M. Gärtner

Sonographic Joint Assessment in Rheumatoid Arthritis: Associations With Clinical Joint Assessment During a State of Remission†

OBJECTIVE Sonography, as compared with clinical assessment, is a sensitive tool for evaluating synovitis in rheumatoid arthritis (RA). However, differences between these assessment tools may depend on how joint activity (i.e., an active joint) is defined. The present study was undertaken to compare clinically active joints with sonographically active joints in patients with RA, applying different sonographic definitions of an active joint. METHODS Sonographic assessment of the finger and wrist joints (total of 11 joints) of each hand was performed in RA patients whose disease was in remission (Clinical Disease Activity Index ≤2.8; n = 60). Gray-scale (GS) and power Doppler (PD) ultrasound signals for synovitis were evaluated on a 4-point scale (grade 0 = none, grade 3 = severe). The sensitivity and specificity of swollen joint counts were investigated using, as reference, increasingly stringent sonographic definitions of an active joint. Sonographic findings were also assessed for correlations with other clinical variables, including the Health Assessment Questionnaire (HAQ) disability index (DI). Followup analyses were performed after 6-12 months. RESULTS GS ultrasound signals yielded positive findings for synovitis in 67.2% of the 1,320 joints assessed, and PD ultrasound signals indicated signs of synovitis in 20.4% of the joints assessed. Clinical identification of joint swelling was 100% specific for sonographic joint activity, independent of the stringency of the sonographic definition used; maximum sensitivity of the swollen joint counts was 25% for the most stringent definition (i.e., GS grade 3 and PD grade 3). Furthermore, patients with a higher-grade PD signal (grade 3) showed a higher HAQ DI score compared to patients with lower-grade PD signals (mean ± SD HAQ DI 0.45 ± 0.62 versus 0.20 ± 0.35). A higher grade of PD signal at baseline was found in joints that were assessed as clinically swollen at the consecutive followup visit. CONCLUSION Low-grade PD and GS ultrasound signals may not necessarily reflect the presence of active synovitis in RA joints. High-grade PD signals correlate well with the presence of clinical joint swelling and clinical disease activity, and a higher grade of PD signal is associated with higher degrees of functional impairment.

The zymogen granule protein 2 (GP2) binds to scavenger receptor expressed on endothelial cells I (SREC-I).

The pancreatic zymogen granule membrane protein (GP2) is expressed by pancreatic acinar cells and M cells of the ileum. GP2 is the closest related homologue of the urine resident Tamm–Horsfall protein (THP). Recently, it was shown that THP is a ligand of various scavenger receptors (SRs). Therefore, we were interested, if GP2 has similar properties. cDNA of different SRs was stably transfected into a murine thymoma cell line. GP2 was recombinantly expressed, purified and biotinylated. Binding or uptake of GP2 by transfected cells or monocyte-derived dendritic cells (moDCs) was analyzed by flow-cytometry. GP2 is a binding partner of the scavenger receptor expressed on endothelial cells I (SREC-I) but not of SR-AI and SR-BI. The dissociation constant (Kd) of GP2 binding to SREC-I is 41.3 nM. SREC transfected cells are able to internalize GP2. moDCs express SREC-I and also bind and internalize GP2. Inhibition of SREC-I on moDCs with anti-SREC-I antibodies does not result in a decreased GP2 binding. Interaction of GP2 with SREC-I and uptake might have profound effects in antigen clearance and mediation of the immune response. In addition to SREC-I other presently unknown receptors for GP2 on DCs might be involved in this process.

