715

ACR Presidential Address: On the Edge of the Millennium: Prospects and Problems for Our Patients and Us

Bevra Hannahs Hahn

720

Conference Summary: Report on the Fourth International Workshop on Reactive Arthritis

Joachim Sieper, Jurgen Braun, and Gabrielle H. Kingsley

734

New Manuscripts to be Sent to Dr. David Pisetsky

735

Involvement of Fc[gg] Receptor IIIA Genotypes in Susceptibility to Rheumatoid Arthritis

Antonio Nieto, Rafael Caliz, Maria Pascual, Luis Mataran, Sergio Garcia, and Javier Martin

This study reveals a novel risk factor, the Fc[gg]RIIIA-158FF genotype, for RA. The significance of Fc[gg] receptors, particularly Fc[gg]RIII, in type II and III hypersensitivity reactions has been firmly established. Therapies focused on Fc[gg]R are currently under development. In addition to a better understanding of the disease, this study may help in the identification of individuals at higher risk for RA and other autoimmune conditions. In the future, this marker may be useful in the selection of patients for a more specific treatment.

740

Role of Fc Receptor [gg] Chain in Inflammation and Cartilage Damage During Experimental Antigen-Induced Arthritis

P. L. E. M. van Lent, A. J. van Vuuren, A. B. Blom, A. E. M. Holthuysen, L. B. A. van de Putte, J. G. J. van de Winkel, and W. B. van den Berg

This study investigated the role of FcR [gg] chain, which is an essential component of FcR recognizing IgG-containing immune complexes, in severe cartilage destruction during chronic arthritis. The FcR [gg] chain appeared to be a crucial factor in the induction of cartilage erosion, probably by regulating activation of latent metalloproteinases present in the cartilage matrix. FcR may be a new target for future therapy in RA.

753

Tumor Necrosis Factor [ga] 5`-Flanking Region, Tumor Necrosis Factor Receptor II, and HLA-DRB1 Polymorphisms in Japanese Patients with Rheumatoid Arthritis

Tsukasa Shibue, Naoyuki Tsuchiya, Tae Komata, Masaki Matsushita, Michiko Shiota, Jun Ohashi, Masatoshi Wakui, Kunio Matsuta, and Katsushi Tokunaga

The substantial role of TNF[ga] in the pathogenesis of RA is widely recognized. In this study, the contribution of the polymorphisms in the recently described TNFA upstream promoter region, TNFR2 and HLA-DRB1, were examined in patients with RA. Among the 3 genes, HLA-DRB1 was most strongly associated with RA. These results will help us to understand the genetic contribution of HLA and TNF[ga] to RA.

758

Noninherited Maternal Antigens Do Not Play a Role in Rheumatoid Arthritis Susceptibility in Europe

P. Barrera, A. Balsa, H. Alves, R. Westhovens, K. Maenaut, F. Cornelis, P. Fritz, T. Bardin, G. de Almeida, A. Lopes-Vaz, D. Pascual Salcedo, E. G. de la Concha, T. R. D. J. Radstake, L. B. A. van de Putte, P. Migliorini, J. F. Prud'homme, D. Charron, M. Spyropoulou, A. Mendes, M. Spaepen, M. Martinez, V. Lepage, and C. Stravopoulos, for the European Consortium on Rheumatoid Arthritis Families

It has been long recognized that genetic factors, especially those related to HLA, play a role in susceptibility to RA. The immunologic system of mother and child are in close contact during fetal life, and it has been suggested that noninherited maternal HLA-DR alleles might play a role in RA susceptibility in non-genetically predisposed patients. In the present study of a large sample of European families, this hypothesis could not be confirmed.

765

Selective Recruitment of Polarized T Cells Expressing CCR5 and CXCR3 to the Inflamed Joints of Children with Juvenile Idiopathic Arthritis

Lucy R. Wedderburn, Nicola Robinson, Alka Patel, Hemlata Varsani, and Patricia Woo

This is the first study of chemokine receptor expression in juvenile idiopathic arthritis. The study addresses the hypothesis that synovial T cells in juvenile arthritis may express different chemokine receptors from those found on peripheral blood T cells and that this may lead to selective recruitment of inflammatory T cells to the joint. In addition, it demonstrates a strongly polarized Th1-type cytokine balance in synovial T cells. An understanding of the mechanisms that mediate recruitment of these cells to the inflamed joint should allow for the logical design of new therapeutic agents that either prevent this migration or restore the cytokine balance within the joint.

