1191

In Appreciation of William P. Arend, MD: Editor, Arthritis & Rheumatism, 1995-2000

Gary S. Hoffman and Jane S. Diamond

1192

Review: Intraarticular Injection of Hyaluronan as Treatment for Knee Osteoarthritis: What is the Evidence?

Kenneth D. Brandt, Gerald N. Smith, Jr., and Lee S. Simon

1204

Review: Natural Killer Cells and Natural Killer T Cells

William E. Seaman

1218

Lytic Epstein-Barr Virus Infection in the Synovial Tissue of Patients with Rheumatoid Arthritis

Tsuyoshi Takeda, Yuzo Mizugaki, Lina Matsubara, Shosuke Imai, Takao Koike, and Kenzo Takada

In this study, synovial tissues were obtained from RA patients and control patients with osteoarthritis at synovectomy or arthroplasty, and EBV DNA was detected by Southern blot hybridization and/or polymerase chain reaction amplification. The study shows that there is an extremely high EBV load in the synovial tissue of RA, as demonstrated by direct Southern blot analysis of genomic DNA. Immunohistochemical staining and in situ hybridization analyses indicated that lytic EBV infection occurred in both lymphocytes and synovial lining cells. These findings therefore suggest a possible role of EBV in the pathogenesis of RA.

1226

Differential Expression Pattern of Membrane-Type Matrix Metalloproteinases in Rheumatoid Arthritis

Thomas Pap, Yukio Shigeyama, Stefan Kuchen, Janet K. Fernihough, Beat Simmen, Renate E. Gay, Michael Billingham, and Steffen Gay

Using reverse transcription-polymerase chain reaction, in situ hybridization, and immunohistochemistry, these studies demonstrate differences in the expression pattern of 4 novel membrane-type matrix metalloproteinases (MT-MMPs) in RA. It is shown that in contrast to normal synovium, MT1-MMP is expressed most intensively in RA synovium, with prominent staining in fibroblasts and macrophages of the lining layer. MT3-MMP is also markedly expressed in RA synovium, whereas only limited staining in some fibroblasts is seen for MT2- and MT4-MMP. The data suggest a role for MT1-MMP, and potentially for MT3-MMP, in the matrix degradation in RA.

1233

Human Cartilage gp-39+,CD16+ Monocytes in Peripheral Blood and Synovium: Correlation with Joint Destruction in Rheumatoid Arthritis

Dominique Baeten, Annemieke M. H. Boots, Peter G. A. Steenbakkers, Dirk Elewaut, Ebo Bos, Gijs F. M. Verheijden, Gust Verbruggen, Andre M. M. Miltenburg, Antonius W. M. Rijnders, Eric M. Veys, and Filip De Keyser

Human cartilage (HC) gp-39 has recently been proposed as an autoantigen in RA. HC gp-39 mRNA is present in cartilage and synovial tissue in RA, and both serum and synovial fluid levels are elevated. Little is known, however, about the cellular source of HC gp-39 in vivo and its expression pattern in the joint. In this study, CD16+ cells were shown to be a cellular source of HC gp-39 in RA, and synovial expression of HC gp-39 was correlated with joint destruction. Identification of HC gp-39-producing cells in peripheral blood and the joint could contribute to a better understanding of its role in inflammation and joint destruction and lead to new therapeutic approaches in RA.

1244

Macrophage-Derived Cytokine and Nuclear Factor [gk]B p65 Expression in Synovial Membrane and Skin of Patients with Psoriatic Arthritis

C. L. Danning, G. G. Illei, C. Hitchon, M. R. Greer, D. T. Boumpas, and I. B. McInnes

This study demonstrates the presence and distribution of key pro- and antiinflammatory cytokines in the synovium and skin of patients with PsA and demonstrates modest divergence from the pattern of expression seen in the synovium of patients with rheumatoid arthritis. With increasing availability of novel therapeutic antiinflammatory cytokines or agents targeting cytokines, the present data will be critical to facilitate rapid application of such therapies to PsA.

