Rheumatoid Arthritis: Peterfy CG

Peterfy CG. · Synarc, Inc., San Francisco, California 94105, USA. · J Rheumatol. · Pubmed #15088286 links to  free full text

This publication has no abstract.

Conaghan PG, McQueen FM, Peterfy CG, Lassere MN, Ejbjerg B, Bird P, O'Connor PJ, Haavardsholm E, Edmonds JP, Emery P, Genant HK, Ostergaard M, Anonymous00379. · Academic Unit of Musculoskeletal Disease, University of Leeds, Leeds, UK. · J Rheumatol. · Pubmed #16331788 No free full text.

Abstract: Magnetic resonance imaging (MRI) has now been used extensively in cross-sectional and observational studies as well as in controlled clinical trials to assess disease activity and joint damage in rheumatoid arthritis (RA). MRI measurements or scores for erosions, bone edema, and synovitis have been developed and validated by several groups. The OMERACT criteria require that outcome measures demonstrate adequate validity, discriminative power, and feasibility if they are to be useful in clinical trials. Specific performance targets for these criteria depend on the scientific, regulatory, logistical, and financial context of the study in question. We review the extent to which MRI assessments of joint erosion, bone edema, and synovitis fulfil these criteria, particularly as they relate to proof-of-concept RA clinical trials.

Guermazi A, Taouli B, Lynch JA, Peterfy CG. · Synarc Inc., San Francisco, California 94105, USA. · Semin Musculoskelet Radiol. · Pubmed #15643569 No free full text.

Abstract: Rheumatoid arthritis (RA) is the most common type of inflammatory arthritis, with a prevalence of 1% in the United States. Recently introduced disease-modifying antirheumatic drugs have been extremely successful in preventing irreversible joint damage, particularly if initiated early. Accordingly, accurate and early diagnosis of RA has become imperative. This shift places increased demands on imaging to identify even the slightest traces of erosive joint damage and predict future structural and functional deterioration. Unfortunately, conventional radiography has been shown to be insensitive for bone erosions, particularly in early stages of the disease. Computed tomography (CT) is rarely used, but its tomographic perspective offers advantages over projectional radiography. Ultrasound (US) detects more erosions than radiography does and also can evaluate synovitis. Scintigraphy also can detect inflammation and bone turnover at sites of active erosion. It lacks spatial resolution but offers greater anatomical coverage, making whole-body assessments possible. Of all imaging modalities, however, magnetic resonance imaging (MRI) shows the greatest sensitivity for detecting and monitoring bone erosions and also can detect and follow pre-erosive features of RA, such as synovitis, bone marrow edema or osteitis, and tendinous and ligamentous abnormalities. In this article, we review the appearance of bone erosions on conventional radiography and alternative imaging modalities including MRI, CT, US, and scintigraphy. We also review alternative acquisition techniques for MRI in RA and discuss the utility of fat suppression and contrast enhancement.

Peterfy CG. · Synarc, Inc, San Francisco, California 94105, USA. · Curr Opin Rheumatol. · Pubmed #12707583 No free full text.

Abstract: Despite the advances made in medical imaging over the past 3 decades and the central role that magnetic resonance imaging and other sophisticated technologies now play in routine clinical practice, patients with rheumatoid arthritis have benefited relatively little from these advances thus far. Over the past few years, however, evidence has accumulated to show that magnetic resonance imaging and ultrasonography can identify joint damage in patients with rheumatoid arthritis earlier and more sensitively than other techniques can, and that these techniques 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, we can anticipate increased demand for expertise and experience in evaluating disease progression and treatment response, and to the emergence of magnetic resonance imaging systems specifically adapted for this application. The following discussion reviews the current status of this development, and notable advances that have been reported in the literature in the past year.

Peterfy CG. · Synarc, Inc., 455 Market Street, Suite 1850, San Francisco, CA 94105, USA. · Semin Musculoskelet Radiol. · Pubmed #11595971 No free full text.

Abstract: 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.

Peterfy CG. · Synarc Inc, San Francisco, CA 94105, USA. · Semin Arthritis Rheum. · Pubmed #11404821 No free full text.

Abstract: 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.

Peterfy CG. · Synarc, Inc., San Francisco, CA 94105, USA. · J Rheumatol. · Pubmed #11361203 No free full text.

Abstract: 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.

