For rheumatoid arthritis (RA), clinical definitions of

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1 RHEUMATOID ARTHRITIS Ultrasound-Defined Remission and Active Disease in Rheumatoid Arthritis: Association with Clinical and Serologic Parameters Christian Dejaco, MD, PhD,* Christina Duftner, MD, PhD, Edith Wipfler-Freißmuth, MD, Helmut Weiss, MD, Winfried B. Graninger, MD,* and Michael Schirmer, MD Objective: To assess the association of clinical and/or serological parameters with ultrasounddefined disease activity in rheumatoid arthritis (RA). Methods: Retrospective analysis of 149 consecutive RA patients routinely assessed by sonography of the wrists, metacarpo-phalangeal, and proximal interphalangeal joints. Semiquantitative scoring of synovial hypertrophy/effusion and power Doppler (PD) signals was performed. Sonographic remission was defined by the absence of PD signals. Number of tender and swollen joints, global assessment of disease activity by the physician (VAS-phys) and patient (VAS-pt), C-reactive protein (CRP), erythrocyte sedimentation rate, duration of morning stiffness (MS), simplified disease activity index, disease activity score for 28 joints, clinical disease activity index, and health assessment questionnaires were recorded. Results: PD signals as a sign of active disease were observed in 117 (78.5%) RA patients. CRP, erythrocyte sedimentation rate, and MS were higher in patients with PD signals than in patients in remission. CRP 5.0 mg/l (normal values mg/l), MS 15 minutes, or the combination of both revealed odds ratios of 5.0, 3.0, or 18.9, respectively, to indicate sonography-defined active disease. The other parameters showed no association with the presence or absence of PD-signals. Conclusions: Sonography-defined disease activity is associated with CRP and MS, whereas current composite scores and its clinical components did not match this definition Elsevier Inc. All rights reserved. Semin Arthritis Rheum 41: Keywords: rheumatoid arthritis, ultrasonography, outcome measures, immunosuppressants, quality of health care *Department of Rheumatology, Medical University Graz, Graz, Austria. Department of Internal Medicine, General Hospital of Kufstein, Kufstein, Austria. Department of Internal Medicine, Hospital of the Barmherzigen Brüder Marschallgasse, Graz, Austria. Department of Radiology, General Hospital of the Elisabethinen, Klagenfurt, Austria. Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria. The authors have no conflicts of interest to disclose. Address reprint requests to Michael Schirmer, MD, Department of Internal Medicine I, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria. [email protected] /12/$-see front matter 2012 Elsevier Inc. All rights reserved. doi: /j.semarthrit For rheumatoid arthritis (RA), clinical definitions of remission and active disease are based on composite index scores such as the simplified disease activity index (SDAI), the disease activity score for 28 joints (DAS-28), or the clinical disease activity index (CDAI) (1). These definitions, however, lack the sensitivity and specificity to predict the absence of inflammation as shown by magnetic resonance imaging and ultrasound studies (2,5). Imaging-based assessment of disease activity has become more and more important during the last several years (6). Recently, new definitions of sonographic remission and active disease were proposed by Balsa and coworkers and Saleem and coworkers (6,7). One definition proposed by both groups of authors was based on the absence or presence of power Doppler (PD) signals, recognizing that hypervascularized inflammatory lesions are associated with future clinical deterioration and progression of radiological damage despite apparent clinical remission of RA patients (3,5,8). The question of whether clinical and laboratory parameters including the components of current composite 761

2 762 Ultrasound-defined remission and active disease in RA scores are associated with these sonographic definitions of remission and active disease is still unresolved and is addressed by the present study. METHODS Patients We performed a retrospective analysis of 149 consecutive RA patients attending the Hospital of the Elisabethinen Klagenfurt, Austria, for new diagnosis (n 45) or follow-up of RA (9). Demographic and clinical characteristics of each patient including age, gender, disease duration, and current treatment with disease-modifying antirheumatic drugs were recorded by chart review. RA was clinically diagnosed by the treating physician; however, 91.2% of patients fulfilled the American College of Rheumatology European League Against Rheumatism (ACR-EULAR) 2010 classification criteria if they were retrospectively