Clinical and laboratory assessment.
Patient demographics and RA features, including the presence of rheumatoid factor (RF; by nephelometry, positive at >20 IU), anti–citrullinated protein antibodies (ACPAs; by second-generation commercial enzyme-linked immunosorbent assay [Immunoscan RA, Euro-Diagnostica], positive at >25 IU), and radiographic structural damage in the hands or feet, were recorded at study entry. Patients were evaluated for disease activity according to the DAS28 and SDAI criteria by the same investigator in each case (IDlT), who was blinded to previous clinical and laboratory data except the physician-determined remission status established as the inclusion criterion. In addition, functional ability was assessed with a self-assessment Spanish version of the Health Assessment Questionnaire (HAQ). Data on serum markers of inflammation (C-reactive protein level, normal range 0–0.5 mg/dl, and erythrocyte sedimentation rate, normal range 10–20 mm/hour) were obtained from laboratory tests performed on the day of the clinic visit. Clinical remission was defined by 2 criteria: either a DAS28 <2.6 (20) or an SDAI <3.3 (21).
Each patient underwent a B-mode and PD assessment by a rheumatologist experienced in musculoskeletal US (EN), blinded to the clinical, laboratory, and radiographic data, on the day of the clinic visit. To reduce the possibility of bias, the patients were asked not to talk about their clinical data to the US examiner. We maximized the level of darkness in the examination room.
The US assessment consisted of a systematic longitudinal and transverse multiplanar examination of 44 joints using a real-time scanner (Mylab 70 XVG, Esaote) equipped with 2 multifrequency linear array transducers, a 6–18-MHz transducer for superficial areas, and a 4–13-MHz transducer for deep areas.
The following bilateral joints were investigated for the presence of B-mode synovial hypertrophy (SH) and synovial PD signal: glenohumeral (i.e., posterior and axillary recesses and biceps sheath), elbow (i.e., anterior and posterior recesses), wrist (i.e., radiocarpal, midcarpal, distal radioulnar, and ulnar-carpal; dorsal recesses), second through fifth metacarpophalangeal (MCP; i.e., dorsal and palmar recesses), second through fifth proximal interphalangeal (PIP) of the hands (i.e., dorsal and palmar recesses), hip (i.e., anterior recess), knee (i.e., anterior and parapatellar recesses), ankle (i.e., tibiotalar, anterior recess, and subtalar, medial, and lateral recesses), and second through fifth metatarsophalangeal (MTP; i.e., dorsal recess). We considered the wrist SH or synovial PD signal positive if it was detected in the radiocarpal, midcarpal, distal radioulnar, or ulnar-carpal joints. We also considered the ankle SH or synovial PD signal positive if it was detected in either the tibiotalar or the subtalar joints.
B-mode and PD machine settings were optimized before the study and standardized for the entire study. These settings were as follows: B-mode frequency of 10–18 MHz, B-mode gain of 56–62%, Doppler frequency of 6.3–14.3 MHz, Doppler gain of 45–62%, low-wall filters, and pulse repetition frequency of 500–750 Hz, depending on the depth of the anatomic area.
B-mode SH was identified according to the Outcome Measures in Rheumatology definitions as the presence of abnormal hypoechoic (relative to subdermal fat) intraarticular tissue that is nondisplaceable and poorly compressible (22). At each synovial recess, B-mode SH was scored semiquantitatively on a scale of 0–3 (where 0 = absent, 1 = mild, 2 = moderate, and 3 = marked). Synovial PD signal was also scored on a semiquantitative scale of 0–3 (where 0 = absent [no synovial flow], 1 = mild [≤3 PD signals], 2 = moderate [3 PD signals in less than half of the synovial area], and 3 = marked [>3 PD signals in more than half of the synovial area]) (23). Each joint was scored for B-mode SH and synovial PD signal on a scale from 0–3. These scores corresponded to the maximum score for SH and PD signal, respectively, obtained from any one of the synovial sites evaluated at each joint. The wrist and ankle SH and PD signal scores corresponded to the maximum score for these parameters, respectively, obtained from any of the joints evaluated at the above joint regions. A global index for B-mode SH (SHI; range 0–108) and a global index for synovial PD signal (PDI; range 0–108, the sum of the B-mode SH and synovial PD signal scores, respectively, obtained for each evaluated joint or joint region) were calculated for each patient (23–26). The time spent on the US assessment was 20–30 minutes.
We calculated the SHI and PDI for different models of joint combinations as follows: large joints (i.e., bilateral glenohumeral, elbow, wrist, hip, knee, and ankle joints), wrist and hand joints (i.e., bilateral wrist, MCP 2–5, and PIP joints 2–5), reduced wrist and hand joints (i.e., bilateral wrist and MCP joints 2–5), and wrist, MCP, ankle, and MTP joints (i.e., bilateral wrist, MCP 2–5, ankle, and MTP joints 2–5). In addition, we calculated the above scores for the 12-joint US assessment (i.e., bilateral elbow, wrist, MCP 2 and 3, knee, and ankle joints) (24), the 7-joint US assessment (i.e., wrist, MCP 2 and 3, PIP 2 and 3 of the clinically dominant hand, and MTP joints 2 and 5 of the clinically dominant foot) (25), and the 6-joint US assessment (i.e., bilateral wrist, MCP 2, and knee joints) (26), which had been previously validated in published studies on RA therapy monitoring.