953

Review: Molecular Basis and Clinical Use of Biochemical Markers of Bone, Cartilage, and Synovium in Joint Diseases

Patrick Garnero, Jean Charles Rousseau, and Pierre D. Delmas

969

Current Comment: Sonographic Imaging of Tendons

Walter Grassi, Emilio Filippucci, Antonella Farina, and Claudio Cervini

977

In Memoriam: James R. Klinenberg, MD, 1934-1999

Michael H. Weisman

978

Rofecoxib, a Specific Inhibitor of Cyclooxygenase 2, with Clinical Efficacy Comparable with That of Diclofenac Sodium: Results of a One-Year, Randomized, Clinical Trial in Patients with Osteoarthritis of the Knee and Hip

Grant W. Cannon, Jacques R. Caldwell, Peter Holt, Barry McLean, Beth Seidenberg, James Bolognese, Elliot Ehrich, Suarabh Mukhopadhyay, and Brian Daniels, for the Rofecoxib Phase III Protocol 035

Nonsteroidal antiinflammatory drugs, which are nonspecific inhibitors of cyclooxygenase, are clinically effective in the treatment of OA; however, they can cause serious gastrointestinal (GI) complications. Rofecoxib has the potential to provide comparable clinical efficacy with improved GI safety. In this study, rofecoxib had comparable clinical efficacy in the treatment of knee and hip OA compared with the maximum recommended dose of diclofenac for the treatment of OA.

988

Quantification of Progressive Joint Space Narrowing in Osteoarthritis of the Hip: Longitudinal Analysis of the Contralateral Hip After Total Hip Arthroplasty

Berna Goker, Aida M. Doughan, Thomas J. Schnitzer, and Joel A. Block

This report describes a reliable method for the quantification of radiographic joint space widths in the hip, and a longitudinal analysis of disease progression in the contralateral hip after THA for OA. Among other findings, the study determined that radiographically evident hip joint space narrowing may be reliably quantified and followed up longitudinally using standard anteroposterior radiographs. The study provides new prognostic information regarding the natural history of OA and risk factors for disease progression in the contralateral hip after THA.

995

Risk Factors for the Incidence and Progression of Radiographic Knee Osteoarthritis

Cyrus Cooper, Shelagh Snow, Timothy E. McAlindon, Samantha Kellingray, Brenda Stuart, David Coggon, and Paul A. Dieppe

Many risk factors for prevalent radiographically evident knee OA influence incidence more than progression, including obesity, knee injury, involvement of other joint sites, and history of regular participation in sports. This population-based longitudinal study assessed baseline risk factors in 354 subjects and tested these factors for their association with incident and progressive radiographic knee OA by logistic regression. Only baseline obesity was identified as a predictor of radiographic progression. This discordance between risk factors for incidence and progression suggests that OA is initiated by joint injury, but that progression may depend on the intrinsic repair capacities of different individuals.

1001

A Multicenter, Double-Blind, Dose-Ranging, Randomized, Placebo-Controlled Study of Recombinant Human Interleukin-1 Receptor Antagonist in Patients with Rheumatoid Arthritis: Radiologic Progression and Correlation of Genant and Larsen Scores

Yebin Jiang, Harry K. Genant, Iain Watt, Mark Cobby, Barry Bresnihan, Roger Aitchison, and Dorothy McCabe

Recombinant human IL-1Ra reduces radiologic progression of RA and may provide an alternative agent for treating RA patients. This study demonstrates that the correlation between the Genant and Larsen scores in patients treated with IL-1Ra is strong for individual time points at baseline and followup visits but weak for disease progression.

1010

Breast-Feeding and Postpartum Relapse in Women with Rheumatoid and Inflammatory Arthritis

Jennifer H. Barrett, Paul Brennan, Magdalen Fiddler, and Alan Silman

This study tested the hypothesis that breast-feeding increases the risk of postpartum flare in inflammatory polyarthritis. Disease activity during pregnancy and at 6 months postpartum was compared among non-breast-feeders, first-time breast-feeders, and repeat breast-feeders. The study found that postpartum flare may be induced by breast-feeding.

