OARSI Clinical Trials Recommendations: Hip imaging in clinical trials in osteoarthritis.

Imaging of hip in osteoarthritis (OA) has seen considerable progress in the past decade, with the introduction of new techniques that may be more sensitive to structural disease changes. The purpose of this expert opinion, consensus driven recommendation is to provide detail on how to apply hip imaging in disease modifying clinical trials. It includes information on acquisition methods/techniques (including guidance on positioning for radiography, sequence/protocol recommendations/hardware for magnetic resonance imaging (MRI)); commonly encountered problems (including positioning, hardware and coil failures, artifacts associated with various MRI sequences); quality assurance/control procedures; measurement methods; measurement performance (reliability, responsiveness, and validity); recommendations for trials; and research recommendations.

Inhibition of joint damage and improved clinical outcomes with rituximab plus methotrexate in early active rheumatoid arthritis: the IMAGE trial.

OBJECTIVES: Rituximab is an effective treatment in patients with established rheumatoid arthritis (RA). The objective of the IMAGE study was to determine the efficacy of rituximab in the prevention of joint damage and its safety in combination with methotrexate (MTX) in patients initiating treatment with MTX. METHODS: In this double-blind randomised controlled phase III study, 755 MTX-naïve patients with active RA were randomly assigned to MTX alone, rituximab 2×500 mg + MTX or rituximab 2×1000 mg + MTX. The primary end point at week 52 was the change in joint damage measured using a Genant-modified Sharp score. RESULTS: 249, 249 and 250 patients were randomly assigned to MTX alone, rituximab 2×500 mg + MTX or rituximab 2×1000 mg + MTX, respectively. At week 52, treatment with rituximab 2×1000 mg + MTX compared with MTX alone was associated with a reduction in progression of joint damage (mean change in total modified Sharp score 0.359 vs 1.079; p=0.0004) and an improvement in clinical outcomes (ACR50 65% vs 42%; p<0.0001); rituximab 2×500 mg + MTX improved clinical outcomes (ACR50 59% vs 42%; p<0.0001) compared with MTX alone but did not significantly reduce the progression of joint damage. Safety outcomes were similar between treatment groups. CONCLUSIONS: Treatment with rituximab 2×1000 mg in combination with MTX is an effective therapy for the treatment of patients with MTX-naïve RA. ClinicalTrials.gov identifier NCT00299104.

Rituximab inhibits structural joint damage in patients with rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitor therapies.

OBJECTIVE: To determine if treatment with a B cell-targeted therapy can inhibit the progression of structural joint damage in patients with rheumatoid arthritis (RA), exhibiting an inadequate response to tumour necrosis factor (TNF) inhibitors. METHODS: In this phase III study, patients with an inadequate response to a TNF inhibitor and receiving methotrexate were randomised to rituximab or placebo. Radiographs were obtained at baseline, week 24 and week 56 after randomisation. Patients with an inadequate response to their randomised therapy could receive rescue medication from week 16. From week 24, eligible patients from both treatment arms could receive open-label rituximab. Patients were analysed according to their original treatment group. Radiographs were scored using the Genant-modified Sharp method. The primary radiographic endpoint was change in total Genant-modified Sharp score at week 56. RESULTS: Rituximab treatment caused significant reduction in joint damage progression compared with placebo. The mean change from baseline in the total Genant-modified Sharp score at week 56 was significantly lower for patients treated with rituximab than for patients treated with placebo (1.00 vs 2.31; p = 0.005), and was supported by changes in erosion score (0.59 and 1.32 for rituximab plus methotrexate vs placebo plus methotrexate, respectively; p = 0.011) and joint space narrowing score (0.41 and 0.99, respectively; p<0.001). CONCLUSIONS: This study provides the first evidence that a B cell-targeted therapy-rituximab-can significantly inhibit the progression of structural joint damage in patients with RA with long-standing, active and treatment-resistant disease.

Abatacept inhibits progression of structural damage in rheumatoid arthritis: results from the long-term extension of the AIM trial.

