An Explanation for the Apparent Dissociation Between Clinical Remission and Continued Structural Deterioration in Rheumatoid Arthritis

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1 ARTHRITIS & RHEUMATISM Vol. 58, No. 10, October 2008, pp DOI /art , American College of Rheumatology An Explanation for the Apparent Dissociation Between Clinical Remission and Continued Structural Deterioration in Rheumatoid Arthritis A. K. Brown, 1 P. G. Conaghan, 1 Z. Karim, 1 M. A. Quinn, 1 K. Ikeda, 1 C. G. Peterfy, 2 E. Hensor, 1 R. J. Wakefield, 1 P. J. O Connor, 3 and P. Emery 1 Objective. Achieving remission is the aim of treatment in rheumatoid arthritis (RA). This should represent minimal arthritis activity and ensure optimal disease outcome. However, we have previously demonstrated a high prevalence of imaging-detected synovial inflammation in RA patients who were in clinical remission. The purpose of this study was to evaluate the long-term significance of subclinical synovitis and its relationship to structural outcome. Methods. We studied 102 RA patients receiving conventional treatment who had been judged by their consultant rheumatologist to be in remission, as well as 17 normal control subjects. Subjects underwent clinical, laboratory, functional, and quality of life assessments over 12 months. In addition to standard radiography of the hands and feet, imaging of the hands and wrists was performed with musculoskeletal ultrasonography (US) and conventional 1.5T magnetic resonance imaging (MRI) at baseline and 12 months, using validated acquisition and scoring techniques. Supported by a project grant from the Arthritis Research Campaign. 1 A. K. Brown, MB ChB, MRCP(UK), PhD, P. G. Conaghan, MB BS, PhD, FRACP, FRCP, Z. Karim, MB BCh, MRCP, MD, M. A. Quinn, MRCP, MBChB, K. Ikeda, MD, PhD, E. Hensor, PhD, R. J. Wakefield, BM, MRCP, MD, P. Emery, MA, MD, FRCP: University of Leeds, and Chapel Allerton Hospital, Leeds, UK; 2 C. G. Peterfy, MD, PhD: Synarc Inc., San Francisco, California; 3 P. J. O Connor, BM, FRCR: Chapel Allerton Hospital, Leeds, UK. Dr. Brown has received speaking fees and honoraria from Schering-Plough and Abbott Laboratories (less than $10,000 each). Dr. Quinn has received consulting fees, speaking fees, and/or honoraria from Schering-Plough and Abbott Laboratories (less than $10,000 each). Dr. Peterfy owns stock or stock options in Synarc Inc. Address correspondence and reprint requests to P. Emery, MA, MD, FRCP, ARC Professor of Rheumatology, Section of Musculoskeletal Disease, Leeds Institute of Molecular Medicine, University of Leeds, Chapel Allerton Hospital, Leeds LS7 4SA, UK. p.emery@leeds.ac.uk. Submitted for publication September 24, 2007; accepted in revised form June 27, Results. Despite their being in clinical remission, 19% of the patients displayed deterioration in radiographic joint damage over the study period. Scores on musculoskeletal US synovial hypertrophy, power Doppler (PD), and MRI synovitis assessments in individual joints at baseline were significantly associated with progressive radiographic damage (P 0.032, P < 0.001, and P 0.002, respectively). Furthermore, there was a significant association between the musculoskeletal US PD score at baseline and structural progression over 12 months in totally asymptomatic metacarpophalangeal joints (P 0.004) and 12 times higher odds of deterioration in joints with increased PD signal (odds ratio 12.21, P < 0.001). Conclusion. Subclinical joint inflammation detected by imaging techniques explains the structural deterioration in RA patients in clinical remission who are receiving conventional therapy. Our findings reinforce the utility of imaging for the accurate evaluation of disease status and the prediction of structural outcome. Remission is the aim of treatment in patients with rheumatoid arthritis (RA) (1). The remission state should represent an absence of inflammation, synonymous with no clinical symptoms or signs, and should result in optimal structural, functional, and quality of life outcomes. Modern RA therapy now enables a more complete suppression of inflammation, as reflected by the increasing rates of remission that have been reported (2 4). However, disease remission may not necessarily be associated with a consistently good outcome. A number of reports have suggested a disparity between clinical state and outcome, providing evidence of progression of joint damage despite apparent remission (5,6). This observation has been interpreted by some investigators as evidence of dissociation between syno- 2958