775

Identification of Known and Novel Genes in Activated Monocytes from Patients with Rheumatoid Arthritis

Bruno Stuhlmuller, Ute Ungethum, Susann Scholze, Lorena Martinez, Marina Backhaus, Hans-G. Kraetsch, Raimund W. Kinne, and Gerd-R. Burmester

Differential activation of known and novel genes was observed in activated (first leukapheresis) versus nonactivated (third leukapheresis) monocytes (MO) from 3 patients with RA. Overexpression (maximum 102-fold compared with normal subjects) of these genes was verified by reverse transcriptase-polymerase chain reaction (RT-PCR) in MO from an additional 26 RA patients. Notably, the messenger RNA levels of some novel genes correlated (positively or negatively) with the erythrocyte sedimentation rate and the C-reactive protein level. The combined strategy of differential gene analysis and semiquatitiative RT-PCR may open new avenues for defining MO activation patterns during different disease phases (including therapy-induced remission) and for identifying novel MO genes with pathogenetic relevance in RA.

791

Differentiated Dendritic Cells Expressing Nuclear RelB are Predominantly Located in Rheumatoid Synovial Tissue Perivascular Mononuclear Cell Aggregates

Allison R. Pettit, Kelli P. A. MacDonald, Brendan O'Sullivan, and Ranjeny Thomas

The frequency and distribution of cells expressing nuclear RelB, a marker of differentiated and functional dendritic cells (DC), were examined among peripheral blood and synovial fluid (SF) cells and in synovial tissue (ST) of patients with RA. Rheumatoid SFDC appear to be maintained in a less-differentiated state than DC in ST. Thus, DC in adjacent synovial compartments are likely to have received different activation signals, resulting in a subset of fully differentiated, potent, antigen-presenting cells in perivascular MNC aggregates of ST, and also resulting in a subset of SFDC that have the functional potential to capture, process, and present antigens in vivo.

801

Interleukin-1 Induction of Collagenase 3 (Matrix Metalloproteinase 13) Gene Expression in Chondrocytes Requires p38, c-Jun N-Terminal Kinase, and Nuclear Factor [gk]B: Differential Regulation of Collagenase 1 and Collagenase 3

John A. Mengshol, Matthew P. Vincenti, Charles I. Coon, Aaron Barchowsky, and Constance E. Brinckerhoff

Osteoarthritic chondrocytes secrete collagenase 3 (MMP-13), which then degrades type II collagen in articular cartilage. The inflammatory cytokine IL-1 plays a central role in osteoarthritis pathogenesis, in part by inducing expression of MMP-13 in chondrocytes. This work examines the mechanism of collagenase-3 gene regulation by IL-1.

812

Production of Tissue Inhibitor of Metalloproteinases 3 is Selectively Enhanced by Calcium Pentosan Polysulfate in Human Rheumatoid Synovial Fibroblasts

Masayuki Takizawa, Eiko Ohuchi, Hajime Yamanaka, Hiroyuki Nakamura, Eiji Ikeda, Peter Ghosh, and Yasunori Okada

This study investigated the effects of a new antiarthritic drug, CaPPS, on the production of matrix metalloproteinases and their endogenous regulators, TIMP, in cultures of rheumatoid synovial fibroblasts. The study shows for the first time that CaPPS selectively enhances TIMP-3 production at the posttranscription level in cultured rheumatoid synovial fibroblasts and in the lining cells of rheumatoid synovium. By this mechanism, CaPPS may be able to modulate joint tissue destruction in rheumatoid arthritis.

821

Expression of Osteoclast Differentiation Factor at Sites of Bone Erosion in Collagen-Induced Arthritis

Evan Romas, Olga Bakharevski, Daphne K. Hards, Vicky Kartsogiannis, Julian M. W. Quinn, Peter F. J. Ryan, T. John Martin, and Matthew T. Gillespie

Bone loss is a critical feature of rheumatoid arthritis; however, few therapeutic interventions have been identified to stop bone loss, and its mechanisms are only partly understood. The results of this study indicate that the inflamed synovium in rats with CIA is a source of the osteoclast differentiation factor (also known as receptor activator of nuclear factor [gk]B ligand) and that osteoclasts are responsible for focal bone destruction. These lines of investigation provide a rationale for directly targeting the cellular mechanism responsible for bone erosion in rheumatoid arthritis.