OBJECTIVE: Assess the effect of abatacept on progression of structural damage over 2 years in patients with rheumatoid arthritis who had an inadequate response to methotrexate. METHODS: 539 patients entered an open-label extension of the AIM (Abatacept in Inadequate responders to Methotrexate) trial and received abatacept. Radiographic assessment of the hands and feet was performed at baseline, year 1 and year 2. At year 2, each patient's radiographs were scored for progression blinded to sequence and treatment allocation. RESULTS: In patients treated with abatacept for 2 years, greater reduction in progression of structural damage was observed in year 2 than in year 1. The mean change in total Genant-modified Sharp scores was reduced from 1.07 units in year 1 to 0.46 units in year 2. Similar reductions were observed in erosion and joint space narrowing scores. Following 2 years of treatment with abatacept, 50% of patients had no progression of structural damage as defined by a change in the total score of < or =0 compared with baseline. 56% of patients treated with abatacept had no progression during the first year compared with 45% of patients treated with placebo. In their second year of treatment with abatacept, more patients had no progression than in the first year (66% vs 56%). CONCLUSIONS: Abatacept has a sustained effect that inhibits progression of structural damage. Furthermore, the mean change in radiographic progression in patients treated with abatacept for 2 years was significantly lower in year 2 versus year 1, suggesting that abatacept may have an increasing disease-modifying effect on structural damage over time.

The osteoarthritis initiative: report on the design rationale for the magnetic resonance imaging protocol for the knee.

OBJECTIVES: To report on the process and criteria for selecting acquisition protocols to include in the osteoarthritis initiative (OAI) magnetic resonance imaging (MRI) study protocol for the knee. METHODS: Candidate knee MR acquisition protocols identified from the literature were first optimized at 3Tesla (T). Twelve knees from 10 subjects were scanned one time with each of 16 acquisitions considered most likely to achieve the study goals and having the best optimization results. The resultant images and multi-planar reformats were evaluated for artifacts and structural discrimination of articular cartilage at the cartilage-fluid, cartilage-fat, cartilage-capsule, cartilage-meniscus and cartilage-cartilage interfaces. RESULTS: The five acquisitions comprising the final OAI MRI protocol were assembled based on the study goals for the imaging protocol, the image evaluation results and the need to image both knees within a 75 min time slot, including positioning. For quantitative cartilage morphometry, fat-suppressed, 3D dual-echo in steady state (DESS) acquisitions appear to provide the best universal cartilage discrimination. CONCLUSIONS: The OAI knee MRI protocol provides imaging data on multiple articular structures and features relevant to knee OA that will support a broad range of existing and anticipated measurement methods while balancing requirements for high image quality and consistency against the practical considerations of a large multi-center cohort study. Strengths of the final knee MRI protocol include cartilage quantification capabilities in three planes due to multi-planar reconstruction of a thin slice, high spatial resolution 3D DESS acquisition and the multiple, non-fat-suppressed image contrasts measured during the T2 relaxation time mapping acquisition.

Large telangiectatic focal nodular hyperplasia presenting with normal radionuclide studies: case report.

A 9 cm-lesion of telangiectatic focal nodular hyperplasia was incidentally identified in a 31-yr-old female. Despite a typical appearance by X-ray computed tomography and ultrasonography, scintigraphy with technetium-99m-(99mTc) colloid, 99mTc-diethyliminodiacetic acid, and 99mTc-labeled red cells failed to demonstrate any abnormalities. These findings are felt to reflect the relative lack of architectural disruption that histologically characterizes this particular lesion. The present report described the imaging characteristics of the telangiectatic form of focal nodular hyperplasia.

Magnetic resonance imaging of rheumatoid arthritis: the evolution of clinical applications through clinical trials.

Powerful techniques are being developed for evaluating rheumatoid arthritis with magnetic resonance imaging (MRI). Much of this development is being driven by the pharmaceutical and biotechnology industries searching for novel therapies for this disease. Accordingly, the imaging tools that ultimately will be used to direct patients to specific therapies and then to monitor treatment effectiveness and safety are currently being refined and validated in rigorous multicenter and multinational clinical trials aimed at gaining regulatory approval of these new therapies. As these trials approach completion, rheumatologists can anticipate an increased demand for expertise and experience in evaluating disease progression and treatment response with these techniques and the emergence of MRI systems specifically designed for this market. The following discussion reviews this novel pathway for evolving imaging techniques for clinical use through clinical drug trials, lists the most promising MRI markers available today for evaluating joint destruction in rheumatoid arthritis, and speculates on how these techniques will find their way into clinical practice.

Trainable rule-based algorithm for the measurement of joint space width in digital radiographic images of the knee.