1016

Single Values of Serum Transferrin Receptor and Transferrin Receptor Ferritin Index Can Be Used to Detect True and Functional Iron Deficiency in Rheumatoid Arthritis Patients with Anemia

Pauli Suominen, Timo Mottonen, Allan Rajamaki, and Kerttu Irjala

Anemia is a common occurrence in RA. Serum transferrin receptor (sTfR) and transferrin receptor-log ferritin index (TfR-F Index) have been shown to effectively distinguish between iron-deficiency anemia (IDA) and anemia of chronic disease (ACD), yet evidence delineating their use to detect functional iron deficiency (FID) has remained somewhat vague. The results of this study elucidate the roles of sTfR and TfR-F Index in the differential diagnosis between IDA and ACD and offer direct evidence that these parameters are useful in detecting FID regardless of the concurrent iron storage status.

1021

An Interdisciplinary Approach to the Care of Patients with Wegener's Granulomatosis: Long-Term Outcome in 155 Patients

Eva Reinhold-Keller, Nadja Beuge, Ute Latza, Kirsten de Groot, Heinrich Rudert, Bernhard Nolle, Martin Heller, and Wolfgang L. Gross

In this study, a treatment adapted to the activity and extent of disease, combined with regular interdisciplinary surveillance, resulted in a long-term median survival of [lt]21 years in 155 patients with WG. Involvement of kidney or lung at diagnosis was predictive of [lt]3-fold higher mortality. Although less-aggressive regimens were used, cyclophosphamide remains essential in the treatment of most cases of WG.

1033

Chylomicron Metabolism is Markedly Altered in Systemic Lupus Erythematosus

Eduardo F. Borba, Eloisa Bonfa, Carmen G. C. Vinagre, Jose A. F. Ramires, and Raul C. Maranhao

A significant impairment of the lipolytic process of triglyceride-rich lipoproteins in SLE was identified in this study, as indicated both by the reduction of chylomicron lipolysis and removal of their remnants after infusion of a double-labeled chylomicron-like emulsion in vivo. A decrease of in vitro postheparin lipolysis was further observed and might explain the pattern of dyslipoproteinemia detected in SLE. Disturbances in lipoprotein metabolism in SLE may be a major contributing factor to the accelerated atherosclerotic process in this disease.

1041

Treatment of Giant Cell Arteritis: Interleukin-6 as a Biologic Marker of Disease Activity

Cornelia M. Weyand, James W. Fulbright, Gene G. Hunder, Jonathan M. Evans, and Jorg J. Goronzy

Corticosteroids are the treatment of choice in GCA; however, it is not known whether current recommendations on the dosage and regimen of steroids allow for optimal disease suppression while minimizing side effects. Optimization of therapy would require the availability of a sensitive biologic marker reflecting disease activity. This study compared the value of the erythrocyte sedimentation rate and plasma concentrations of the proinflammatory cytokine IL-6 to monitor response to treatment. Plasma IL-6 levels were found to be more sensitive in detecting active GCA in treated and untreated patients.

1049

QT Interval Prolongation in Asymptomatic Anti-SSA/Ro-Positive Infants Without Congenital Heart Block

Rolando Cimaz, Marco Stramba-Badiale, Antonio Brucato, Luca Catelli, Paola Panzeri, and Pier Luigi Meroni

This study analyzed sera from mothers and children for anti-SSA/Ro and anti-SSB/La antibodies and included a retrospective chart review for electrocardiogram (EKG) analysis. The results demonstrate for the first time that a high proportion of infants born to mothers who are positive for anti-Ro antibodies show a prolongation of the QT interval on EKG, even after correction for heart rate. Since a prolonged corrected QT interval is a risk factor for sudden infant death, these infants should be monitored during the first year of life.

1054

Induction of Immune Tolerance to Human Type I Collagen in Patients with Systemic Sclerosis by Oral Administration of Bovine Type I Collagen

Kevin M. McKown, Laura D. Carbone, Juan Bustillo, Jerome M. Seyer, Andrew H. Kang, and Arnold E. Postlethwaite

This report describes the use of oral type I collagen in patients with systemic sclerosis to induce tolerance to type I collagen, an autoantigen in systemic sclerosis. The induction of oral tolerance is of great interest to clinicians because of the potential specificity and safety of this form of therapy. This interest would be especially keen in the case of systemic sclerosis, for which there is currently no effective, safe therapy.