applied (10). Patients underwent complete clinical assessment for the number of tender (TJ) and swollen joints (SJ) using the 28 reduced articular index [and a 22-joint count focusing on wrists, metacarpo-phalangeal (MCP), and proximal interphalangeal (PIP) joints only], average duration of morning stiffness (MS) (minutes) during the last week before the actual visit (11), physician s (VAS-phys) and patient s (VAS-pt) global assessment of disease activity on a visual analog scale (range, mm), and functional capacity with the German version of the health assessment questionnaire (HAQ) (12). All clinical assessments were equally performed by the same trained nurse and documented on the local computer system. Blood samples were routinely tested for erythrocyte sedimentation rate (ESR, measured by the Westergren method, normal range, 0-9 mm/1st hour) and C-reactive protein (CRP) levels (measured by nephelometry; normal range, 0-5 mg/l). Composite index scores including the SDAI, DAS-28, and CDAI were calculated as previously described (1). This retrospective analysis was accepted by the Carinthian Institutional Review board. Ultrasound Examination Sonographic examination was equally performed in all RA patients on 22 joints (wrists, MCP I-V, and PIP I-V joints of both hands) by rheumatologists trained and experienced in musculoskeletal sonography [CDe (3-years experience); CDu (3-years experience), and EWF (4- years experience)] under the guidance of a senior radiologist (HW) using an Acuson Antares Siemens ultrasound machine Siemens Medical Solutions, Mountain View, CA, USA with a linear probe at 5 to 13 MHz and a Doppler frequency of 5 to 8.9 MHz. Patients were examined in a sitting position with their hands positioned on the examination table in a darkened room in which the temperature was held constant at 20 C. Scan images were registered on the hard disc of the ultrasound unit. A frequency of 11.4 MHz was used for B-mode ultrasound, and imaging parameters were adjusted to maximize the contrast between examined structures. PD settings were standardized accordingly: a frequency of 7.2 MHz, a pulse repetition frequency of 500 Hz, and medium persistence remained fixed throughout the study. The PD gain was optimized by increasing gain until noise appeared and then reducing gain just enough to suppress the noise. The window of the color box was restricted to the areas studied. We used the spectral Doppler to confirm that the PD signal represented real blood flow. B-mode and PD examinations were performed at transverse and longitudinal scanning of dorsal and volar view of MCP and PIP joints, which were held in extended position during the examination. Wrists (neutral position) were investigated at the dorsal view only. The duration of each examination was between 15 and 25 minutes. Synovial hypertrophy and/or joint effusion (SH/E) was identified by B-mode imaging in each joint as abnormal hypoechoic poorly compressible and/or anechoic compressible intraarticular material, respectively, and was used as a combined measure as proposed previously (13). SH/E was subjectively graded from 0 to 3 in which 0 represented no SH/E, 1 minimal SH/E covering the area between periarticular bones and not crossing a line linking the tops of the bones (dorsal view) or minimal SH/E seen under the flexor tendon(s) (volar view); 2 SH/E causing some distension of carpal bones and extensor tendons at wrists, or SH/E bulging into extensor tendon(s) with or without small extension of the joint capsule along the bone diaphyses at MCP and PIP joints (dorsal view), or moderate SH/E without significant distension of the joint capsule (ie, not crossing a line along the top of the head of metacarpal/interphalangeal bones and the basis of the phalanges; volar view); 3 SH/E leading to extensive bulging and dislocation of the extensor tendon(s) with significant extension to 1 or both bone diaphyses at wrists, MCP, or PIP joints (dorsal view), or extensive SH/E leading to the distension of the joint capsule (volar view). PD signals were also semiquantitatively graded on a scale from 0 to 3, in which 0 represented no PD signal, 1 up to 3 single or 2 confluent vessels, 2 less than one-half of the synovia, and 3 one-half or more of the synovia covered by PD signals Supplementary Fig. 1, found at com, provides examples). SH/E and PD were independently graded at dorsal and volar views and the higher value was counted for the score. Scores were expressed per joint (possible range, 0-6), and a total score was calculated by the addition of all joint scores (possible range, 0-132). All data were recorded for the physicians report on the local computer system Supplementary Fig. 2, found at provides documentation form).