2 CLINICAL REMISSION AND CONTINUED STRUCTURAL DETERIORATION IN RA 2959 vitis and subsequent erosive joint damage (5,7). Alternatively, it may reflect the inadequate sensitivity of the traditional clinical approaches, such as the American College of Rheumatology (ACR; formerly, the American Rheumatism Association) remission criteria (8) and the Disease Activity Score 28-joint assessment (DAS28) criteria (9,10), to accurately detect synovitis and therefore assess true remission status. While these measurement techniques are composite scores based on clinical and laboratory assessments, they have the disadvantage of not directly measuring inflammation at the primary site of disease and may be subject to confounding influences (11). We previously studied a cohort of RA patients with clinically quiescent disease who were treated with disease-modifying antirheumatic drugs (DMARDs), and we assessed the prevalence of synovial inflammation using validated musculoskeletal ultrasonography (US) and magnetic resonance imaging (MRI) outcome measures (12). We demonstrated that 93% of the patients had synovitis on MRI and that 85% had synovial hypertrophy on gray-scale (GS) and 60% had increased power Doppler (PD) signal on musculoskeletal US, even though the majority of the patients fulfilled the ACR and DAS28 remission criteria. These results suggested that satisfying conventional remission criteria may not accurately reflect an absence of synovial inflammation. These data generated the hypothesis that subclinical inflammation detected by imaging techniques may explain the structural progression reported in RA patients in clinical remission. In the present study, we performed a longitudinal evaluation of this DMARD-treated clinical remission cohort. Our aim was to determine the structural significance of this subclinical inflammation and to investigate whether imaging-detected synovitis can be used to predict subsequent progression of joint damage. PATIENTS AND METHODS Patients and controls. In this prospective longitudinal cohort study, consultant rheumatologists used their clinical judgment to identify RA patients from their outpatient clinics whose disease was considered to be in remission while taking conventional DMARDs. In addition, all patients satisfied the following 6 criteria: RA classified according to the ACR criteria (13), age 18 years, disease duration of at least 12 months, no disease flare within the preceding 6 months, stable therapy for 6 months, and no clinical indication for a change in treatment. A control group of 17 sex-matched normal subjects was also studied. None of these subjects had a history of joint disease, nor did they have any musculoskeletal symptoms or signs at the time of evaluation. All control subjects underwent a clinical assessment and an MRI scan of their dominant hand and wrist at baseline, using the same technique as used in the RA patients (see below). 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 study inclusion. Study assessments. Inclusion criteria were applied at 2 months and at 0 months (baseline). At baseline and 12 months, all patients underwent complete clinical, laboratory, radiographic, functional, quality of life, and imaging assessments. In addition, at 3, 6, and 9 months clinical, laboratory, functional, and quality of life assessments were performed. Assessment of demographic and clinical characteristics. Demographic characteristics recorded at baseline included age, sex, duration of current remission, current therapy, and previous DMARDs received. Clinical data were recorded at every visit and included the duration of morning stiffness; Likert and visual analog scales (VAS) for fatigue, joint pain, physician s assessment of disease activity, and 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) (14) and the RA Quality of Life (RAQoL) questionnaire (15) were completed at every visit, and the scores were calculated. Remission and disease activity scores at each visit were calculated using the ACR remission criteria (8) (5 of 6 criteria satisfied on separate occasions 2 months apart) and the DAS28 criteria (10). Laboratory assessment. A complete blood cell count, erythrocyte sedimentation rate, and C-reactive protein level were measured at every visit. Rheumatoid factor (RF) titers and HLA type were determined at baseline to assess the presence of RA susceptibility (shared epitope) alleles. Radiographic assessment. Posteroanterior radiographs of the hands, wrists, and feet were obtained at baseline and at 12 months using standardized techniques. Radiographic joint damage was scored according to the Genant-modified Sharp scoring method (16). A single experienced reader (CGP) who was blinded to all other imaging and clinical findings and the chronological sequence of the baseline and followup radiographs performed this assessment. Ultrasonographic assessment. Each patient underwent a musculoskeletal US assessment of the joints of the dominant hand and wrist at baseline and at 12 months using GS and PD techniques. Eight joint regions were imaged by musculoskeletal US: metacarpophalangeal (MCP) joints 2 5 and the radiocarpal, ulnar-carpal, distal radioulnar, and intercarpal compartments of the wrist. Musculoskeletal US was performed by a single experienced sonographer (ZK) who was blinded to all other study findings, using an ATL HDI 3000 machine (ATL Ultrasound, Bothell, WA) with a 10 5 MHz linear array hockey stick transducer, according to the European League Against Rheumatism (EULAR) guidelines (17). The presence and location of any synovial hypertrophy and erosions were recorded with reference to standardized definitions subsequently agreed upon by the Outcome Measures in Rheumatology (OMERACT) group (18). Synovial hypertrophy on GS images was graded according to a semiquantitative scoring method (0 3 scale, where