1061

Errata: Errors in Articles by Garc|fia-Porrua et al (Arthritis Rheum, March 2000) and van der Heijden et al (Arthritis Rheum, March 2000)

1062

Detection of Cellular Microchimerism of Male or Female Origin in Systemic Sclerosis Patients by Polymerase Chain Reaction Analysis of HLA-Cw Antigens

Carol M. Artlett, Lori A. Cox, and Sergio A. Jimenez

This study identifies the presence of microchimerism in male and female SSc patients and provides support for the hypothesis that persistent microchimeric cells may cause SSc by initiating a graft-versus-host reaction. Confirmation of the hypothesis would allow the development of novel therapeutic approaches for this incurable and devastating disease.

1068

Microsatellites and Intragenic Polymorphisms of Transforming Growth Factor [gb] and Platelet-Derived Growth Factor and Their Receptor Genes in Native Americans with Systemic Sclerosis (Scleroderma): A Preliminary Analysis Showing No Genetic Association

Xiaodong Zhou, Filemon K. Tan, David N. Stivers, and Frank C. Arnett

Although dysregulation of the cytokines/growth factors, transforming growth factor [gb] and platelet-derived growth factor, has been demonstrated in SSc, it is unknown whether these abnormalities are genetic in origin. Genotyping of markers within and near these gene families in Choctaw Native Americans with SSc revealed no evidence of genetic anomalies.

1074

Longitudinal Analysis of Autoantibody Response to Topoisomerase I in Systemic Sclerosis

Masataka Kuwana, Junichi Kaburaki, Tsuneyo Mimori, Yutaka Kawakami, and Takeshi Tojo

This study identifies a subset of SSc patients in whom serum anti-topo I antibody disappears during the course of the disease. Since the SSc patients in this subset have a less extensive restrictive lung disease as well as a better prognosis than the patients who continue to have anti-topo I antibody, disappearance of anti-topo I antibody during followup may be a predictive marker for favorable outcomes in SSc patients.

1085

Correlation Between Increased Nitric Oxide Production and Markers of Endothelial Activation in Systemic Sclerosis: Findings with the Soluble Adhesion Molecules E-Selectin, Intercellular Adhesion Molecule 1, and Vascular Cell Adhesion Molecule 1

Grethe Neumann Andersen, Kenneth Caidahl, Elsadig Kazzam, Ann-Sofi Petersson, Anders Waldenstrom, Lucia Mincheva-Nilsson, and Solbritt Rantapaa-Dahlqvist

The results of this study demonstrate enhanced production of NO in SSc patients compared with age- and sex-matched controls. They further show that this NO production is likely to be derived from activated endothelial cells. These findings may have implications in the search for new drugs to target vascular engagement in SSc.

1094

Gene Therapy That Inhibits Nuclear Translocation of Nuclear Factor [gk]B Results in Tumor Necrosis Factor [ga]-Induced Apoptosis of Human Synovial Fibroblasts

Huang-Ge Zhang, Ning Huang, Di Liu, Lupita Bilbao, Xiaowu Zhang, Pingar Yang, Tong Zhou, David T. Curiel, and John D. Mountz

In this study, an adenovirus gene therapy vector expressing a mutant inhibitor of NF-[gk]B (AdCMVI[gk]B-DN) that prevents nuclear translocation of NF-[gk]B was transfected into human rheumatoid arthritis synovial fibroblast (RASF) cell lines in vitro and into human RASF cell lines in SCID mice in vivo. There was extensive apoptosis of [lt]85% of cells treated with AdCMVI[gk]B-DN plus TNF[ga], but no apoptosis of cells treated with AdCMVI[gk]B-DN or TNF[ga] alone. X-linked inhibitor of apoptosis (XIAP) was up-regulated by TNF[ga], and this up-regulation was inhibited by AdCMVI[gk]B-DN plus TNF[ga]. Transfection of the AdCMVXIAP antisense gene into RA synovial cell lines resulted in decreased expression of XIAP and increased TNF[ga]-induced apoptosis. Modulators of TNF receptor or the Fas apoptosis pathway may be therapeutically beneficial in facilitating apoptosis of synovial tissue in patients with RA.