3 C. Dejaco et al. 763 Table 1 Clinical Characteristics of Patients with Rheumatoid Arthritis 18.0 ( ) 2.0 (0-22.0) 30.0 (0-72.0) Age [yr], n 149 a 63.7 ( 13.4) Female, n (%) 126 (84.6) Disease duration [mo], n 145 b SDAI, n 119 a 21.5 ( 12.9) DAS-28, n 112 a 4.5 ( 1.3) CDAI, n 120 a 20.9 ( 12.5) Swollen joint count, n 120 b Tender joint count, n 120 b 6.0 (0-26.0) Patients global assessment 45.4 ( 30.0) [VAS], n 121 a morning stiffness [minutes], n 132 b ESR [mm/1st hour], n 143 b 21.0 ( ) CRP [mg/l], n 147 b 7.0 ( ) HAQ, n 118 a 1.0 ( 0.76) Current DMARD treatment Methotrexate, n (%) 90 (60.8) Anti-TNF therapy, n (%) 15 (10.1) Rituximab, n (%) 2 (1.4) Tocilizumab, n (%) 2 (1.4) SDAI, simplified disease activity index; DAS-28, disease activity score-28; CDAI, clinical disease activity index; VAS, visual analogue scale (range mm); ESR, erythrocyte sedimentation rate (normal values 0-9 mm/1st hour); CRP, C-reactive protein (normal values 0-5 mg/l), HAQ, health assessment questionnaire. a Mean (standard deviation). b Median (range). Statistical Analysis Statistical analysis was performed with SPSS (version 17.0). Descriptive statistics were used to summarize the data. According to the results of the Kolmogorov Smirnov test, the Mann Whitney or the Student s t tests were applied as appropriate. Correlations between clinical and serological items were analyzed by the Spearman s rank correlation coefficient. Proportions were calculated by the 2 test. Single predictor and backward logistic regression models (maximum likelihood method) were performed to identify the association of clinical and laboratory parameters with sonography-defined disease activity. Parameters were applied as categorical or continuous parameters and adequate transformations (eg, logarithmic, cube root) were performed in the case of nonnormal distribution. Using CRP and MS as categorical predictors, cutoff values of 5.0 mg/l and 15 minutes were chosen for the final analysis, respectively, because the normal values of CRP are 0 to 5 mg/l, and a cutoff level of 15 minutes for MS statistically provided the best discrimination between patients in ultrasound remission and active disease. Besides, this cutoff for MS was already proposed by the 1981 American Rheumatism Association (ARA) remission criteria (14). Goodness of fit was tested with Hosmer Lemeshow statistics; mavericks and influential points were also addressed. RESULTS Complete clinical, serologic, and ultrasound data were available in 111 RA patients. Clinical characteristics are depicted in Table 1. The median number of joints per patient showing SH/E or PD signals was 7.0 (range, ) or 3.0 (0-18.0), respectively. Median global ultrasound, SH/E, and PD scores were 15.0 (0-86.0), 11.0 (0-54.0), and 4.0 (0-32.0), respectively. Global ultrasound, SH/E, and PD scores showed moderate or weak correlations with CRP, ESR, MS, DAS-28, and HAQ as outlined in Table 2. No association was found between ultrasound scores and tender or swollen joint counts (28- as well as 22-joint counts), patients or physicians global assessment, as well as disease duration. Analysis of global ultrasound, SH/E, and PD scores at different levels of disease activity according to current composite scores are shown in Supplementary Table 1, found at Patients with active disease according to DAS-28 had higher global ultrasound scores compared with patients in clinical remission [median 16.0 (range, ) versus 9.5 (3-19.0), P 0.05]. Patients showing a HAQ score 0 displayed higher global ultrasound and SH/E scores [16.0 (0-86.0) versus 11.0 (0-44.0), P 0.05, and 11.0 (0-54.0) versus 5.0 (0-23.0), P 0.05, respectively] compared with patients without disability. Differences Regarding Clinical and Serological Parameters Comparing Patients in Ultrasound-Defined Remission and Active Disease Thirty-two RA patients (21.5%) showed no PD signals and were categorized as being in sonographic remission (6,7). SDAI, DAS-28, CDAI, and HAQ did not differ Table 2 Correlations Between Composite Scores, Clinical and Laboratory Variables, as Well as Ultrasound Scores GU score SH/E score PD score CRP 0.455*** 0.392*** 0.452*** ESR 0.394*** 0.345*** 0.380*** Duration of MS 0.227** 0.187* 0.254** SDAI DAS ** 0.245** 0.202* CDAI HAQ 0.223* 0.271** Spearman s rank correlation coefficients are shown. NS, no significant correlation; GU score, global ultrasound score; SH/E score, synovial hypertrophy and/or joint effusion score; PD score, power Doppler score; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; MS, morning stiffness; SDAI, simplified disease activity index; DAS-28, disease activity score-28; CDAI, clinical disease activity index; HAQ, health assessment questionnaire. *P 0.05, **P 0.01, ***P (not corrected for multiple testing).