827

Regulation of Macrophage Migration Inhibitory Factor by Endogenous Glucocorticoids in Rat Adjuvant-Induced Arthritis

Michelle Leech, Christine Metz, Richard Bucala, and Eric F. Morand

This study explored the regulation of MIF by endogenous glucocorticoids in rat AIA. AIA was induced in adrenalectomized (ADX) or sham-operated rats, and either anti-MIF monoclonal antibody (mAb) or isotype-matched control antibody was administered to ADX rats. Adrenalectomy was associated with reduced levels of synovial MIF and increased levels of serum and pituitary MIF, and the anti-MIF mAb conferred 100% protection from lethality during arthritis development while decreasing disease expression in survivors. The study provides the first in vivo confirmation of the interaction among glucocorticoids, MIF, and inflammation.

834

CD8+,CD57+ T Cells from Healthy Elderly Subjects Suppress Neutrophil Development in Vitro: Implications for the Neutropenia of Felty's and Large Granular Lymphocyte Syndromes

G. Coakley, M. Iqbal, D. Brooks, G. S. Panayi, and J. S. Lanchbur

This study addressed the clinically challenging problem of neutropenia in Felty's and large granular lymphocyte syndromes. The results demonstrated that large granular lymphocytes from normal individuals and from 1 of 6 patients with Felty's syndrome had the ability to suppress neutrophil precursors. The mechanism was shown to be independent of Fas/Fas ligand interactions and the chemokines interleukin-8 and macrophage inhibitory protein 1[ga]. These findings cast light on possible mechanisms by which cyclosporin A treatment may be effective for the neutropenia of these conditions.

844

T Lymphocytes are Not Required for the Spontaneous Development of Entheseal Ossification Leading to Marginal Ankylosis in the DBA/1 Mouse

Alexandre Corthay, Ann-Sofie Hansson, and Rikard Holmdahl

This study examined the role of T lymphocytes in naturally occurring arthritis in male DBA/1 mice by using mice lacking either [ga]/[gb] or [gg]/[gd] T cells due to a deletion in T cell receptor [gb] (TCR[gb]) or TCR[gd] genes. The study shows that this arthritis is an enthesopathy characterized by periarticular hyperostosis and marginal ankylosis, and that it does not require the presence of [ga]/[gb] or [gg]/[gd] T lymphocytes. These findings suggest that the ossification leading to peripheral ankylosis of the joints in human enthesopathies, such as diffuse idiopathic skeletal hyperostosis and seronegative spondylarthropathies, is a T cell-independent process.

851

Arthritis & Rheumatism and Arthritis Care and Research Available Online

852

Serum Matrix Metalloproteinase 3 as a Predictor of the Degree of Joint Destruction During the Six Months After Measurement, in Patients with Early Rheumatoid Arthritis

Hisashi Yamanaka, Yuko Matsuda, Michi Tanaka, Wako Sendo, Hiroshi Nakajima, Atsuo Taniguchi, and Naoyuki Kamatani

This study shows the significance of elevation of the serum concentration of MMP-3 in patients with recent-onset RA. The level of serum MMP-3 in patients with early RA showed a correlation with the progression of joint damage in the subsequent 6-12 months of disease. Thus, MMP-3 is a useful marker for predicting bone damage in early RA, and especially useful for deciding when aggressive therapy is indicated.

859

Influence of Polymorphism in the Manganese Superoxide Dismutase Locus on Disease Outcome in Rheumatoid Arthritis: Evidence for Interaction with Glutathione S-Transferase Genes

Derek L. Mattey, Andrew B. Hassell, Peter T. Dawes, Peter W. Jones, Lilian Yengi, Julie Alldersea, Richard C. Strange, and Anthony A. Fryer

This study investigated whether polymorphism in the MnSOD gene is associated with susceptibility or erosive damage in RA. The results suggest that polymorphism in the MnSOD gene is not associated with susceptibility to RA, but it may influence the radiologic outcome of the disease. However, this relationship may not be independent of the effect of the HLA-DRB1 shared epitope (SE), although interaction between MnSOD and other reactive oxygen species-detoxifying genes (glutathione S-transferases) appears to influence radiologic outcome independently of the SE.

