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.

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.

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.

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.

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.

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.

Presence of significant synovitis in rheumatoid arthritis patients with disease-modifying antirheumatic drug-induced clinical remission: evidence from an imaging study may explain structural progression.

OBJECTIVE: More timely and effective therapy for rheumatoid arthritis (RA) has contributed to increasing rates of clinical remission. However, progression of structural damage may still occur in patients who have satisfied remission criteria, which suggests that there is ongoing disease activity. This questions the validity of current methods of assessing remission in RA. The purpose of this study was to test the hypothesis that modern joint imaging improves the accuracy of remission measurement in RA. METHODS: We studied 107 RA patients receiving disease-modifying antirheumatic drug therapy who were judged by their consultant rheumatologist to be in remission and 17 normal control subjects. Patients underwent clinical, laboratory, functional, and quality of life assessments. The Disease Activity Score 28-joint assessment and the American College of Rheumatology remission criteria, together with strict clinical definitions of remission, were applied. Imaging of the hands and wrists using standardized acquisition and scoring techniques with conventional 1.5T magnetic resonance imaging (MRI) and ultrasonography (US) were performed. RESULTS: Irrespective of which clinical criteria were applied to determine remission, the majority of patients continued to have evidence of active inflammation, as shown by findings on the imaging assessments. Even in asymptomatic patients with clinically normal joints, MRI showed that 96% had synovitis and 46% had bone marrow edema, and US showed that 73% had gray-scale synovial hypertrophy and 43% had increased power Doppler signal. Only mild synovial thickening was seen in 3 of the control subjects (18%), but no bone marrow edema. CONCLUSION: Most RA patients who satisfied the remission criteria with normal findings on clinical and laboratory studies had imaging-detected synovitis. This subclinical inflammation may explain the observed discrepancy between disease activity and outcome in RA. Imaging assessment may be necessary for the accurate evaluation of disease status and, in particular, for the definition of true remission.

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.

Examining a whole-organ magnetic resonance imaging scoring system for osteoarthritis of the knee using Rasch analysis.

OBJECTIVE: The ability to reliably quantify all the structural abnormalities in osteoarthritis (OA) of the knee is a long-standing goal of OA research. On December 5 and 6, 2002, Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis Research Society, International held a Workshop for Consensus on Osteoarthritis Imaging in Bethesda, MD, with the aim of providing a state-of-the-art review of imaging outcome measures for OA of the knee. As part of the Workshop, data from previous clinical trials and epidemiological studies of OA were analysed with respect to the metrological properties of the measurement methods used. The following report outlines the results of analyses aimed at evaluating the internal construct validity of a whole-organ, ordinal (semi-quantitative) magnetic resonance imaging score (WORMS) using Rasch analysis. The fit of data to the Rasch model offers a measure of the validity of summing different items into a subscale score and the degree to which this score behaves as a unidimensional, interval level measurement tool. METHODS: The Rasch model was applied in two OA studies. The first was a clinical cohort comprising OA knee subjects entering a clinical trial; study entry criteria included patients with at least moderate pain, radiographic osteophytes and a minimum of 1.5mm tibiofemoral joint-space width. The second cohort was from the Boston Osteoarthritis Knee Study, an observational cohort of subjects with symptomatic knee OA with pain on most days and a definite osteophyte in either the tibiofemoral or patellofemoral joints. Baseline WORMS scores from both studies were used for the Rasch analysis, performed with RUMM 2020 software. RESULTS: There was a substantial proportion of subjects in both study populations with zero scores in several of the subscales of WORMS. Few of the subscales met the requirements of the Rasch measurement model when summated across all sites, and summations of some postulated compartmentally based sites also failed to fit the Rasch model. The existing scoring categories also required rescoring at many sites. CONCLUSION: There remain important issues in constructing outcome measurements that summate different features across multiple anatomical sites. The whole-organ scoring system evaluated here is no exception. Resolving these issues will improve the ability of imaging studies to assess complex pathological structural change.

Whole-Organ Magnetic Resonance Imaging Score (WORMS) of the knee in osteoarthritis.