Persistence of subclinical sonographic joint activity in rheumatoid arthritis in sustained clinical remission

Background Sonographic assessment, measuring grey scale (GS) and power Doppler (PD) signals, is a sensitive tool for the evaluation of inflammatory joint activity in patients with rheumatoid arthritis (RA). We evaluated the persistence of PD and GS signals in previously clinically active RA joints that have reached a state of continuous clinical inactivity. Methods We performed sonographic imaging of 22 joints of the hands of patients with RA, selected all joints without clinical activity but showing ongoing sonographic signs of inflammation, and evaluated the time from last clinical joint activity. Results A total of 90 patients with RA with 1980 assessed joints were included in this study. When comparing the mean time from clinical swelling, we found a significantly longer period of clinical inactivity in joints showing low sonographic activity (mean±SD time from swelling of 4.1±3.2 vs 3.1±2.9 years for PD1 vs PD≥2, p=0.031 and 4.5±3.4 vs 3.3±3.2 years for GS1 vs GS≥2, p≤0.0001). Conclusions We conclude that subclinical joint activity is long-lasting in RA joints in clinical remission, but attenuates over time. The latter conclusion is based on the observed shorter time duration from last clinical activity for strong compared with weaker sonographic signals.

Quantification of α-galactosidase activity in intact leukocytes.

BACKGROUND Mutations of the α-galactosidase (α-Gal) A gene in Fabry disease lead to a severe disturbance in glycosphingolipid catabolism. The atypical clinical picture of Fabry disease hampers diagnosis, resulting in a delayed start of therapy. Current tests utilize leukocyte lysates to evaluate the activity of α-Gal A. It has never been investigated whether cell homogenisation is necessary. METHODS Isolated leukocyte subsets were incubated with the α-Gal substrate methylumbelliferyl-α-D galactopyranosid (MU-Gal) and substrate conversion was measured by fluorimetry. Specificity of the reaction was evaluated using the α-Gal inhibitor deoxygalactonojirimycin (DGJ). The novel procedure was compared to the standard method. A reference population and Fabry patients were tested. RESULTS Substrate conversion in intact leukocytes was a function of substrate concentration, cell number and time and could be inhibited by DGJ. Monocytes showed the highest enzyme activity among leukocyte populations. The novel procedure highly correlated with the standard method. Both Fabry hemizygotes and heterozygotes showed reduced substrate conversion. CONCLUSION We here present a novel sensitive, fast and simple procedure for the evaluation of α-Gal activity suitable to identify enzyme deficiencies in Fabry patients. Furthermore, we show for the first time that leukocyte subtypes have different α-Gal activities.

Clinical joint inactivity predicts structural stability in patients with established rheumatoid arthritis

Objectives Clinical joint activity is a strong predictor of joint damage in rheumatoid arthritis (RA), but progression of damage might increase despite clinical inactivity of the respective joint (silent progression). The aim of this study was to evaluate the prevalence of silent joint progression, but particularly on the patient level and to investigate the duration of clinical inactivity as a marker for non-progression on the joint level. Methods 279 patients with RA with any radiographic progression over an observational period of 3–5 years were included. We obtained radiographic and clinical data of 22 hand/finger joints over a period of at least 3 years. Prevalence of silent progression and associations of clinical joint activity and radiographic progression were evaluated. Results 120 (43.0%) of the patients showed radiographic progression in at least one of their joints without any signs of clinical activity in that respective joint. In only 7 (5.8%) patients, such silent joint progression would go undetected, as the remainder had other joints with clinical activity, either with (n=84; 70.0%) or without (n=29; 24.2%) accompanying radiographic progression. Also, the risk of silent progression decreases with duration of clinical activity. Conclusions Silent progression of a joint without accompanying apparent clinical activity in any other joint of a patient was very rare, and would therefore be most likely detected by the assessment of the patient. Thus, full clinical remission is an excellent marker of structural stability in patients with RA, and the maintenance of this state reduces the risk of progression even further.