The progression of osteoarthritis (OA) can be monitored by measuring the minimum joint space width (mJSW) between the edges of the femoral condyle and the tibial plateau on radiographs of the knee. This is generally performed by a trained physician using a graduated magnifying lens and is prone to the subjectivity and variation associated with observer measurement. We have developed software that performs this measurement automatically on digitized radiographs. The test data consisted of 180 digitized radiographs of the knee (90 duplicate acquisitions) from 18 normal (nonarthritic) subjects and 38 images from 10 subjects with OA. These were digitized and manually cropped so that the images were free of nonanatomical structures and the knee was approximately centered. The software first determined the edge of the femoral condyle on 400 microm pixel subsampled images. Contours marking the location of the tibial plateau in the medial compartment were found on 100 microm images using the femoral edge as a reference. The algorithm was trained using an independent but similar data set and using a jackknife approach with the test data. The results were compared to contours drawn by a trained reader and the duplicate acquisitions were used to measure the reproducibility of the mJSW measurement. The reproducibility was 0.16 mm and 0.18 mm for normal and osteoarthritic knees, respectively, representing an improvement of approximately a factor of 2 over manual measurement. The algorithm also showed excellent agreement with the hand-drawn contours and with mJSW determined by the manual method.

Automated measurement of radiographic hip joint-space width.

Radiographic joint-space narrowing (JSN) is the principle indicator of cartilage loss in osteoarthritis (OA). JSN is usually assessed qualitatively by visual inspection or in clinical research, is measured manually with a graduated handheld lens directly applied to the x-ray film, or from digitized radiographs by hand tracing the joint margins with a mouse. The minimum joint-space width (mJSW) and joint-space area (JSA) are recorded as the indices of OA progression in epidemiological studies and clinical drug trials. We present a computerized method that automatically finds the articular margins of the hip to improve determination of mJSW and JSA. The algorithm requires that three seed points are manually identified on the femoral head and uses three steps to process each digitized hip x-ray. First, a Hough transform finds the center and radius (R) of a circle that approximates the femoral head. Finding R indicates whether magnification differences must be corrected on repeat exams. Second, a gradient algorithm finds the edge of the femoral head and acetabulum. Third, the mid-line of the femoral neck is automatically found and used to define the joint portion (theta) that is assessed for narrowing. theta is fixed for follow-up exams of the same subject. The algorithm was evaluated in three ways to determine its performance characteristics. First, the inter-reader and intra-reader variability for mJSW and JSA associated with the selection of the seed points was found to be negligible (< 1%) compared to the variability associated with manual scoring with a lens or by tracing the joint margins with a mouse. Second, from duplicate hip x-rays of 19 subjects with OA, the Root Mean Square Standard Deviation and coefficient of variation for mJSW and JSA defined by the algorithm was determined to be better than manual techniques by at least a factor of 2. Third, the algorithm correctly identified the joint margin in more than 85% of the 105 cases tested. Automated measures of radiographic hip joint-space narrowing is less subjective than manual methods and may be applicable for monitoring OA progression in clinical research.

Emerging applications of magnetic resonance imaging in the evaluation of articular cartilage.

MR imaging rapidly is emerging as a tool of unparalleled power for examining the articular cartilage and other important structures in diarthrodial joints. In addition to delineating the morphology of cartilage, MR imaging is capable of quantifying a variety of compositional and functional parameters relevant to arthritis. Moreover, because MR imaging is a nondestructive technique, multiple parameters can be analyzed in the same region of tissue and frequent serial examinations can be performed on even asymptomatic patients. This offers an unprecedented opportunity to study arthritis in ways not imaginable before and potentially to expand the envelope of MR imaging to include a population of patients for whom imaging has had relatively little to offer.

Dedicated extremity MR imaging. An emerging technology.

Dedicated extremity MR imaging represents a radical departure from conventional whole-body scanning. Extremity MR imaging offers such advantages as reduced cost, more convenient and inexpensive setting, greater patient comfort and safety, and high diagnostic power. This article examines some of the features of extremity MR imaging and how this technology is affecting musculoskeletal imaging in today's environment of cost containment and health care reform.

Recent advances in magnetic resonance imaging of the musculoskeletal system.

Numerous recent technical innovations in magnetic resonance imaging have dramatically improved the imaging evaluation of musculoskeletal disease; however, with the introduction of new techniques comes the risk of inappropriate applications and unanticipated pitfalls in interpretation. Some of the practical and theoretical implications of these recent innovations as well as potential caveats associated with their use are highlighted in the following discussion.

MR imaging of the arthritic rabbit knee joint using albumin-(Gd-DTPA)30 with correlation to histopathology.