3 2960 BROWN ET AL 0 no synovial hypertrophy, 1 mild synovial hypertrophy, 2 moderate, and 3 severe) (19,20). The area of maximum enhancement on PD images was recorded using a previously described semiquantitative technique (0 3 scale, where 0 normal/minimal vascularity, 1 mild hyperemia, 2 moderate, and 3 marked) (21). Erosions were scored according to their location and severity/size using a similar 0 3 semiquantitative scale (22). Each patient s total musculoskeletal US score for each pathologic feature (GS/PD/erosion) was calculated by summing the corresponding scores for each joint region. Magnetic resonance imaging assessment. MRI of the dominant hand and wrist was performed at baseline and 12 months using a conventional 1.5T Phillips MRI scanner (Philips, Surrey, UK). The same joint regions were imaged by MRI as for musculoskeletal US. The subjects were placed in a supine position with their arm outstretched in a superman position. A dual-coil approach was used in order to image the hand and wrist in a single sitting. T1 and T1 spectral presaturation with inversion recovery (SPIR; a method of fat suppression) sequences were recorded in the axial and coronal planes after intravenous administration of gadolinium. Synovitis, bone marrow edema (BME), and erosions were defined according to OMERACT guidelines (23). Images were graded by a single experienced reader (PGC) who was blinded to all other imaging and clinical findings, using the OMERACT RA MRI Scoring (RAMRIS) system (23). Synovitis was scored semiquantitatively (0 3 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 BME, corresponding to the proportion of each bone containing edema (0 3 scale, where 0 no edema, % of bone edematous, %, and %). Erosions were graded on a scale of 0 10, with each point representing a 10% loss of bone volume. Each patient s total MRI score for each pathologic feature (synovitis/bme/ erosion) was calculated by summing the corresponding scores for each joint region. Statistical analysis. Data evaluation and statistical analysis were performed using SPSS version 14.0 software (SPSS, Chicago, IL). Analyses were conducted at the patient and individual joint level. Patients were also stratified according to standard clinical remission criteria (ACR and DAS28) as well as signs and symptoms ( asymptomatic patients had clinically normal joints without any evidence of pain, tenderness, or swelling). Normally distributed continuous data were analyzed using parametric tests (independent t-test) and were summarized with means and 95% confidence intervals (95% CIs). Non-normally distributed and ordinal data were analyzed using nonparametric tests (Wilcoxon s signed rank test, Mann- Whitney U test) and were summarized with medians and interquartile ranges (IQRs). Categorical data were analyzed using chi-square tests, with continuity correction where necessary if the expected frequency for a cell in a cross-table was 5. Binary logistic regression was used to examine which baseline factors were associated with radiologic progression. HAQ and RAQoL data were Rasch-transformed to linearity (24). Intrareader reliability of radiographic scoring was assessed using the Bland-Altman plot technique (25). The smallest detectable change (SDC) for paired radiographic change scores was calculated according to the following formula: SDC 1.96 SD difference in change scores / 2 k where k represents the number of readings over which one wants to average the analyses of the trial (in this case, k 1) (26). RESULTS Patient population. A total of 102 RA patients who satisfied the inclusion criteria were evaluated. Full sets of radiographs at both time points (baseline and 12 months) were available for 90 patients; these formed the core dataset for the imaging analysis. Patients who did not have a complete set of films did not differ significantly from those with complete data in terms of age, sex, shared epitope, RF positivity at baseline, or ACR/ DAS28 remission status throughout the study. Due to patient migration and contraindications or intolerance of scanning procedures, complete MRI and musculoskeletal US data at both