with no objective signs on joint examination, continue to have ongoing active synovial inflammation when assessed with objective imaging techniques. Therefore, it appears that such clinical remission criteria may not select patients with an absence of inflammation and may therefore be inaccurate measures of true remission. This may explain the apparent discrepancy between clinical improvement and progression of joint damage in some patients with RA and could be important in making therapeutic decisions, such as how far to pursue disease suppression. Imaging techniques, such as MRI and US, ensure a sensitive measure of joint inflammation and may provide a more accurate assessment of remission. Modification of the current RA remission criteria may be required in light of these findings in order to optimize the assessment of disease activity and facilitate the most favorable outcome for our patients.

These data support the use of imaging for accurate evaluation of disease status in patients with RA, even when clinical measures of response have normalized. We propose a model of remission that is analogous to the concept applied in other diseases and suggest that the term “true remission” should be reserved for patients who are not only in a state of clinical remission, but also show an absence of synovitis on imaging studies.

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  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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