4 764 Ultrasound-defined remission and active disease in RA between patients in ultrasound-defined remission and active disease (9). Also, comparisons of composite scores at various percentiles of sonographic disease activity did not reveal significant differences (Supplementary Table 2, found at Analysis of single clinical and serologic parameters showed a longer duration of MS [median 30.0 (range, ) versus 12.5 ( ) minutes, P 0.05], higher CRP [8.2 ( ) versus 3.0 (0-31.0) mg/l, P 0.001] and ESR levels [25.0 ( ) versus 14.0 (0-74.0) mm/1st hour, P 0.05] in patients with ultrasound-defined active disease compared with those patients in remission (Fig. 1). No differences were found regarding the median number of TJ and SJ (28- as well as 22-joint count), VAS-phys, VAS-pt, and HAQ. None of the parameters analyzed differed between those 10 patients without sonographic lesions and the 22 patients showing SH/E but no PD signals. Association of Ultrasound-Defined Disease Activity with Clinical and Serologic Parameters Using logistic regression analysis with age, disease duration, CRP, ESR, MS, number of TJ and SJ (28- as well as 22-joint count), VAS-phys, VAS-pt, as well as HAQ as possible predictors, we found an odds ratio (OR) of 5.0 (95% confidence interval , P 0.001) for CRP 5.0 mg/l and an OR of 3.0 ( , P 0.017) for MS 15 minutes to indicate sonography-defined active disease. ESR was not associated with the presence of PD signals in single-predictor models, although ESR was highly correlated with CRP values (corr coeff 0.690). Patients demonstrating CRP 5.0 mg/l plus MS 15 minutes were at an OR of 18.9 ( , P 0.001) to have active disease compared with patients with normal CRP and no MS. CRP ( 2.08, P 0.002) and MS ( 0.26, P 0.038) were also significantly related to active disease when applied as continuous (transformed) predictors. Sensitivity Analysis The following sensitivity analyses were performed for all comparisons: calculations were restricted to patients (1) with complete clinical, serologic, and ultrasound data sets; (2) fulfilling the ACR-EULAR 2010 classification criteria for RA; and (3) with established RA (ie, excluding newly diagnosed patients). All these analyses revealed a result similar to our primary calculations, thus confirming the robustness of our data. DISCUSSION This retrospective analysis indicates that sonography-defined disease activity is associated with CRP levels and duration of MS, whereas current composite scores and its components including the number of TJ and SJ (28- as well as 22-joint counts), VAS-phys, and VAS-pt as well as HAQ did not match this definition. The question, which approach is most useful to define remission for daily clinical practice and outcome studies, has not been clarified so far. A SDAI 3.3 (or all of the following: number of TJ 1, number of SJ 1, CRP 1 mg/dl, and VAS-pt 1) was recently proposed by the ACR-EULAR commission to redefine remission in RA (15). As these criteria are very stringent, only a few patients fulfill this clinical definition of remission (8-26% in earlier clinical studies) (15). Up to one-half of RA patients in 2010 ACR-EULAR remission still have active inflammation at ultrasound examination, and persistent sonographic disease activity despite clinical remission has been associated with clinical flares and radiographic progression (5-8). Besides, a significant proportion of clinically active patients do not have PD signals, implying sonographic remission (9). Whether patients with high clinical disease activity but low or no signs of inflammation at ultrasound examination have better outcomes than patients with high clinical and sonographic scores still has to be clarified. Current composite scores rely on subjective clinical symptoms, and joint examination findings underlie a high interobserver variance (16,17). In addition, concomitant fibromyalgia and/or osteoarthritis influence clinical assessments, resulting in a variable sensitivity and specificity of clinical examination to detect joint inflammation in RA (18,19). The quality of ultrasound results certainly depends on the expertise of the examiner and the power of the ultrasound machine; however, a high reproducibility of sonographic findings was recurrently demonstrated even for less experienced sonographers (2,20). Sonographic remission was recently defined by the absence of PD signals accepting the presence of even highgrade SH/E in these patients (6,7). The resolution of both PD and SH/E lesions remains the ultimate therapeutic goal in RA; however, many patients show chronic thickening of the synovium without active inflammation. Active inflammation as indicated by the presence of PD signals appears to be the most relevant ultrasound finding concerning clinical and structural outcomes in RA and a definition of remission based on PD findings seems thus very promising (3,5,8). Time-integrated ultrasound results (including baseline and follow-up examinations) in particular were closely associated with the progression of structural damage and thus may be considered in the follow-up of RA patients in the future (21). In the present cohort, MS was the only clinical item associated with sonography-defined disease activity. Although the identified cutoff of 15 minutes may raise concerns about its specificity to classify correctly RA-related MS (as opposed to MS caused by concomitant osteoarthritis), this cutoff revealed the highest OR in uni- and multivariate analysis and was previously proposed as a relevant cutoff to define clinical remission in RA (1981