time points were not available for all patients. Demographic, clinical, and laboratory characteristics at baseline. The baseline demographic, clinical, and laboratory characteristics of the RA patients are shown in Table 1. The study population was predominantly female (67%) and had a mean age of 57 years; 64% of were RF positive, and 61% were shared epitope positive. The median disease duration was 7 years, and the median period of remission at the baseline assessment was almost 2 years. During the course of their disease, 99% of the patients had received DMARD therapy, and the majority had received 1 such drug. At baseline, 91% of the cohort were currently taking DMARDs, with oral methotrexate and sulfasalazine being the most commonly used medications. Twenty-one percent of the patients were taking combination DMARD therapy, and 2 of the patients had previously received biologic agents. Thirty-nine percent were currently receiving a nonsteroidal antiinflammatory drug (NSAID), and 2% were taking oral prednisolone (all 5 mg/day). Clinical and laboratory measures of disease activity all showed low activity, as measured by VAS assessments, the duration of early morning stiffness, the formal joint counts, and levels of acute-phase reactants. The study group had generally low levels of functional impairment, as measured by the HAQ (median 0.31 [IQR ]), and had mild-to-moderate quality of life impairment, as measured by the RAQoL (median 7.5 [IQR ]). A total of 54% fulfilled the ACR

4 CLINICAL REMISSION AND CONTINUED STRUCTURAL DETERIORATION IN RA 2961 Table 1. Demographic, clinical, and laboratory features of the 102 RA patients at baseline* Age, mean (range) years 57 (24 81) Sex, % female/male 67/33 Duration of RA, median (range) years 7 (2 38) Duration of remission, median (range; IQR) months 22 (6 144; 12 36) % RF positive (median titer) 64 (134) % shared epitope positive 61 Homozygotes 14 Heterozygotes 47 Current medications, % of patients DMARDs No. of DMARDs received, median (range) 1 (0 3) None 9 1 DMARD (specific agent received, %) 70 (41 oral MTX; 22 SSZ) 2 DMARDs (specific agents received, %) 15 (10 SSZ/MTX) 3 DMARDs (specific agents received, %) 6 (6 SSZ/MTX/HCQ) Oral steroids (daily dose) 2 ( 5 mg) Assessments by VAS (0 100 scale), median (IQR) score Fatigue 20 (8 33) Joint pain 14 (5 25) Patient s global assessment 14 (7 25) Physician s global assessment 10 (5 15) Morning stiffness, median (IQR) minutes 0 (0 0) Joint counts, median (IQR) Painful joints (80 assessed) 0 (0 1) Tender joints (28 assessed) 0 (0 2) Swollen joints (28 assessed) 1 (0 4) ESR, median (IQR) mm/hour 10 (6 18) CRP, median (IQR) mg/liter 5 (0 9) % meeting ACR remission criteria 54 DAS28 remission criteria Mean score 2.53 % in remission (score 2.6) 56 % with low disease activity (score ) 20 % with moderate disease activity (score ) 23 % with high disease activity (score 5.1) 1 *RA rheumatoid arthritis; IQR interquartile range; RF rheumatoid factor (positive titer 40 IU); DMARDs disease-modifying antirheumatic drugs; MTX methotrexate; SSZ sulfasalazine; HCQ hydroxychloroquine; VAS visual analog scale; ESR erythrocyte sedimentation rate; CRP C-reactive protein; ACR American College of Rheumatology; DAS28 Disease Activity Score 28-joint assessment. remission criteria, and 56% satisfied the DAS28 remission criteria (DAS28 score 2.6). The mean SD DAS28 score in the entire cohort was (95% CI 2.34, 2.72). Findings of imaging assessments at baseline. The majority of patients (57 of 90 [63%]) had evidence of radiographic joint damage, as assessed using the Genant-modified Sharp technique (60% with erosions and 51% with joint space narrowing [JSN]; median total joint damage score [IQR ]). On musculoskeletal US (n 88), 68% of patients had erosions, 89% had evidence of synovial hypertrophy, and 63% had increased PD signal. Using MRI (n 76), 96% of patients had erosions, 92% had synovitis, and 53% had BME. Of the patients who satisfied the ACR remission criteria, 87% (39 of 45) had synovial hypertrophy and 56% (25 of 45) had increased PD signal on musculoskeletal US, and 95% (36 of 38) had detectable synovitis on MRI. Similarly, of the patients who fulfilled the DAS28 remission criteria, 84% (41 of 49) and 51% (25 of 49) had synovial hypertrophy and increased PD signal, respectively, on musculoskeletal US, and 88% (36 of 41) had demonstrable synovitis on MRI. Considering the completely asymptomatic and clinically normal joints (i.e., no pain, tenderness, or swelling) in the dominant hand or wrist, 38% (145 of 378) had synovial hypertrophy and 15% (56 of 378) had increased PD signal on musculoskeletal US, and 50% (160 of 322) had detectable synovitis on MRI, despite the normal clinical findings. High levels of intra- and interobserver reliability for imaging scoring have previously been reported in this cohort (12).