SAT0356 Predictive Utility of Anti-Citrullinated Peptide Antibodies and Rheumatoid Factor – a Retrospective Data Analysis

Background Antibody profiling encompassing rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPA) supports diagnosis in patients with Rheumatoid arthritis (RA). However, RF and ACPA are not specific for RA, and predictive values of tests depend heavily on the selection of individuals in which such tests are performed. Because testing for these antibodies is frequently ordered by non-Rheumatologists, at substantial costs, we sought to determine the predictive values of such testing in patients of a large tertiary hospital. Objectives To evaluate the positive and negative predictive values (PPV, NPV) of RF and ACPA tested in a pre-selected population of all patients of the Vienna general hospital between 2006 and 2012. Methods Results of all RF and ACPA tests performed between 2006 and 2012 were obtained from the Department of Laboratory Medicine and the ordering departments were determined. Diagnoses were extracted from the hospital-wide database. Results Between 2006 and 2012 more than 45,000 RF and ACPA tests in 5496 patients were performed. Among these, 21% were positive for RF, 3% for ACPAs and 22% were positive for both antibodies. For 2250 patients (41% of all patients in whom RF/ACPA was tested) the tests were not ordered by the Department of Rheumatology. The tests were requested by the Departments of Infectiology (32.5%), Angiology (11.1%), Orthopedics (8%), Nephrology (8%), and Dermatology (7%). 1572 of these 2250 patients had a documented diagnosis. Figure 1 shows the distribution of diseases according to the ICD-10. Among the 2250 patients 134 (6%) were positive for RF, 72 (3.2%) for ACPA and 31 (1.4%) patients tested positive for both antibodies. PPV and NPV for the presence of musculoskeletal diseases were 22.4% and 89.9% for RF and 26.4% and 88.8% for ACPA testing. However, for presence of chronic inflammatory musculoskeletal diseases (ICD-10-Codes M05.X to M09.X and M30.X to M35.X) PPV was only 11.9% for RF and 16.7% for ACPA. NPV was 95.3% and 95.2%, respectively. Conclusions RF and ACPA testing was frequently ordered by non-Rheumatologists. In this patient group, we found a relatively high NPV (95%) but a very low PPV of 11-17%. Thus, >83% of positive tests did not contribute to a diagnosis of inflammatory musculoskeletal disease. This observation underscores the necessity to use such testing only in the appropriate clinical context. Disclosure of Interest None declared

Reply: To PMID 23686535.

of clinical assessment itself, which is clearly subjective. Second, the authors report that the Health Assessment Questionnaire (HAQ) disability index (DI) (4) was associated with clinical but not sonographic findings. However, detailed results on the correlation of global sonographic findings (e.g., total scores or scores on a sonography-based clinical disease activity index) with the HAQ DI or change in the HAQ DI are needed in order to assess the superiority of clinical measures to sonographic ones, especially given that the sample size for individual patients was limited (n 60) and the subanalysis (Table 3 in Gärtner and colleagues’ report) may not represent the true associations. In addition, treatment information is necessary for accurate interpretation of the association between synovitis and functional outcome, given the effect of nonsteroidal antiinflammatory drugs (5), corticosteroids, and tumor necrosis factor antagonists (6). Third, more detailed information on the methods used for the longitudinal analysis (e.g., interval or treatment modification) would be helpful for accurate interpretation. We are particularly interested in whether the physicians were blinded with regard to the baseline ultrasound findings since if they were not, the presence of inflammation seen on sonography could have influenced clinical decision making and resulted in treatment escalation, weakening the association of sonographic findings with relapse. As Gärtner et al discuss, a more comprehensive sonographic assessment including other joints (e.g., large joints), other views (e.g., palmar aspect), and other synovial tissues (e.g., tenosynovium) could have demonstrated a closer association with disability, and furthermore, radiographic data would have been informative, as previous studies have shown (2,6,7). We completely agree with the authors that more detailed assessment of sonographic data is needed to fully understand the value of ultrasound in the management of RA. Drs. Ikeda’s and Koike’s authorship is on behalf of the Japan College of Rheumatology Committee for the Standardization of Musculoskeletal Ultrasonography.

