Patients
The present study is part of the ongoing Genetics, Osteoarthritis, and Progression (GARP) study [14]. The primary goal of GARP is to determine risk factors for OA development and disease progression. Probands, aged between 40 and 70 years, and their siblings (n = 382), with symptomatic OA at multiple sites were eligible after giving informed consent. Sibling pairs (n = 210) with at least one subject having symptomatic hip OA or knee OA (but not radiological end-stage disease defined as a Kellgren and Lawrence (KL) score of 4 [15]) were followed for 2 years. Of the 210 patients at baseline, 186 completed the 2-year follow-up with complete data and were thus included. Median age was 60.2 years; 150 were female, and mean body mass index (BMI) was 26.5 kg/m2 (Table 1). Of the included patients, 74 had definite knee OA as defined by a KL score of 2 or more. Our institution's medical ethical review board approved the study.
Table 1 Demographics of 186 patients with OA at multiple sites and characteristics of imaged knees in these subjects
Diagnosis of osteoarthritis
Subjects were included with symptomatic OA at two or more of the following joints sites: hand, spine (cervical or lumbar), knee, or hip defined by the presence of radiographic OA in any of the four joints groups, or for the hands the presence of two or more Heberden nodes, Bouchard nodes, or squaring of at least one first carpometacarpal (CMCJ1) joint on physical examination.
Symptomatic OA in the knee and hip was defined according to the American College of Rheumatology recommendations for knee and hip OA [16, 17]. Knee OA was defined as pain or stiffness for most days of the preceding month and osteophytes at the joint margins of the tibiofemoral joint (X-ray spurs). Hip OA was defined as pain or stiffness in the groin and hip region on most days of the preceding month in addition to femoral or acetabular osteophytes or axial joint space narrowing on radiography. Prosthetic joints in the hips or knees as a result of end-stage OA were defined as OA in that particular joint.
Radiograph acquisition
The standardized, nonfluoroscopic, fixed-flexion protocol was used in a single center to obtain posteroanterior weight-bearing radiographs of the knee at baseline and after 24 months [18]. Uniform anatomical alignment of the knees was facilitated by the use of a specifically designed positioning frame (Synaflexer®, San Francisco, USA) [18] that places the patient’s feet in 5° of external rotation, the knees and thighs in contact with the cassette and coplanar with the hips and tips of the great toes, resulting in a fixed knee angulation of approximately 20° flexion. The X-ray tube was angled to point 10° downwards and the knees were exposed to the X-ray beam centered at the joint line. Radiographic severity of knee OA at baseline was scored according to the KL score [15]. The intraclass correlation coefficient for reproducibility was 0.92 [14].
Radiographic progression
Baseline and 2-year knee radiographs were scored for medial JSW on a scale of 0 (normal)–3 (total JSN) with help of the Osteoarthritis Research Society International (OARSI) atlas [19, 20] by two experienced readers (respectively 3 and 30 years of experience) reading in consensus. In cases of disagreement, the lower, more conservative score was adopted. An increase of at least 1 grade between baseline and follow-up was considered to be radiographic progression. The observers were blinded to clinical information such as age, gender, and time sequence.
MRI acquisition
Knees were imaged using a dedicated knee coil in a 1.5-T magnet (Philips Medical Systems, Best, the Netherlands). Each examination consisted of the following sequences, optimized for software available at time of inclusion from 2002 to 2005: (1) Coronal proton density (PD) and T2-weighted dual spin echo (SE) sequence (repetition time (TR) of 2,200, an echo time (TE) of 20/80, 5-mm slice thickness, 0.5-mm intersection gap, 160-mm field of view (FOV), and 205 × 256 acquisition matrix); (2) sagittal PD and T2-weighted dual SE images (TR 2,200, TE 20/80, 4-mm slice thickness, 0.4-mm intersection gap, 160-mm FOV, 205 × 256 acquisition matrix); (3) sagittal 3D T1-weighted spoiled gradient echo (GE) frequency-selective fat-suppressed images (TR 46, TE 2.5, flip angle 40°, 3.0-mm slice thickness, slice overlap 1.5 mm, no gap, 180-mm FOV, 205 × 256 acquisition matrix); (4) axial proton density and T2-weighted turbo SE fat-suppressed images (TR 2,500, TE 7.1/40, echo train length 6, 2-mm slice thickness, no gap, 180-mm FOV, 205 × 256 acquisition matrix). The total acquisition time (including the initial survey sequence) was 30 min.