5 2962 BROWN ET AL Table 2. Percentages of patients whose total joint damage scores deteriorated over 12 months, according to assessment technique, and significance of the differences from baseline* Radiography of Dominant-hand MCP joints 2 5 Score both hands and feet Radiography US MRI All patients No. of patients % with erosion P versus baseline % with JSN 17 3 NA NA P versus baseline Total radiographic score 19 7 NA NA P versus baseline Asymptomatic patients No. of patients % with erosion P versus baseline % with JSN 16 7 NA NA P versus baseline Total radiographic score NA NA P versus baseline * MCP metacarpophalangeal; US ultrasonography; MRI magnetic resonance imaging; JSN joint space narrowing; NA not applicable. Significantly different versus baseline. All P values were determined by Wilcoxon s signed rank test. Findings of clinical and imaging assessments in the control group. All control subjects had normal findings on clinical examination. Three control subjects (18%) had evidence of synovitis on MRI. This comprised a total of 4 joints (3%), all of which were graded as mild. BME was not seen in any joints of the control subjects. Change in RA disease activity over 12 months. There were no statistically significant differences in the results of disease activity measures between the baseline and outcome assessments. At 12 months, 45% of the patients (38 of 85) fulfilled the ACR remission criteria and 61% (52 of 85) fulfilled the DAS28 remission criteria. The mean change in the DAS28 score was (95% CI 0.255, 0.223) (t 0.134, P Student s paired t-test). Only 5% of patients required a change in therapy due to increased disease activity throughout the study period, despite regular clinical assessments at 3-month intervals. Progression of structural changes in each patient over 12 months. The calculated SDC for the erosion score (both hands and feet) and for the total radiographic score (combined erosion and JSN scores in both hands and feet) was 1. The SDC for the JSN score (both hands and feet) and for the erosion/jsn/combined score (dominant-hand MCP joints 2 5) did not exceed the smallest unit of change in the scale, which was 0.5. A total of 19% of patients (17 of 90) experienced a deterioration in their total radiographic joint damage scores that exceeded the SDC over the study period. The quantitative change in the total radiographic damage score was statistically significant (Z 3.26, P by Wilcoxon s signed rank test) (Table 2). The probability plot shown in Figure 1 illustrates the proportion of patients with a change in the total radiographic score, as well as a quantitative measure of the difference in scores, over the 12-month study period. Musculoskeletal US and MRI scanning detected changes in the total erosion score in the dominant-hand MCP joints in a larger proportion of patients (24% [23 of 95] and 20% [15 of 74], respectively) than did radiography (6% [5 of 90]) (Table 2). There were significant quantitative changes in the total erosion scores in the dominant hand and wrist, as measured by musculoskeletal US (n 82) (median change 0 [IQR 0 1]; Z 2.41, P by Wilcoxon s signed rank test) and by MRI (n 66) (median change 0 [IQR 0 1]; Z 3.37, P 0.001). The change in dominant-hand MCP score was statistically significant only for the MRI assessment (n 74) (median change 0 [IQR 0 0]; Z 3.12, P 0.002), although US showed a trend toward significance (n 95) (median change 0 [IQR 0 0]; Z 1.74, P 0.082) (Table 2). We performed univariate binary logistic regression analyses to investigate the association between baseline factors and radiographic progression and found that in addition to known predictive factors, such as RF (borderline significant; odds ratio [OR] 2.95, P 0.054)