The purpose of this study was to demonstrate a technique, in a pilot study, for measuring abnormal capillary permeability in synovial tissue of rabbit arthritic knees using dynamic MRI with a gadolinium-based blood pool agent. Arthritis, simulating rheumatoid arthritis, was induced in knees of 8 rabbits by intra-articular injection of carrageenan (n = 4) or ovalbumin (n = 4). Sequential fat presaturated T1-weighted Spoiled Grass images were obtained before and up to 30 min after intravenous administration of albumin-(Gd-DTPA)30. Estimates of synovial tissue plasma-volume (PV), fractional-leak-rate (FLR), and permeability-surface-area-product (PS) were computed. Histologic correlation was obtained in the corresponding regions. Dynamic MRI showed extravasation of albumin-(Gd-DTPA)30 into hypertrophic synovium in six of the eight arthritic knees. Histologic examination of these six knees showed markedly inflamed synovium. The two knees that did not show abnormal vascular permeability contained non-hypertrophic synovium. None of the rabbits showed abnormal permeability in muscle. MRI derived microvascular characteristics (PV, FLR and PS) correlated positively (r2 = 0.51, 0.97 and 0.86) with the histology. Factors involving the structural and functional microvascular characteristics of synovial tissue can be estimated non-invasively using albumin-(Gd-DTPA)30. This technique may be useful for monitoring disease progression and treatment response in rheumatoid arthritis.

Scratching the surface: articular cartilage disorders in the knee.

Powerful techniques with MR imaging are being developed for evaluating articular cartilage. Pharmaceutical and biotechnology development is driven largely by the search for novel therapeutic solutions to the growing problem of arthritis in our aging society. Accordingly, imaging tools that will be used to direct patients to specific therapies and then to monitor treatment effectiveness and safety presently are being refined and validated in rigorous multicenter and multinational clinical trials aimed at gaining regulatory approval. As trials approach completion, radiologists can anticipate an increased demand for expertise and experience in evaluating articular cartilage disorders. This article reviews this novel mechanism for evolving imaging techniques for clinical use through clinical drug trials, lists the most promising MR imaging markers available for evaluating cartilage integrity, and speculates on how these techniques will find their way into clinical practice.

Assessment of needle arthroscopy, standard arthroscopy, physical examination, and magnetic resonance imaging in knee pain: a pilot study.

Nine patients with mechanical or osteoarthritic knee pain present for more than 6 weeks were evaluated by clinical examination, needle arthroscopy, and standard arthroscopy. Each knee was assessed for patellofemoral cartilage disruption, cartilage abnormalities in the tibiofemoral joints, meniscal tears, and synovitis. Needle arthroscopy was performed immediately before standard arthroscopy in the operating room under local anesthesia. Six of the nine patients had magnetic resonance imaging (MRI) scans before the arthroscopic procedures. The clinical examination was 100% sensitive for the detection of patellofemoral disease, 62% sensitive for medial meniscal tears, and 14% sensitive for lateral meniscal tears. Visualization of the femoral-tibial joint was significantly better with standard arthroscopy than with needle arthroscopy (p = 0.002). Percent visualization with the needle arthroscope was higher for the patellofemoral and the medical tibiofemoral cartilage compared to the lateral tibiofemoral cartilage and menisci (p < 0.05). The needle arthroscope and MRI scan were equivalent to the standard arthroscope in the detection of patellofemoral cartilage disruption of any depth and in the detection of meniscal tears. However, the standard arthroscope was better in detecting cartilage abnormalities in the medial and lateral joint spaces (p < 0.05 and p < 0.01, respectively). The costs for diagnostic standard arthroscopy, needle arthroscopy, and MRI of the knee in an academic center are $3900, $1650, and $900, respectively. These data suggest that the majority of reversible causes of knee pain are diagnosed by physical examination. Therefore, after a complete history and physical examination, if the physician thinks that the patient has an internal derangement of the knee and that surgical intervention is needed, we suggest that the patient go directly to standard arthroscopy, which offers both confirmation and therapy. The MRI scan or needle arthroscopy should be considered only if, after a history and physical examination, the diagnosis of the knee pain is unclear.

Femoral neck and intertrochanteric fractures: radiographic indicators of fracture healing.

Serial hip radiographs from 280 patients with proximal femoral fractures were analyzed retrospectively by 3 radiologists to evaluate conventional radiographic healing patterns. Patients with hemiarthroplasty or insufficient follow-up were excluded. In the remaining 41 patients, the fracture line and callus was assessed. Intertrochanteric fractures demonstrated increasing callus and sclerosis at the fracture site. No such association was seen in femoral neck fractures. Traditional indicators of fracture healing cannot be readily applied at the hip. Radiographic features relate more to fracture type and fixation method.

Denosumab-mediated increase in hand bone mineral density associated with decreased progression of bone erosion in rheumatoid arthritis patients.