Cohen SB, Dore RK, Lane NE, Ory PA, Peterfy CG, Sharp JT, van der Heijde D, Zhou L, Tsuji W, Newmark R, Anonymous00022. · Metroplex Clinical Research Center, Dallas, Texas 75235, USA. · Arthritis Rheum. · Pubmed #18438830 links to  free full text

Abstract: OBJECTIVE: RANKL is essential for osteoclast development, activation, and survival. Denosumab is a fully human monoclonal IgG2 antibody that binds RANKL, inhibiting its activity. The aim of this multicenter, randomized, double-blind, placebo-controlled, phase II study was to evaluate the effects of denosumab on structural damage in patients with rheumatoid arthritis (RA) receiving methotrexate treatment. METHODS: RA patients received subcutaneous placebo (n = 75), denosumab 60 mg (n = 71), or denosumab 180 mg (n = 72) injections every 6 months for 12 months. The primary end point was the change from baseline in the magnetic resonance imaging (MRI) erosion score at 6 months. RESULTS: At 6 months, the increase in the MRI erosion score from baseline was lower in the 60-mg denosumab group (mean change 0.13; P = 0.118) and significantly lower in the 180-mg denosumab group (mean change 0.06; P = 0.007) than in the placebo group (mean change 1.75). A significant difference in the modified Sharp erosion score was observed as early as 6 months in the 180-mg denosumab group (P = 0.019) as compared with placebo, and at 12 months, both the 60-mg (P = 0.012) and the 180-mg (P = 0.007) denosumab groups were significantly different from the placebo group. Denosumab caused sustained suppression of markers of bone turnover. There was no evidence of an effect of denosumab on joint space narrowing or on measures of RA disease activity. Rates of adverse events were comparable between the denosumab and placebo groups. CONCLUSION: Addition of twice-yearly injections of denosumab to ongoing methotrexate treatment inhibited structural damage in patients with RA for up to 12 months, with no increase in the rates of adverse events as compared with placebo.

Keystone E, Emery P, Peterfy CG, Tak PP, Cohen S, Genovese MC, Dougados M, Burmester GR, Greenwald M, Kvien TK, Williams S, Hagerty D, Cravets MW, Shaw T. · Division of Rheumatology, University of Toronto, Toronto, Canada. · Ann Rheum Dis. · Pubmed #18388156 No free full text.

Abstract: 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.

Brown AK, Quinn MA, Karim Z, Conaghan PG, Peterfy CG, Hensor E, Wakefield RJ, O'Connor PJ, Emery P. · Chapel Allerton Hospital, University of Leeds, Leeds, UK. · Arthritis Rheum. · Pubmed #17133543 links to  free full text

Abstract: 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.

Brown AK, Conaghan PG, Karim Z, Quinn MA, Ikeda K, Peterfy CG, Hensor E, Wakefield RJ, O'Connor PJ, Emery P. · Leeds Institute of Molecular Medicine, University of Leeds, and Chapel Allerton Hospital, Leeds, UK. · Arthritis Rheum. · Pubmed #18821687 No free full text.

Abstract: 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.

Genant HK, Peterfy CG, Westhovens R, Becker JC, Aranda R, Vratsanos G, Teng J, Kremer JM. · University of California, San Francisco, San Francisco, CA, USA. · Ann Rheum Dis. · Pubmed #18086727 links to  free full text

Abstract: 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.

Yocum DE, Conaghan PG, Olech E, Peterfy CG. · Genentech, South San Francisco, California 94080-4990, USA. · Arthritis Rheum. · Pubmed #16572438 links to  free full text

This publication has no abstract.

Ostergaard M, McQueen FM, Bird P, Ejbjerg B, Lassere MN, Peterfy CG, O'Connor PJ, Haavardsholm E, Shnier R, Genant HK, Emery P, Edmonds JP, Conaghan PG, Anonymous00378. · Copenhagen University Hospitals, Herlev, Copenhagen, Denmark. · J Rheumatol. · Pubmed #16331787 No free full text.

Abstract: This article updates the work and results of the OMERACT MRI in RA Working Group as presented at the OMERACT 7 meeting in May 2004, focusing on the development of the EULAR-OMERACT rheumatoid arthritis magnetic resonance imaging reference image atlas, and on areas for future research.

Carano RA, Lynch JA, Redei J, Ostrowitzki S, Miaux Y, Zaim S, White DL, Peterfy CG, Genant HK. · Osteoporosis and Arthritis Research Group, Department of Radiology, Box 1250, University of California, San Francisco, CA 94143, USA. · Magn Reson Imaging. · Pubmed #15120170 No free full text.