OBJECTIVES: To describe a semi-quantitative scoring method for multi-feature, whole-organ evaluation of the knee in osteoarthritis (OA) based on magnetic resonance imaging (MRI) findings. To determine the inter-observer agreement of this scoring method. To examine associations among the features included in the scoring method. METHODS: Nineteen knees of 19 patients with knee OA were imaged with MRI using conventional pulse sequences and a clinical 1.5 T MRI system. Images were independently analyzed by two musculoskeletal radiologists using a whole-organ MRI scoring method (WORMS) that incorporated 14 features: articular cartilage integrity, subarticular bone marrow abnormality, subarticular cysts, subarticular bone attrition, marginal osteophytes, medial and lateral meniscal integrity, anterior and posterior cruciate ligament integrity, medial and lateral collateral ligament integrity, synovitis/effusion, intraarticular loose bodies, and periarticular cysts/bursitis. Intraclass correlation coefficients (ICC) were determined for each feature as a measure of inter-observer agreement. Associations among the scores for different features were expressed as Spearman Rho. RESULTS: All knees showed structural abnormalities with MRI. Cartilage loss and osteophytes were the most prevalent features (98% and 92%, respectively). One of the least common features was ligament abnormality (8%). Inter-observer agreement for WORMS scores was high (most ICC values were >0.80). The individual features showed strong inter-associations. CONCLUSION: The WORMS method described in this report provides multi-feature, whole-organ assessment of the knee in OA using conventional MR images, and shows high inter-observer agreement among trained readers. This method may be useful in epidemiological studies and clinical trials of OA.

Metallic artefacts in MR imaging: effects of main field orientation and strength.

AIM: To determine the effect of metallic implant positioning on magnetic resonance (MR) imaging artefacts, and to determine the optimal imaging parameters for minimization of metallic artefacts. MATERIALS AND METHODS: In a phantom and in three joints with non-ferromagnetic metallic implants imaged at 1.5 and/or at 0.2 T, we examined the influence of the static magnetic field (B(0)) strength and orientation, frequency-encoding direction, and type of imaging sequence on metallic artefacts. RESULTS: The impact of artefacts caused by metallic objects depends mainly on the relationship between the anatomy of interest and the orientation of the object relative to the direction of B(0). The main field strength plays a less important role, but its orientation depends on the type of MR imager. CONCLUSION: MR artefacts can be easily minimized by optimally positioning patients with metallic implants in the magnet. Knowledge of how this influences MR imaging is helpful in patient selection and guiding limb positioning.

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.

Role of MR imaging in clinical research studies.

There have been numerous advances in cartilage imaging with magnetic resonance imaging (MRI) over the past several years. However, in the absence of effective treatments for articular cartilage disease, these innovations have had little applicability to clinical practice. Putative new therapies do exist but only in clinical trials aimed at establishing the efficacy and safety of these therapies before they are released into general use. These trials, therefore, represent the earliest opportunity to develop imaging methods specifically for such therapies and the diseases that they treat. Accordingly, it is the commercial, regulatory, and logistical demands of the clinical trials process, rather than those of clinical practice, that ultimately shape the early evolution of these imaging tools. Understanding this process and its priorities is essential to contributing to this development and to keeping radiology in sync with advances in the rest of medicine. The following article reviews this novel pathway for innovation in medical imaging and reflects on how recent advances in cartilage MRI might fit in.

Magnetic resonance imaging of the wrist in rheumatoid arthritis.

Despite the extraordinary advances made in medical imaging over the past two decades and the central role that magnetic resonance imaging (MRI) and other sophisticated technologies now play in routine clinical practice, rheumatology has benefited relatively little from these advances thus far. Over the past few years, however, evidence has accumulated to show that MRI can identify joint damage in patients with rheumatoid arthritis earlier and more sensitively than other techniques can, and that MRI can directly visualize and monitor changes in synovium and bone that precede actual bone erosion. Much of this development is being driven by the pharmaceutical and biotechnology industries as they search for novel therapies to combat 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 therapies become available for clinical use, radiologists can anticipate increased demand for expertise and experience in evaluating disease progression and treatment response with these techniques and the emergence of MRI systems specifically adapted for this application. The following discussion reviews the current status of this development, and points to areas where further advances are anticipated in the near future.

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.

Magnetic resonance imaging in rheumatoid arthritis: current status and future directions.

The performance of alternative imaging endpoints in clinical trials can be compared in terms of validity, rate of change, measurement precision, and convenience and cost. With respect to technical performance, magnetic resonance imaging (MRI) appears to show greater sensitivity than radiography for detecting bone abnormalities in rheumatoid arthritis (RA). In addition to monitoring changes in the bones, cartilage, and synovium, MRI can directly visualize the full spectrum of tendon pathology, and has been shown to identify tendonitis and tendon rupture with greater accuracy than clinical examination. MRI is currently regarded to be the most sensitive imaging technique for identifying trauma, infection, ischemia, and primary and secondary neoplasia of bone. Several studies have also shown MRI to be highly sensitive for detecting what appear to be bone erosions in the hands and wrists of patients with RA. MRI shows remarkable promise as a tool for identifying and monitoring structural damage in the joints of patients with RA. MRI appears to be able to identify bone erosions with greater sensitivity than radiography, and to disclose edema-like changes in the marrow, which may precede actual erosion formation. As new therapies with structure modifying capabilities enter the clinic, the ability to identify patients appropriate for those therapies and then to monitor the effectiveness and safety of treatment become increasingly important.

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.