SAT0053 Persistence of Subclinical Joint Activity in Rheumatoid Arthritis Joints

Background Ultrasound (US) assessment was shown to be a sensitive tool for the evaluation of joint activity in patients with rheumatoid arthritis (RA). Synovial effusion and synovial hypertrophy can be evaluated by gray scale (GS), while hypervascularisation, as a marker of inflammation, can be measured using power Doppler signals (PD). Both types of signals are highly sensitive, and may persist even in clinical inactivity, i.e. when swelling or tenderness are absent. It is conceivable that such subclinical US signals may resolve if clinical inactivity is sustained, but this has not yet been shown during long-term follow-up. Objectives To investigate the persistence of subclinical US signals in previously clinically active joints in relation to prolonged clinical inactivity. Methods We performed US imaging including GS and PD, each graded on a four point scale (0=no, 1=mild, 2=moderate and 3=marked) of 22 joints of the hands of RA patients. We then selected all joints with no clinical activity at the time of the US examination. Based on a routine clinic database with 3-monthly joint assessments, the last time point of clinical joint activity (swelling, tenderness or both) was identified. The time between the last clinical joint activity and the current sonographic assessment in that joint was determined and persistence of subclinical US activity was estimated for all patients and all joints. Results We assessed a total of 1980 joints in 90 RA patients. 1329 (67.1%) joints were positive on GS and 410 (20.7%) showed PD signals. The median (IQR) time between the last visit exhibiting swollen or tender joint(s) and the US assessment showing PD/GS-signals in the same now clinically inactive joint(s) was 3.6 (1.2; 6.3) and 3.5 (1.3; 5.6) years, respectively. We found that the time between last clinical activity (swelling and/or tenderness) and positive sonographic assessment was significantly shorter in joints showing GS signals ≥2 than in joints with GS=1 (median [IQR] 2.6 [0.6; 2.6] vs. 3.9 [1.9; 6.6]; p<0.001), for PD signals there was also a trend towards shorter periods of clinical remission in highly active joints (median [IQR] of 2.4 [0.5; 5.3] for PD≥2 vs. 4.3 [1.0; 6.2] for PD=1; p=0.066). In joints showing highly positive GS and PD signals (both ≥2), the time to the last clinical activity was even shorter, with a median of 1.4 years. (Figure 1) Figure 1. Kaplan Meier curve for subclinical sonographic activity in joints showing GS ≥2 and PD signals. GS, grey scale; PD, power Doppler. Conclusions We conclude that subclinical joint activity is long lasting in RA joints in clinical remission, but resolves over time. The latter is indicated by a shorter period from last clinical activity for strong signals (PD ≥2, GS ≥2) as compared to weak signals (PD ≤1, GS ≤1). Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.3247