1257

Dysregulated Intracellular Ca2+ Stores and Ca2+ Signaling in Synovial Fluid T Lymphocytes from Patients with Chronic Inflammatory Arthritis

David M. Carruthers, Helen P. Arrol, Paul A. Bacon, and Stephen P. Young

Calcium ions are intracellular second messengers essential to the regulation of diverse T cell functions, ranging from activation to cell death. This study demonstrates changes in the temporal and spatial control of local and global Ca2+ concentrations in T cells from patients with chronic inflammatory arthritis, most prominent in cells isolated from synovial fluid. The authors propose that these novel observations contribute to the well-described alteration in T cell function seen in rheumatoid arthritis T cells.

1266

Temporal Expression of Inflammatory Cytokines and Chemokines in Rat Adjuvant-Induced Arthritis

Zoltan Szekanecz, Margaret M. Halloran, Michael V. Volin, James M. Woods, Robert M. Strieter, G. Kenneth Haines, III, Steven L. Kunkel, Marie D. Burdick, and Alisa E. Koch

Proinflammatory cytokines and chemokines are key players in chronic inflammation, and thus in the pathogenesis of rheumatoid arthritis (RA). In this study, clinical and laboratory assessments of the course of rat AIA, a model relevant to human RA, were performed over a 47-day period. The study showed the temporal and spatial regulation of cytokine and chemokine expression during the course of the rat AIA. Targeting the production of these inflammatory mediators in animal models of arthritis, and later in humans, may be important for specific antirheumatic therapy.

1278

Identification of Four New Quantitative Trait Loci Regulating Arthritis Severity and One New Quantitative Trait Locus Regulating Autoantibody Production in Rats with Collagen-Induced Arthritis

Marie M. Griffiths, Jianping Wang, Bina Joe, Svetlana Dracheva, Yutaka Kawahito, Jennifer S. Shepard,
 Van R. Reese, Shawna McCall-Vining, Akira Hashiramoto, Grant W. Cannon, Elaine F. Remmers, and Ronald L. Wilder

Collagen-induced arthritis is a suitable rat model for identifying candidate genetic loci that may govern susceptibility to several human chronic inflammatory/autoimmune diseases. This study suggests that a large number of genes, both major histocompatibility complex (MHC)-linked and outside of the MHC, may regulate susceptibility to complex diseases such as rheumatoid arthritis (RA). Identification of these regulatory loci in a surrogate disease model will greatly enhance the rate at which the human RA disease genes are identified. Knowledge of the genetic background of RA will permit the identification of novel drug targets and safer, patient-individualized therapeutic protocols.

1290

Selective Inhibition of Inducible Nitric Oxide Synthase Reduces Progression of Experimental Osteoarthritis In Vivo: Possible Link with the Reduction in Chondrocyte Apoptosis and Caspase 3 Level

Jean-Pierre Pelletier, Dragan V. Jovanovic, Viorica Lascau-Coman, Julio C. Fernandes, Pamela T. Manning, Jane R. Connor, Mark G. Currie, and Johanne Martel-Pelletier

This study shows that the selective inhibition of iNOS in experimental OA could reduce progression of the structural changes of the disease. It also demonstrates that the effect could be related, at least in part, to the reduction in the level of caspase 3, an enzyme known to play an important role in vivo in the mechanisms leading to cellular apoptosis.

1300

Reduction of Interleukin-17-Induced Inhibition of Chondrocyte Proteoglycan Synthesis in Intact Murine Articular Cartilage by Interleukin-4

Erik Lubberts, Leo A. B. Joosten, Fons A. J. van de Loo, Liduine A. M. van den Bersselaar, and Wim B. van den Berg

IL-17 is a novel cytokine that is secreted by activated T cells and produced in the synovium of rheumatoid arthritis (RA) patients. This study shows that IL-17, like IL-1, inhibits chondrocyte proteoglycan synthesis through a nitric oxide-mediated pathway, indicating a contribution to joint destruction. IL-4-pretreated cartilage is less sensitive to the suppressive effect of IL-17, indicating that IL-4 is protective in T cell-driven cartilage disturbances. Since IL-4 is not expressed in RA synovium, the data have significant implications for the prevention of cartilage damage in RA. Furthermore, IL-4 may contribute to the modulation of the uneven balance of Th1/Th2 and to the destructive nature of RA. Thus, it seems warranted to try IL-4 treatment protocols in RA.