5 C. Dejaco et al. 765 Figure 1 Clinical and laboratory items in RA patients with and without active inflammation as defined by sonography. Duration of morning stiffness (n 132) (minutes), C-reactive protein levels (CRP; n 147) (mg/l), and the erythrocyte sedimentation rate (ESR; n 143) (mm/1st hour) are shown for patients with RA without hypervascularization ( remission) and with hypervascularization ( active disease) as assessed by power Doppler (PD) ultrasound. Whiskers box plots show the median and 50% of cases within the boxes and all data excluding mavericks between the endpoints of the whiskers. Differences were tested with the Mann Whitney U test. *P 0.05; ***P ARA criteria) (14). Our observation on the importance of MS for imaging-based definition of remission is supported by the results of previous MRI studies showing a good correlation of MS with inflammation (22,23). In contrast, current composite scores and its clinical components did not match ultrasound-defined remission and the values of these scores were comparable across different levels of sonographic disease activity. Similarly, earlier prospective studies reported variable results comparing the number of TJ and SJ, VAS-pt, and sonographic findings (24-26). A relevant consideration in this regard is that the strength of association between manual and ultrasound joint counts diminishes as patients are in or near to remission (3). In cohorts with high disease activities (such as in studies on anticytokine therapy), manual joint counts better correlate with sonography, whereas in the setting of low disease activity or remission, divergent results are observed (3,4,9,24,25). Whether the modification of current composite scores by the inclusion of MS strengthens the association with sonography-defined remission or whether existing patients questionnaires incorporating MS such as the Rheumatoid Arthritis Disease Activity Index correlate with ultrasound findings remains to be addressed by future studies (27). Acute phase reactants, such as ESR and CRP, are useful to monitor disease activity in RA and are included in most clinical composite scores (28). In the present and previous ultrasound studies ESR and CRP correlated with scores of inflammation (24,25,29); however, only CRP is useful to discriminate patients with ultrasound-defined remission from those with active inflammation according to our present logistic regression analysis. This observation may be explained by a higher sensitivity of CRP than ESR to detect low-grade and/or recent-onset inflammation. In support of this hypothesis, it was demonstrated that both ESR and CRP were adjunctive with sonographic measures of disease activity at baseline, but as soon as clinical remission was achieved (and low-grade inflammation is considered), only CRP correlated with ultrasound findings of disease activity (3). Our study is limited by the retrospective design, the missing clinical records in some patients, and the absence of data on inter- and intraobserver agreement; however, a good reliability of sonography in RA patients was reported previously (20,30). In clinical routine, we restricted the sonographic examination to 22 joints, rather than investigating all 28 joints included in current composite scores. The bulk of the disease is often found in wrists, MCP, and PIP joints, and time constraints would have made a 28-joint assessment (that requires undressing of each patient) by sonography impractical in a routine clinical setting (24). Previous studies revealed that reduced ultrasound joint counts have a high sensitivity to detect patients with active inflammation, and the assessment of wrists and 2nd and 3rd MCP joints had a sensitivity of 85% to retrieve patients with positive PD signals in a 44-joint ultrasound count (30-32). As this study was cross-sectional, we had no possibility of comparing clinical findings between patients with and without sustained (usually for 6 months) ultrasound remission and to investigate prognostic values of PD, SH/E, and global ultrasound scores at different stages of disease activity. Besides, the low number of patients in clinical remission defined by the new ACR-EULAR criteria restricts possible conclusions for that group. These issues require further investigations. The duration of MS was not assessed on a visual analog scale as incorporated in the Rheumatoid Arthritis Disease Activity Index (27), and we did not question for the severity of MS as had been done in previous clinical studies (33,34). Whether these methods for the assessment of MS are more useful in ultrasound studies than our approach must be addressed by future studies. Sonographically defined remission and active disease are associated with CRP and MS. Current composite

6 766 Ultrasound-defined remission and active disease in RA scores and their clinical components did not match this definition, thus questioning the value of clinical indices to predict the absence of inflammation. Future research is required to compare the relevance of sonographic and clinical remission assessments (particularly the new ACR- EULAR remission criteria) for radiographic and functional outcomes in RA. APPENDIX: SUPPLEMENTARY DATA Supplementary data associated with this article can be found, in the online version, at doi: /j.semarthrit REFERENCES 1. Aletaha D, Smolen J. The Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI): a review of their usefulness and validity in rheumatoid arthritis. Clin Exp Rheumatol 2005;23(Suppl 39):S Schirmer M, Duftner C, Schmidt WA, Dejaco C. Ultrasonography in inflammatory rheumatic disease: an overview. Nat Rev Rheumatol 2011;7: Scirè CA, Montecucco C, Codullo V, Epis O, Todoerti M, Caporali R. 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