1106

Differential Regulation of Fas-Mediated Apoptosis of Rheumatoid Synoviocytes by Tumor Necrosis Factor [ga] and Basic Fibroblast Growth Factor is Associated with the Expression of Apoptosis-Related Molecules

Tetsuya Kobayashi, Kazuyoshi Okamoto, Tetsuji Kobata, Tomoko Hasunuma, Tomohiro Kato, Hirofumi Hamada, and Kusuki Nishioka

This study investigated the behavior of intracellular signaling molecules that regulate Fas-mediated apoptosis, which is closely associated with the pathophysiology of RA. The sensitivity of rheumatoid arthritis (RA) synoviocytes to Fas-mediated apoptosis was found to be differentially regulated by TNF[ga] and bFGF, which can induce synovial proliferation in RA. In addition, the regulatory mechanisms of apoptosis were found to involve the formation of the death-inducing signaling complex, especially at the level of caspase 8 activation, and this process may be associated, at least in part, with the expression of FLIPL, the long form of the Fas-associated death domain-like interleukin-1[gb]-converting enzyme-inhibitory protein, and FLIP43, a C-terminal truncated form of FLIPL. These findings enhance our understanding of the pathophysiology of RA and may be helpful in the design of novel strategies for RA therapy.

1115

Regulation of Synovial B Cell Survival in Rheumatoid Arthritis by Vascular Cell Adhesion Molecule 1 (CD106) Expressed on Fibroblast-Like Synoviocytes

Carelle C. Reparon-Schuijt, Wim J. E. van Esch, Cees van Kooten, Babette C. D. Rozier, Eleonora W. N. Levarht, Ferdinand C. Breedveld, and Cornelis L. Verweij

This study demonstrates that contact of rheumatoid synovial B lymphocytes with fibroblast-like synoviocytes through VCAM-1 greatly contributes to the survival of these B cells in the inflamed joints of patients with RA. This interaction endows the persistent presence of memory B lymphocytes and plasma cells at the site of inflammation, which might contribute to the pathogenesis of RA.

1122

Soluble Vascular Cell Adhesion Molecule 1 Mediation of Monocyte Chemotaxis in Rheumatoid Arthritis

Michihide Tokuhira, Shigeru Hosaka, Michael V. Volin, G. Kenneth Haines, III, Kenneth J. Katschke, Jr., Soyun Kim, and Alisa E. Koch

This report describes a novel function for sVCAM-1 as a mediator of monocyte recruitment in RA. The study also identifies very late activation antigen 4 as the probable receptor for sVCAM-1 on monocytes and suggests that G proteins and protein kinase C are required for VCAM-1-induced monocyte migration. These results are significant because they identify a new potential therapeutic target for modulating monocyte ingress into the inflamed RA synovial tissue.

1134

Stimulation of 92-kd Gelatinase (Matrix Metalloproteinase 9) Production by Interleukin-17 in Human Monocyte/Macrophages: A Possible Role in Rheumatoid Arthritis

Dragan V. Jovanovic, Johanne Martel-Pelletier, John A. Di Battista, Francois Mineau, Francois-Cyril Jolicoeur, Mohamed Benderdour, and Jean-Pierre Pelletier

Identification of factors involved in the induction of MMP in human macrophages is important in the understanding of connective tissue turnover during inflammatory processes such as RA. The results of this study indicate that IL-17 produced in T cells may contribute to an unbalanced production of proinflammatory cytokines and MMP in diseased articular joint tissues, and could contribute substantially to the degradation and remodeling of connective tissue. This cytokine could thus be a target for the treatment of RA.

1145

Extracellular Signal-Regulated Kinase 1/Extracellular Signal-Regulated Kinase 2 Mitogen-Activated Protein Kinase Signaling and Activation of Activator Protein 1 and Nuclear Factor [gk]B Transcription Factors Play Central Roles in Interleukin-8 Expression Stimulated by Monosodium Urate Monohydrate and Calcium Pyrophosphate Crystals in Monocytic Cells

Ru Liu, Maria O'Connell, Kristen Johnson, Kenneth Pritzker, Nigel Mackman, and Robert Terkeltaub

Understanding the signal transduction involved in inflammation is critical to devising more selective and effective therapeutic means to suppress arthritis. Unlike rheumatoid arthritis and many other inflammatory disorders, gout and pseudogout are caused by crystals of single, chemically defined compounds. This study illustrates how urate and CPPD crystals utilize certain intracellular transduction pathways typically used during more specific growth responses, as well as tissue degradative, immune, and inflammatory responses, to promote acute neutrophilic inflammation.