1307

Profile of Glycosaminoglycan-Degrading Glycosidases and Glycoside Sulfatases Secreted by Human Articular Chondrocytes in Homeostasis and Inflammation

Alexander R. Shikhman, Diana C. Brinson, and Martin Lotz

Glycosidases and glycoside sulfatases represent an important, but as yet poorly studied, group of enzymes that participate in cartilage matrix degradation. The present study analyzed these enzymes in cultured human articular chondrocytes and revealed that hexosaminidase is the dominant secreted glycosidase, and it is selectively up-regulated by interleukin-1[gb]. The profile of glycosidases and glycoside sulfatases in synovial fluid from patients with osteoarthritis was found to be similar to that in cultured chondrocytes.

1315

Stimulation of Hyaluronan Metabolism by Interleukin-1[ga] in Human Articular Cartilage

Yoshihiro Nishida, Aloma L. D'Souza, Eugene J.-M. A. Thonar, and Warren Knudson

Degenerative joint diseases such as osteoarthritis are characterized by a dramatic loss of extracellular matrix components such as hyaluronan. This study indicates that a change in the principal role of chondrocyte CD44, which mediates the uptake of hyaluronan in human articular cartilage, appears to occur following treatment of the cartilage with IL-1[ga], i.e., from matrix assembly and retention to hyaluronan internalization. Since hyaluronan plays a key role in the retention of the cartilage proteoglycan aggrecan, depletion of hyaluronan in the upper layers of the tissue is likely to be a factor in the prominent loss of aggrecan from the tissue.

1327

Small Nucleolar RNP Scleroderma Autoantigens Associate with Phosphorylated Serine/Arginine Splicing Factors During Apoptosis

Karin Overzet, Timothy J. Gensler, Susan J. Kim, Meghan E. Geiger, Walther J. van Venrooij, K. Michael Pollard, Paul Anderson, and Paul J. Utz

The etiology of the autoimmune response to nucleolar proteins that is characteristic of scleroderma is currently unknown. In this study, a panel of monoclonal antibodies derived from mice exposed to mercury (a well-characterized murine model of the anti-snoRNP autoimmune response) was screened for the ability to selectively precipitate phosphoproteins from radiolabeled lysates prepared from Jurkat T cells subjected to stressful stimuli. The study demonstrates that a subset of scleroderma autoantigens is posttranslationally modified during apoptosis. Although the study does not address this question, it is possible that these modified proteins may be recognized as foreign, promoting the formation of specific autoantibodies.

1337

Treatment of Rolling Neutrophils with Antineutrophil Cytoplasmic Antibodies Causes Conversion to Firm Integrin-Mediated Adhesion

David J. Radford, Caroline O. S. Savage, and Gerard B. Nash

This study used an in vitro, flow-based adhesion assay to examine the effects of ANCA on neutrophil adhesion and demonstrated that ANCA can directly activate flowing neutrophils to adhere firmly to a model vessel wall. In vivo, these adherent neutrophils may obstruct flow, initiate tissue damage, and contribute to the pathogenesis of systemic vasculitis.

1345

Erratum: Incomplete Listing of Leflunomide Rheumatoid Arthritis Investigators Group Members in Articles by Sharp et al and Tugwell et al (Arthritis Rheum, March 1999)

1346

Successful Treatment of Active Ankylosing Spondylitis with the Anti-Tumor Necrosis Factor [ga] Monoclonal Antibody Infliximab

Jan Brandt, Hildrun Haibel, Daniel Cornely, Werner Golder, Jose Gonzalez, Jaqueline Reddig, Wolfgang Thriene, Joachim Sieper, and Jurgen Braun

AS can have a severe and progressive course in young patients. To date, there has not been an effective therapy for this disease. The results of this study strongly suggest that anti-TNF[ga] is efficacious in the treatment of active AS.

1353

The X-Chromosome and Susceptibility to Ankylosing Spondylitis

Emma Hoyle, Steven H. Laval, Andrei Calin, B. Paul Wordsworth, and Matthew A. Brown

The published sex ratio for AS has ranged from 10:1 (male:female) to the more recent and widely accepted range of 2.5:1-5:1. A biologic explanation is needed for the exaggerated male preponderance in AS. This linkage study was performed with 234 affected sibling pairs to determine any contribution of the X-chromosome to AS susceptibility. The study shows that the gender bias is not due to a significant X-chromosomal genetic effect.