MR images at baseline of the knee were performed successfully in 205 of 208 patients. One patient was excluded due to claustrophobia, and in two others image quality was inadequate due to motion artifacts.
MRI interpretation
All MR images were analyzed by means of consensus between three readers. During the assessment, the readers were blinded to radiographic results, patient symptoms, patient age, and other clinical data. A published knee OA scoring system (KOSS) was used to assess osteoarthritic defects [21]. The MR images of patients including a 2-year follow-up MRI were assessed simultaneously using the ΔKOSS [21].
Cartilaginous defects and BML were assigned to any of the following anatomical locations: the crista patellae, medial or lateral patellar facet, the medial or lateral trochlear facets, the medial or lateral femoral condyle, and the medial or lateral tibial plateau. The medial and lateral menisci were reviewed for the presence of meniscal tears and/or subluxation out of the joint line.
Cartilaginous defects were graded as diffuse or focal. The coronal and sagittal SE images and sagittal GE images were used to assess the tibiofemoral cartilage. Axial turbo SE images and sagittal GE and SE images were used to assess patellofemoral cartilage. The surface extent of a diffuse or focal cartilaginous defect was classified by its maximal diameter and was graded as follows: grade 0, absent; grade 1, minimal (<5 mm); grade 2, moderate (5–10 mm); grade 3, severe (>10 mm). The depth of a cartilaginous defect was graded using a modification of the Yulish classification [22]: grade 0, absent; grade 1, <50% reduction of cartilage thickness; grade 2, >50% reduction of cartilage thickness; grade 3, full thickness or nearly full thickness cartilage defect.
A BML was defined as an ill-defined area of increased signal intensity on T2-weighted images in the subchondral bone, extending away from an articular surface or at places where traction changes occur [23]. The lesions were graded as follows: grade 0, absent; grade 1, minimal (<5 mm); grade 2, moderate (5–2 cm); grade 3, severe (>2 cm).
A meniscal tear was defined as a region of intermediate signal intensity on PD-weighted images within the meniscus, communicating with its superior and/or inferior surfaces or inner margin, on more than one slice [24]. The meniscal roots were examined also.
Meniscal subluxation was defined as protrusion over the edge of the tibial plateau seen at the level of the body of the meniscus on coronal PD-weighted images and was graded as follows: grade 0, absent; grade 1, minimal (<1/3 width of the meniscus bulging); grade 2, moderate (1/3–2/3 meniscal width involved); grade 3, severe (>2/3 meniscal width involved).
Osteophytes were defined as focal bony excrescences, seen on axial, sagittal, or coronal images, extending from a cortical surface. Osteophytes were further specified as being marginal, intercondylar, or central. Osteophytes were assessed using the following scale: grade 0, absent; grade 1, minimal (<3 mm); grade 2, moderate (3–5 mm); grade 3, severe (>5 mm) [25].
Subchondral cysts were defined as well-defined foci of high signal intensity on T2-weighted images, in the cancellous bone underlying the joint cartilage. Their greatest dimension was measured and they were graded as follows: grade 0, absent; grade 1, minimal (<3 mm); grade 2, moderate (3–5 mm); grade 3, severe (>5 mm).
The presence of joint effusion was evaluated on T2-weighted coronal, sagittal, and axial sequences. A joint effusion was assumed to be absent when only a small physiological sliver of synovial fluid was observed. A small effusion was scored as present when a small amount of fluid distended one or two of the joint recesses (suprapatellar pouch, medial or lateral patellar recess, dorsal tibiofemoral joint space, popliteal tendon sheath, recesses surrounding the cruciate ligaments, meniscosynovial recesses), a moderate effusion when more than two joint recesses were partially distended, and massive effusion when full, marked distention of all the joint recesses was present.
Statistical analysis
Logistic regression analysis was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to determine a relation between MR parameters seen at baseline and JSN on radiographs 2 years later for the entire population and separately for the KL < 2 group and KL ≥ 2 of patients. The ORs were adjusted for sex, age, BMI, and family effect using STATA 8.0 for Windows (STATA Corp, TX, USA). These ORs were then converted to relative risks (RR) and 95% CI were calculated also using the formula described by Zhang and Yu [26].
In patients showing JSN, the baseline grades were subtracted from the scores 2 years later. For cartilage, change in either diffuse thinning or focal thinning on either the femur or tibia facet was considered to be progression. This was also the case for osteophytes, BML, and subchondral cysts. For meniscal tears and subluxation, progression was considered to be a new tear or extension of the original tear into any of the other compartments (anterior, body, or posterior). This was analyzed also by subtracting the baseline score from the score 2 years later.