AB0185 Clinical joint involvement is decisive for radiographic progression

Background Today’s therapeutic targets in rheumatoid arthritis (RA) are remission or low disease activity, but it was shown that joint damage may continue to progress despite these favourable clinical states.1;2 While progression of joint damage is related to joint swelling,3;4 radiographic damage may progress even without evidence of clinical synovitis, at least in early RA.5 Objectives To evaluate the frequency of radiographic progression in clinically persistently inactive joints of patients with established RA. Methods We included 80 random RA patients (mean disease duration: 7.32±9.78 yrs.) with radiographic progression (increase≥1) by the Sharp van der Heijde (SvdH) score over an observational period of at least three to a maximum five years. To conform with the records of clinical joint assessment, we only considered radiographic progression in any of the 22 hand/finger joints (10 proximal interphalangeal joints[PIP], 10 metacarpophalangeal joints[MCP], and the 2 wrists), but excluded the feet (not assessed by the 28 joint count). Clinical data on individual joints (swelling and tenderness) from each clinical visit performed between one year prior to the baseline x-ray until the time of the x-ray endpoint were collected from the patient charts. We evaluated whether there are joints showing radiographic progression despite clinical inactivity and compared them to progressing joints that were clinically active. Further, patients with radiographic progression in clinically inactive joints were compared to those with clinical activity. Results The mean±SD time between x-rays was 3.51±0.41 yrs and the mean number of clinical visits per patient was 16.3±4.32. A total of 104 (5.9%) of the 1760 evaluated joints showed progression in erosions and 206 (12.8%) worsened in joint space narrowing (JSN). Of all joints with progression in erosions, 30 (28.8%) were never swollen during the observation period (in 19 patients), 16 (53.3%) were never swollen in the total patient history, and only 7 (6.7%) never showed any activity also by tenderness. In the total patient population, progression was higher in joints with clinical swelling (during the observation period) compared to joints without swelling (2.36±1.7 vs 1.76±1.62). The number of visits with swelling correlated to a low but significant extent with the rate of radiographic progression (r=0.13; p<0.01). The overall sensitivity for progression of damage of any joint activity during the observation period was 78.8% for erosion, and 77.7% for JSN. Sensitivity increased to >90% when including ever clinically active joints since onset of disease. Conclusions Only 7% of joints with radiographic progression in patients with established RA show consistent lack of clinical activity, and these joints show a low degree of progression. Thus, radiographic progression despite lacking clinical activity is a negligible event on the joint level. Clinical joint involvement is decisive for progression of joint damage and continues to be a highly predictive outcome measure for monitoring patients with RA. References Aletaha D et al. Arthritis Rheum 2009; 60(5):1242-1249. Molenaar ET et al. Arthritis Rheum 2004; 50(1):36-42. Aletaha D et al. Ann Rheum Dis 2011; 70(11):1975-1980. van Riel PL et al. J Rheumatol 1995; 22(9):1797-1799. Klarenbeek NB et al. Ann Rheum Dis 2010; 69(12):2107-2113. Disclosure of Interest None Declared

SAT0474 Differences of clinical and ultrasound (US) remission in rheumatoid arthritis (RA) depend on the stringency of the us methodology

Background Progression of joint damage in RA occurs primarily in joints that are clinically swollen, and repair is seen only in joints with no clinical swelling.1;2 On the other hand, joints exhibiting US but not clinical swelling may progress radiologically despite clinical remission.3 This discrepancy requires elucidation to understand the value of clinical compared with US joint assessment, since except for histology, there is no true gold standard for US joint activity. Objectives To evaluate the differences in number of clinically and US active joints in RA, with special regards to the impact of US definitions of activity. Methods We performed US imaging of 22 joints of the hands of RA patients in clinical remission (CDAI≤2.8). Each joint was assessed for grey scale synovial hypertrophy (GSSH; 0=no hypertrophy; 1=hypertrophy) and power Doppler (PD) signal (0= no hyperaemia, 1= mild, 2=moderate, 3=marked). We investigated the sensitivity and specificity of clinically swollen joints (SJC) for presence of US changes and repeated this analysis using different cut points and combinations of US definitions. We further assessed changes of CDAI if clinical SJC were replaced by US active joints. Results Of the 58 patients in clinical remission, 96.6% had GSSH and 93.1% had positive PD signals. The sensitivity and specificity of clinical SJC for any US abnormality (GSSH>0 or PD>0) was 1.7% and 100%, respectively. When we used more stringent definitions of US activity (GSSH>0 & PD=3), these values changed to 22.2% and 99%. Replacing clinical by US counts in the calculation of CDAI, the US CDAI values approached the clinical CDAI with increasing stringency of the definition used (Fig.). In fact, the most stringent definition (GSSH>0 & PD=3) revealed identical average values as seen in the clinical CDAI. Conclusions Low PD signals increase the numbers of patients classified as having active joints and lead to a poor sensitivity of clinical assessment in comparison to US assessment. When the PD signal is combined with assessment of GSSH, or the strength of the PD signal is considered, the differences decrease, particularly when looking at their impact on composite indices. The relevance of this finding will have to be tested in relation to radiographic progression of joint damage. References Klarenbeek NB et al. ARD 2010; 69(12):2107-2113. Lukas C et al. ARD 2010; 69(5):851-855. Brown AK et al. Arthritis Rheum 2008; 58(10):2958-2967. Disclosure of Interest None Declared