1356

The Familial Form of Spondylarthropathy: A Clinical Study of 115 Multiplex Families

Roula Said-Nahal, Corinne Miceli-Richard, Jean-Marie Berthelot, Agnes Duche, Emmanuelle Dernis-Labous, Genevieve Le Blevec, Alain Saraux, Aleth Perdriger, Sandrine Guis, Pascal Claudepierre, Jean Sibilia, Bernard Amor, Maxime Dougados, and Maxime Breban, on Behalf of Groupe Francais D'Etude Genetique Des Spondylarthropathies

This clinical study identified a cohort of 329 SpA patients from 115 multiplex families. The main features of familial SpA were a sex ratio close to 1 and high frequencies of axial skeletal involvement and HLA-B27 positivity (97% each). Most manifestations appeared randomly distributed in families, suggesting that ubiquitous genetic or environmental factors contribute to phenotype diversity.

1366

Primary Association of Tumor Necrosis Factor-Region Genetic Markers with Susceptibility to Rheumatoid Arthritis

Alfonso Mart|finez, Miguel Fernandez-Arquero, Dora Pascual-Salcedo, Laura Conejero, Helena Alves,
 Alejandro Balsa, and Emilio G. de la Concha

This study showed an independent association of genetic markers near the TNF gene region with susceptibility to RA. This points to a nearby gene having a primary pathogenic role, with the gene coding for TNF[ga] itself being an interesting possibility.

1371

Antineutrophil Cytoplasmic Antibodies in Patients with Early Rheumatoid Arthritis: An Early Marker of Progressive Erosive Disease

Anu Mustila, Leena Paimela, Marjatta Leirisalo-Repo, Heini Huhtala, and Ari Miettinen

This study evaluated the clinical associations of ANCA in patients with early RA, as well as the possible predictive role of ANCA, and also assessed the overlap of ANCA with other specific serologic markers of RA. The study findings strongly suggest that the presence of perinuclear ANCA in early RA independently predicts more rapid radiographic joint destruction. Clinicians need differentiating prognostic markers in early RA to help make decisions about early, aggressive treatment with disease-modifying antirheumatic drugs, which are more effective but may have harmful, even toxic, side effects.

1378

Computer-Based Methods for Measuring Joint Space and Estimating Erosion Volume in the Finger and Wrist Joints of Patients with Rheumatoid Arthritis

John T. Sharp, Jill C. Gardner, and Earl M. Bennett

In this study, computer-based methods for measuring joint space width and estimating erosion volume were either comparable with or more sensitive than standard methods of scoring radiographic disease progression in the finger and wrist joints of patients with RA. Although scoring films has proven useful in many therapeutic trials, increased reliability and sensitivity in detecting treatment effects would be helpful in the development of new disease-controlling antirheumatic therapies.

1387

Social, Emotional, and Behavioral Functioning of Children with Juvenile Rheumatoid Arthritis

Robert B. Noll, Kathryn Kozlowski, Cynthia Gerhardt, Kathryn Vannatta, Janalee Taylor, and Murray Passo

This work examines the social, emotional, and behavioral functioning of children with JRA from the perspective of teachers, peers, parents, and the children themselves. The findings suggest that children with JRA function well in these broad domains, and compared with other sources of information, mothers may overreport difficulties. The data suggest that broad psychosocial programs may not be necessary for all children with JRA and when children with JRA are having significant psychological problems, they may not be caused by JRA.

1397

Polymorphism at NRAMP1 and D2S1471 Loci Associated with Juvenile Rheumatoid Arthritis

C. B. Sanjeevi, E. N. Miller, P. Dabadghao, I. Rumba, A. Shtauvere, A. Denisova, D. Clayton, and J. M. Blackwell

In this study, DNA from JRA patients and healthy controls was genotyped for a functional repeat polymorphism in the promoter of NRAMP1 and a linked microsatellite D2S1471. The study determined which alleles conferred increased risk of, or protection against, JRA. Understanding how the NRAMP1 gene influences susceptibility will lead to a better understanding of the molecular pathology associated with JRA, and of the possible interventions that may be developed. Of particular interest is the possibility that NRAMP1 is directly involved in rheumatoid joints through the deposition of iron, and indirectly through orchestration of the inflammatory response.