6 CLINICAL REMISSION AND CONTINUED STRUCTURAL DETERIORATION IN RA 2963 Figure 1. Cumulative probability distribution of the percentages of symptomatic and asymptomatic patients with a given change in total radiographic (x-ray [XR]) score (smallest detectable change [SDC]). and ACR remission (borderline significant; OR 0.33, P 0.054), the total baseline PD score was also associated with an adverse structural outcome radiographically (increase in OR per unit increase in score 1.36, P 0.038). The PD score for the dominant-hand MCP joints was also significantly associated with radiographic progression in any joint anywhere in the hands and feet (increase in OR per unit increase in score 1.64, P 0.036) (Table 3). In the completely asymptomatic patients, who had no painful, tender, or swollen joints, 16% (4 of 25) experienced radiographic progression, as reflected by an increased total joint damage score exceeding the SDC in the hands and feet. In the dominant-hand MCP joints, 7% (2 of 30) had a worse erosion score on radiography, 22% (6 of 27) had a worse erosion score on musculoskeletal US, and 25% (5 of 20) on MRI (Table 2 and Figure 1). At 12 months, 11% of the patients who satisfied the ACR remission criteria and 12% of the patients who satisfied the DAS28 remission criteria also showed radiographic progression (data not shown). Progression of structural changes in individual joints and association with baseline parameters. SDC values were calculated for the radiographic erosion score, JSN score, and the combined score for individual dominant-hand MCP joints. For each of the scores, the calculated SDC did not exceed the smallest unit of change in the scale (0.5). Associations between baseline clinical joint assessments and structural progression in individual joints were evaluated. The dominant-hand MCP joints were used for this purpose since comparable data for each imaging modality were available for each patient at these anatomical sites. While the clinical characteristics were associated with an increased likelihood ratio of structural progression, particularly for joint pain and tenderness (OR 3.32 and OR 2.17, respectively), none of these parameters reached statistical significance (Table 4). In contrast, baseline imaging findings were associated with a statistically significant likelihood of subsequent structural deterioration in the MCP joints. In particular, a positive PD signal (OR 12.21, P 0.001) as well as Table 3. Associations between clinical, laboratory, and imaging findings at baseline and radiographic progression in both hands and feet over 12 months* Baseline variable No radiographic progression (n 73) Radiographic progression (n 17) OR (95% CI) P No. (%) RF positive 28 (38) 11 (65) 2.95 (0.98, 8.86) ESR, median (IQR) mm/hour 10 (6 18) 13 (8 18) 1.01 (0.96, 1.06) CRP, median (IQR) mg/liter 5 (0 9) 0 (0 12) 1.01 (0.93, 1.10) No. (%) meeting ACR remission criteria 41 (56) 5 (29) 0.33 (0.10, 1.02) No. (%) in DAS28 remission (score 2.6) 44 (60) 6 (35) 0.36 (0.12, 1.08) DAS28 score, mean (95% CI) 2.48 (2.26, 2.71) 2.89 (2.40, 3.38) 1.54 (0.89, 2.65) Total US PD score, median (IQR) 1 (0 2) 1 (0 3.5) 1.36 (1.02, 1.81) Dominant-hand US PD score, median (IQR) 0 (0 0.75) 0 (0 2) 1.64 (1.03, 2.61) *OR odds ratio; 95% CI 95% confidence interval; RF rheumatoid factor; ESR erythrocyte sedimentation rate; IQR interquartile range; CRP C-reactive protein; ACR American College of Rheumatology; DAS28 Disease Activity Score 28-joint assessment; US ultrasonography; PD power Doppler.