Abstract: Quantitative measures of rheumatoid arthritis (RA) disease progression can provide valuable tools for evaluation of new treatments during clinical trials. In this study, a novel multispectral (MS) MRI analysis method is presented to quantify changes in bone lesion volume (DeltaBLV) in the hands of RA patients. Image registration and MS analysis were employed to identify MS tissue class transitions between two serial MRI exams. DeltaBLV was determined from MS class transitions between two time points. The following three classifiers were investigated: (a) multivariate Gaussian (MVG), (b) k-nearest neighbor (k-NN), and (c) K-means (KM). Unlike supervised classifiers (MVG, k-NN), KM, an unsupervised classifier, does not require labeled training data, resulting in potentially greater clinical utility. All MS estimates of DeltaBLV were linearly correlated (r(p)) with manual estimates. KM and k-NN estimates also exhibited a significant rank-order correlation (r(s)) with manual estimates. For KM, r(p) = 0.94 p < 0.0001, r(s) = 0.76 p = 0.002; for k-NN, r(p) = 0.86 p = 0.0001, r(s) = 0.69 p = 0.009; and for MVG, r(p) = 0.84 p = 0.0003, r(s) = 0.49 p = 0.09. Temporal classification rates were as follows: for KM, 90.1%; for MVG, 89.5%; and for k-NN, 86.7%. KM matched the performance of k-NN, offering strong potential for use in multicenter clinical trials. This study demonstrates that MS tissue class transitions provide a quantitative measure of DeltaBLV.

Peterfy CG. · Synarc Inc, 575 Market Street, 17th Floor, San Francisco 94105, CA, USA. · Ann Rheum Dis. · Pubmed #15082474 links to  free full text

This publication has no abstract.

Taouli B, Zaim S, Peterfy CG, Lynch JA, Stork A, Guermazi A, Fan B, Fye KH, Genant HK. · Department of Radiology, University of California, San Francisco, 505 Parnassus Ave., Box 0628, San Francisco, CA 94143-0628, USA. · AJR Am J Roentgenol. · Pubmed #15039167 links to  free full text

Abstract: OBJECTIVE: The purpose of this study was to compare the relative results from conventional high-field-strength 1.5-T MRI, 0.2-T low-field-strength dedicated extremity MRI, and radiography to detect and grade bone erosions, joint-space narrowing, and synovitis in the hands and wrists of patients with rheumatoid arthritis. SUBJECTS AND METHODS: Eighteen patients with rheumatoid arthritis underwent conventional high-field-strength MRI, low-field-strength dedicated extremity MRI, and conventional radiography of both hands and wrists. Two independent reviewers searched for the presence and extent of bone erosions, joint-space narrowing, and synovitis. Bone erosions (E scores) and joint-space narrowing (J scores) were evaluated at 14 and 13 sites, respectively, on conventional high-field-strength MRI, low-field-strength dedicated extremity MRI, and radiography, using the Sharp-Genant scoring system. Synovitis (S scores) were evaluated at 13 sites on conventional high-field-strength MRI and low-field-strength dedicated extremity MRI. RESULTS: For the detection of bone erosions, we found no significant difference (p = 0.71) between conventional high-field-strength MRI (mean +/- SD E score, 27.5 +/- 9.8) and low-field-strength dedicated extremity MRI (28.8 +/- 10.0), but a significant difference (p < 0.001) appeared between MRI and radiography (13.1 +/- 8.3). J scores derived from MRI (conventional high-field-strength MRI, 15.2 +/- 8.3; low-field-strength dedicated extremity MRI, 14.5 +/- 10.4) were higher than those derived from radiography (12.7 +/- 9.6), although the difference was not significant (p = 0.70). Conventional high-field-strength MRI (S score, 35.1 +/- 8.6) and low-field-strength dedicated extremity MRI (30.8 +/- 10.2) were equivalent (p = 0.14) for the evaluation of synovitis. The interobserver agreement for MRI scores was good to excellent (intraclass correlation coefficients, 0.83-0.94). CONCLUSION: Conventional high-field-strength MRI and low-field-strength dedicated extremity MRI showed similar results in terms of cross-sectional grading of bone erosions, joint-space narrowing, and synovitis in the hands and wrists of patients with rheumatoid arthritis.

van Dijke CF, Peterfy CG, Brasch RC, Lang P, Roberts TP, Shames D, Kneeland JB, Lu Y, Mann JS, Kapila SD, Genant HK. · Department of Radiology, University of California, San Francisco 94143-0628, USA. · Magn Reson Imaging. · Pubmed #10215479 No free full text.

Abstract: 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.