1405

Nephrotic-Range Proteinuria, the Major Risk Factor for Early Atherosclerosis in Juvenile-Onset Systemic Lupus Erythematosus

Francesco Falaschi, Angelo Ravelli, Alessandra Martignoni, Daniela Migliavacca, Marta Sartori, Angela Pistorio, Guido Perani, and Alberto Martini

Cardiovascular and cerebrovascular diseases due to premature atherosclerosis are important comorbid conditions in patients with SLE. In this study, the carotid intima-media wall thickness was measured by B-mode ultrasound in 26 patients with juvenile-onset SLE. The results suggest that patients with nephrotic-range proteinuria are at higher risk of developing premature atherosclerosis.

1410

The Use of Alternative Medical Therapies in Patients with Systemic Lupus Erythematosus

Andrew D. Moore, Michelle A. Petri, Susan Manzi, David A. Isenberg, Caroline Gordon, Jean-Luc Senecal, Yvan St. Pierre, Lawrence Joseph, John Penrod, Paul R. Fortin, Nurhan Sutcliffe, Jean Richard Goulet, Denis Choquette, Tamara Grodzicky, John M. Esdaile, and Ann E. Clarke, for the Trination Study Group

This study demonstrates that the use of alternative medical therapies in patients with SLE is common and may be a marker for poorer physical health status as rated by the patient and increased care-seeking behavior. Physicians should be aware of these findings and should obtain a detailed history of alternative medicine use by their patients.

1418

``G'' Stands for Gout

John D. Carter, Frank B. Vasey, Joanne Valeriano-Marcet, and Keith S. Kanik

1419

Val58Ile Polymorphism of the Neutrophil Chemoattractant LECT2 and Rheumatoid Arthritis in the Japanese Population

Yosuke Kameoka, Satoshi Yamagoe, Yoshimi Hatano, Tsuyoshi Kasama, and Kazuo Suzuki

1420

Nail Shedding (Beau's Lines) After Severe Gold Dermatitis

E. J. ter Borg, C. G. Ramselaar, and E. H. H. Wiltink

1421

Poly(ADP)-Ribose Polymerase and Susceptibility to Systemic Lupus Erythematosus and Primary Antiphospholipid Syndrome: Comment on the Article by Delrieu et al

Filemon K. Tan, John D. Reveille, Frank C. Arnett, David N. Stivers, and Betty P. Tsao

1422

Reply

O. Delrieu, E. Tournier-Lasserve, and J. C. Piette, for the Group for Research on Auto-Immune Disorders

1423

Analysis of the Association of the Matrillin-1 Gene (CRTM) with Osteoarthritis: Comment on the Article by Meulenbelt et al

John Loughlin, Barbara Dowling, Zehra Mustafa, Anne Smith, Bryan Sykes, and Kay Chapman

1424

Reply

Ingrid Meulenbelt, P. Eline Slagboom, and Cornelia van Duijn

1425

Diagnosis of Osteoarthritis in Relation to Molecular Processes in Cartilage: Comment on the Article by Clark et al

Bengt Mansson, Dick Heinegard, and Tore Saxne

1426

Reply

Virginia B. Kraus, Amy G. Clark, Joanne M. Jordan, Anca D. Dragomir, Gheorghe Luta, and Vladimir Vilim

1427

Trends in the Inflammatory Response in Biopsy-Proven Giant Cell Arteritis: Comment on the Article by Cid et al, and the Letters by Nesher and Sonnenblick and Liozon et al

Miguel A. Gonzalez-Gay, Carlos Garc|fia-Porrua, Pilar Rodr|figuez-Ledo, and Javier Llorca

1428

Reply

Maria C. Cid, Carme Font, Jose Hernandez-Rodr|figuez, Alejandro de la Sierra, Blanca Coll-Vinent, Alfons Lopez-Soto, Alvaro Urbano-Marquez, and Josep M. Grau

17A

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