7 2964 BROWN ET AL Table 4. Associations between the clinical and imaging findings at baseline and radiographic progression in individual joints (dominant-hand MCP joints) over 12 months* Baseline variable No radiographic progression (n 370) Radiographic progression (n 10) OR (95% CI) P Clinical findings, no. (%) of patients Painful joint count 12 (3) 1 (10) 3.32 (0.39, 28.30) Tender joint count 18 (5) 1 (10) 2.17 (0.26, 18.10) Swollen joint count 75 (20) 3 (30) 1.69 (0.43, 6.67) Imaging findings US SH score, median (IQR) 1 (0 1) 1 (0 2) 2.31 (1.06, 5.52) US PD score, median (IQR) 0 (0 0) 0.5 (0 2) 4.00 (1.98, 8.08) MRI synovitis score, median (IQR) 0 (0 1) 2.5 (0 3) 2.98 (1.49, 5.97) MRI BME score, median (IQR) 0 (0 0) 0 (0 0) 2.26 (0.98, 5.22) No. (%) US SH positive 203 (55) 7 (70) 1.92 (0.49, 7.54) No. (%) US PD signal positive 28 (8) 5 (50) (3.34, 44.73) No. (%) MRI synovitis positive 160 (48) 5 (63) 1.79 (0.42, 7.62) No. (%) MRI BME positive 20 (6) 1 (13) 2.23 (0.26, 19.00) * MCP metacarpophalangeal; OR odds ratio; 95% CI 95% confidence interval; US ultrasonography; SH synovial hypertrophy; IQR interquartile range; PD power Doppler; BME bone marrow edema. Magnetic resonance imaging (MRI) was performed in 340 joints (332 without radiographic progression and 8 with radiographic progression). the scores for the PD (OR 4.00, P 0.001) and synovial hypertrophy (OR 2.31, P 0.032) by musculoskeletal US, as well as synovitis (OR 2.98, P 0.002) by MRI, were associated with significantly higher odds of progression (Table 4). Progression of structural changes in asymptomatic joints and association with findings of imaging assessments at baseline. As shown in Figure 2, similar proportions of asymptomatic and symptomatic MCP joints demonstrated structural progression. We assessed whether baseline imaging data were associated with longitudinal radiographic progression in these asymptomatic joints. Despite a relatively small number of joints with radiographic structural deterioration, PD findings were significantly associated with radiographic progression, as measured either by the difference in the PD score (median score 1 [IQR 1 1] in joints without progression and median score 1 [IQR 1 2] in joints with progression; increase in OR per unit increase in score 6.41 [95% CI 1.81, 22.74], P 0.004) or by the number of joints with increased PD signal (4% of joints without progression versus 29% of joints with progression; OR 8.77 [95% CI 1.54, 49.89], P 0.014) (data not shown). Figure 2. Percentages of dominant-hand metacarpophalangeal (MCP) joints with structural deterioration over 12 months, as determined by radiography (x-ray [XR), ultrasonography (US), and magnetic resonance imaging (MRI), in symptomatic and asymptomatic MCP joints. Asymptomatic MCP joints were those without pain, tenderness, or swelling. Symptomatic MCP joints were those with pain and/or tenderness and/or swelling. DISCUSSION In this prospective longitudinal study, we found that structural progression occurs in RA patients receiving conventional therapy despite the presence of clinical remission and that such deterioration is associated with synovitis detected by imaging techniques. We also demonstrated that subclinical inflammation in asymptomatic

8 CLINICAL REMISSION AND CONTINUED STRUCTURAL DETERIORATION IN RA 2965 joints as detected by imaging techniques predicts the progression of joint damage in patients with RA. Over the study period, one-fifth of the RA patients, who were in clinical remission as determined by a physician, experienced deterioration in their total radiographic joint damage score that exceeded the SDC. Applying the established measures of RA remission, such as the ACR and DAS28 criteria, 12% of these patients still showed radiographic deterioration, and moreover, a similar proportion of patients had radiographic progression despite the complete absence of clinical signs and symptoms in their joints. With moresensitive imaging techniques, such as musculoskeletal US and MRI, the proportion with subsequent structural deterioration was greater in each of these groups. These data suggest that the current measures used to assess disease activity in RA, which largely rely on subjective clinical symptoms, joint examination findings, and laboratory measures of acute-phase reactants, are not sufficiently sensitive to exclude ongoing inflammation in patients with low levels of disease activity. This observation is corroborated by the results of a receiver operating curve analysis to investigate the threshold by which the DAS28 score may be used to predict radiographic progression at 1 year. The resulting area under the curve value of (data not shown) supports the relative inaccuracy of the DAS28 score to accurately predict radiographic structural outcome no matter where the cutoff point for remission is set. This has important implications and suggests that traditional measures of RA disease activity may also lack predictive validity since they are unable to accurately predict subsequent structural deterioration as early as 1 year later. To our knowledge, this is the first study to demonstrate a direct association between synovitis, as detected by musculoskeletal US (GS synovial hypertrophy and PD signal) and radiographic progression in individual joints in a large cohort of RA patients. These data also confirm previous reports of the relationship between imaging-detected synovitis and subsequent structural damage (27,28). In addition, this study is the first to demonstrate that subclinical inflammation detected by imaging techniques may predict subsequent radiographic outcome in clinically asymptomatic joints. These data support our hypothesis that subclinical inflammation, which is undetectable by traditional measurement techniques, is the