1156

Genetic Enhancement of Matrix Synthesis by Articular Chondrocytes: Comparison of Different Growth Factor Genes in the Presence and Absence of Interleukin-1

P. Smith, F. D. Shuler, H. I. Georgescu, S. C. Ghivizzani, B. Johnstone, C. Niyibizi, P. D. Robbins, and C. H. Evans

Articular cartilage has very limited powers of repair, and its loss through injury or disease presents major clinical challenges. This study shows that the transfer of growth factor genes to articular chondrocytes greatly stimulates their synthesis of the main matrix macromolecules of cartilage. This could form the basis of a gene therapy approach to cartilage repair.

1165

Hyaluronan Oligosaccharides Perturb Cartilage Matrix Homeostasis and Induce Chondrocytic Chondrolysis

Warren Knudson, Brian Casey, Yoshihiro Nishida, Wolfgang Eger, Klaus E. Kuettner, and Cheryl B. Knudson

The proteoglycan-rich extracellular matrix directly associated with the cells of articular cartilage is tethered to the chondrocyte plasma membrane by way of interaction with the HA receptor CD44. This study sought to determine the role of CD44-mediated matrix assembly in maintaining cartilage homeostasis by treating articular cartilage tissue slices and isolated chondrocytes with small HA oligosaccharides. Uncoupling of the interaction of chondrocytes with their immediate matrix induced a state of chondrocytic chondrolysis similar to that observed in osteoarthritic chondrocytes.

1175

Interaction of Intraarticular Hyaluronan and Albumin in the Attenuation of Fluid Drainage from Joints

D. Scott, P. J. Coleman, R. M. Mason, and J. R. Levick

This study measured fluid escape rate from the joint cavity through synovium at controlled intraarticular pressures using a rabbit knee model in vivo, and assessed hyaluronan-albumin interactions in vitro by viscometry and osmometry. The report describes how the interaction of intraarticular hyaluronan and albumin attenuates synovial fluid drainage and thus conserves synovial fluid in the presence of raised intraarticular pressure. Weakening of the effect in joint effusions will help to limit the fluid retention.

1183

Anterior Crural Neuralgia as a Presenting Manifestation of Lymphocele

Miguel A. Gonzalez-Gay, Carlos Garcia-Porrua, Jose R. Pulpeiro, Francisco Branas, Luis Mateo-Cambon, and Teresa Hernandez

1184

Vasculitis in an Old Tattoo

Gabriel S. Breuer and Caryn A. Libbey

1185

Renal Failure: A Risk Factor for Methotrexate Toxicity

W. Winn Chatham, Sarah L. Morgan, and Graciela S. Alarcon

1186

Romanus Spondylitis

Patrick Mercie and Jean-Pierre Leleu

1187

Hepatitis C Virus Infection in Patients with Sjogren's Syndrome and Non-Hodgkin's Lymphoma: Comment on the Article by Voulgarelis et al

Yoel Drucker

1187

Reply

M. Voulgarelis and H. M. Moutsopoulos

1187

Apoptosis of CD4+ T Cells in Sjogren's Syndrome: Comment on the Article by Zeher et al

Hanadi Kazkaz

1188

Reply

Zsuzsa Szondy and Istvan Szatmari

1188

Vitamin D in Corticosteroid-Induced Osteoporosis: Comment on the Article by Amin et al

H. Richard Barthel and Erich Schacht

1189

Reply

Shreyasee Amin, Michael P. LaValley, Robert W. Simms, and David T. Felson

1190

Interferon-[gb]1a-Induced Juvenile Chronic Arthritis in a Genetically Predisposed Young Patient with Multiple Sclerosis: Comment on the Case Report by Levesque et al

Ricardo Russo, Silvia Tenembaum, Maria J. Moreno, and Cristina Battagliotti

1190

Reply

Marc C. Levesque, Frances E. Ward, Douglas R. Jeffery, and J. Brice Weinberg

27A

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