OBJECTIVE: Periarticular osteoporosis is one of the earliest radiographic signs of bone damage in rheumatoid arthritis (RA). Denosumab, an investigational fully human monoclonal antibody that binds to RANKL, inhibits bone erosion and systemic bone loss in clinical studies of patients with RA. In this hand bone mineral density (BMD) substudy, we investigated the effects of denosumab on hand BMD and its correlation with hand erosion scores. METHODS: Patients receiving methotrexate for erosive RA were randomized in a 1:1:1 ratio to receive subcutaneous placebo, denosumab 60 mg, or denosumab 180 mg at 0 and 6 months. Measurements included BMD (by dual x-ray absorptiometry [DXA]) of both hands (0, 1, 6, and 12 months), magnetic resonance images of the hands/wrists (0 and 6 months), and radiographs of the hands/wrists and feet (0, 6, and 12 months). RESULTS: There were 56 patients (13 placebo, 21 denosumab 60 mg, and 22 denosumab 180 mg). Mean changes in hand BMD at 6 and 12 months were: +0.8% and +1.0%, respectively, for denosumab 60 mg; +2.0% and +2.5%, respectively, for denosumab 180 mg; and -1.2% and -2.0%, respectively, for placebo. Erosion scores remained near baseline in the denosumab groups and increased from baseline in the placebo group. A negative correlation was observed between hand BMD and erosion scores. CONCLUSION: In patients with RA, denosumab provided protection against erosion, and not only prevented bone loss but increased hand BMD as measured by DXA.

An explanation for the apparent dissociation between clinical remission and continued structural deterioration in rheumatoid arthritis.

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 1.5 T magnetic resonance imaging (MRI) at baseline and 12 months, using validated acquisition and scoring techniques. 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.

MRI protocols for whole-organ assessment of the knee in osteoarthritis.

One of the critical challenges in developing structure-modifying therapies for arthritis, especially osteoarthritis (OA), is measuring changes in progression of joint destruction. Magnetic resonance imaging (MRI) offers considerable promise in this regard. Not only can MRI quantify articular cartilage volume and morphology with high precision and accuracy, but it can also examine several other important articular components, and thus offer a unique opportunity to evaluate the knee and other joints as whole organs. On December 5 and 6, 2002, OMERACT (Outcome Measures in Rheumatology Clinical Trials) and OARSI (Osteoarthritis Research Society International), with support from various pharmaceutical companies listed at the beginning of this supplement, held a Workshop for Consensus on Osteoarthritis Imaging in Bethesda, MD. The aim of the Workshop was to provide a state-of-the-art review of imaging outcome measures for OA of the knee to help guide scientists and pharmaceutical companies who want to use MRI in multi-site studies of OA. Applications of MRI were initially reviewed by a multidisciplinary, international panel of expert scientists and physicians from academia, the pharmaceutical industry and regulatory agencies. The findings of the panel were then presented to a wider group of participants for open discussion. The following report summarizes the results of these discussions with respect to MRI acquisition techniques for whole-organ assessment of the knee in OA. The discussion reviews the selection and qualification of imaging sites for clinical trials, designing imaging protocols for whole-organ assessment of OA, and key considerations in image quality (IQ) control and data management.

Responsiveness, effect size, and smallest detectable difference of Magnetic Resonance Imaging in knee osteoarthritis.

OBJECTIVE: The aim of this study was to determine the responsiveness, effect size (ES) and smallest detectable difference (SDD) of two Magnetic Resonance Imaging (MRI) measures for osteoarthritis (OA) of the knee: a whole-organ semiquantitative evaluation and cartilage volume. DESIGN: This analysis was performed on a dataset from a randomized, double-blind trial (Roche NI-15713) conducted in 1998 of a novel therapy in subjects with mild-moderate knee OA, with MRI at baseline and 6-month follow-up. The trial measurements included (1) cartilage volume measured using a proprietary software method; and (2) semiquantitative scoring of other parameters important for "whole organ" evaluation of OA knee joint pathology, using the Whole-Organ MRI Score (WORMS). The analysis initially examined the distributional characteristics of WORMS items, such as cartilage morphology. Standardized response mean (SRM), ES, and SDD between baseline and 6-month follow-up were then calculated in the whole group and the placebo group alone. RESULTS: In general, the differences were small and this was reflected in the small ESs and SRMs. There was also a suggestion of a treatment effect with reduction in differences between baseline and follow-up in the treatment group. CONCLUSION: Of the MRI semiquantitative measures, cartilage morphology, synovitis and osteophytes appeared to be responsive to change and the focus of repeat measures should highlight these articular features. In general, the ESs and SRMs were small.