pathophysiologic mechanism for continued structural progression in RA despite apparent clinical remission. This phenomenon has been observed in this cohort and by other cohorts evaluated by other investigators (5,6), but it has previously defied explanation. The superiority of sensitive imaging methods over conventional clinical measures and established remission criteria as a predictor of structural outcome demonstrated in this study provides further evidence to support this theory. The results of our investigation suggest that, in the majority of RA patients who are treated with conventional DMARDs, joint damage is closely related to subclinical inflammation, which in states of low disease activity, can only be accurately detected by imaging techniques such as musculoskeletal US and MRI. The differences in the capacities of imaging modalities to predict joint damage progression enable us to hypothesize about the pathogenesis of erosive joint damage in RA. Gray-scale musculoskeletal US primarily detects hypertrophy of the synovium, which may become chronically thickened and less reversible in established RA, whereas an increased power Doppler signal may be more likely to signify increased vascularity associated with active inflammation. Gadolinium-enhanced MRI provides information relating to both synovial thickness and increased blood flow. Our data suggest that increased PD signal is the most robust predictor of erosive damage, emphasizing the potentially important role of increased vascularity in the development of subsequent structural progression in patients with established RA. In contrast, bone marrow edema reflects the presence of an inflammatory infiltrate (29), which has been shown to be associated with adverse structural and functional outcomes (30,31). The relative lack of association between the baseline BME score and radiographic progression in our study may be attributed to the relatively small number of joint regions with radiographic deterioration, particularly in the carpus, where the predictive value of BME has been most frequently demonstrated (30,31). However, when the MRI erosion score was used as a more sensitive outcome measure, this resulted in a statistically significant association between the baseline BME score and structural deterioration seen on MRI at the patient and individual joint level (P and P 0.001, respectively, by Mann-Whitney U test) (data not shown). This observation supports our subclinical inflammation based hypothesis and provides further evidence regarding the relative insensitivity of established radiographic measures for assessing structural outcomes. While plain radiographs remain the conventional measure accepted by regulatory authorities for the assessment of structural outcome in RA, there is increasing evidence to support the validity of modern imaging modalities such as musculoskeletal US and MRI in this role (22,32 35). Our study demonstrates the enhanced

9 2966 BROWN ET AL sensitivity of musculoskeletal US and MRI for the detection of structural damage as well as their superior sensitivity to change as compared with radiography. Furthermore, both musculoskeletal US and MRI allow the valid and reliable assessment of both ongoing inflammatory disease activity and structural outcome in RA at the same time. These observations are endorsed by the data from our normal control population, which are consistent with published findings (36), and confirm the specificity of the imaging findings in this RA cohort. Our results demonstrate that objective imaging techniques definitively identify inflammation and the potential for further joint damage across the boundaries of the current remission classification systems, with no differences in the proportion of patients with subclinical synovitis who were judged by physicians to be in remission, regardless of whether they fulfilled the ACR/ DAS28 criteria. This suggests that satisfying the ACR/ DAS28 definitions is a no more valid assessment than that made by an experienced physician. In addition, remission classified according to established clinical criteria may not represent an inflammation-free, nondamaging disease state. So, while the current criteria may confer a safer disease activity level than not, they may still allow persistent, active disease and subsequent structural damage to go unnoticed, thus raising legitimate questions regarding their accuracy. These data have a number of important clinical implications. Our threshold for additional intervention in such patients may need to be lowered, since even in states of low disease activity, patients may benefit from additional therapy. The effects of dosage titration and treatment strategies involving additional or combination therapy with traditional DMARDs or biologic agents merit further investigation in this population. Monitoring treatment-resistant synovial inflammation with imaging studies in such patients may enable the appropriate selection of patients in whom further therapy may result in a more-effective prevention of structural damage. The present study supports the use of sensitive imaging techniques for the accurate evaluation of disease status and the prediction of outcome in patients with RA, even when the findings of standard clinical measures of inflammatory activity have returned to normal. Furthermore, an objective imaging assessment improves the sensitivity of inflammation detection, enabling more-informed treatment decisions and an accurate definition of the remission state, which is most likely to correlate with optimal long-term structural outcome. AUTHOR CONTRIBUTIONS Dr. Brown 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 design. Brown, Conaghan, Karim, Quinn, Wakefield, Emery. 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