865

Joint Symmetry in Early and Late Rheumatoid and Psoriatic Arthritis: Comparison with a Mathematical Model

P. S. Helliwell, J. Hetthen, K. Sokoll, M. Green, A. Marchesoni, E. Lubrano, D. Veale, and P. Emery

PsA is considered to be a less symmetric disease than RA; however, joint symmetry is strongly influenced by the total number of joints involved, and this may explain this contrast. This study confirms that symmetry is largely a function of the total number of joints involved. The results show that there is no difference in symmetry between RA and PsA if the discrepancy in the number of involved joints (usually fewer in PsA) is taken into account. In diagnosing PsA, other distinctive features, such as dactylitis, enthesopathy, distal interphalangeal joint involvement, spinal involvement, and iritis, should be sought.

872

Responses of the Sympathetic Nervous System and the Hypothalamic-Pituitary-Adrenal Axis to Interleukin-6: A Pilot Study in Fibromyalgia

David J. Torpy, Dimitris A. Papanicolaou, Angela J. Lotsikas, Ronald L. Wilder, George P. Chrousos, and Stanley R. Pillemer

At present, the diagnosis of fibromyalgia is syndrome-based, treatment remains difficult, and the pathogenesis is not yet established. This report describes the first evidence of a striking exaggeration of norepinephrine release after stimulation with IL-6 and a mild delay in adrenocorticotropic hormone release in patients with fibromyalgia. A marked increase in heart rate after IL-6 stimulation in patients compared with controls subjects is also reported. The results support the hypothesis that fibromyalgia may be a primary, centrally mediated, stress system disorder, with a corresponding defect in inhibition of pain neurotransmission.

881

Autoantibody Recognition of Distinctly Modified Forms of the U1-70-kd Antigen is Associated with Different Clinical Disease Manifestations

Eric L. Greidinger, Livia Casciola-Rosen, Steven M. Morris, Robert W. Hoffman, and Antony Rosen

This study provides evidence in human subjects that autoimmune responses to different modified forms of a self antigen may predict the biologic phenotype of rheumatic disease. The findings demonstrate that an immune response to the apoptotically cleaved form of the U1-70-kd RNP autoantigen is associated with cutaneous lupus manifestations, while a response to the oxidatively modified form of this antigen is associated with Raynaud's phenomenon. Tests for autoimmune responses to modified self antigens may prove useful in the diagnosis and stratification of rheumatic diseases.

889

Increased Concentrations of the Circulating Angiogenesis Inhibitor Endostatin in Patients with Systemic Sclerosis

Mohamed Hebbar, Jean-Philippe Peyrat, Louis Hornez, Pierre-Yves Hatron, Eric Hachulla, and Bernard Devulder

Endostatin is an angiogenesis inhibitor derived from type XVIII collagen. This study demonstrates increased concentrations of circulating endostatin in most patients with systemic sclerosis. Production of endostatin could result from tissular sclerosis and could represent a link between this sclerosis and some vascular manifestations.

894

Abnormalities of Erythrocyte Membrane Fluidity, Lipid Composition, and Lipid Peroxidation in Systemic Sclerosis: Evidence of Free Radical-Mediated Injury

Roser Solans, Claude Motta, Rosa Sola, Agnes E. La Ville, Joan Lima, Pilar Simeon, Nuria Montella, Lluis Armadans-Gil, Vicent Fonollosa, and Miquel Vilardell

Recent studies have suggested that free radical species may play a role in the pathogenesis of SSc. The findings of this investigation support the idea that oxidative injury occurs in SSc and that, through lipid peroxidation, the erythrocyte membrane experiences structural and functional changes that may contribute to the development of the microvascular abnormalities seen in the disease.

901

Study of 52 Patients with Idiopathic Aortitis from a Cohort of 1,204 Surgical Cases

Francisco Rojo-Leyva, Norman B. Ratliff, Delos M. Cosgrove, III, and Gary S. Hoffman

This study was a retrospective chart and pathology review of aortic surgical specimens gathered over 20 years at a tertiary care medical center. Among 1,204 aortic surgical specimens, 52 (4.3%) were noted to have idiopathic inflammatory changes. Inflammatory aneurysms from this surgical series were generally not associated with systemic illness, and almost all were in the thoracic aorta. Cardiovascular surgeons are likely to consult rheumatologists for guidance in the management of patients with idiopathic aortitis.

908

Salivary Gland Lymphomas in Patients with Sjogren's Syndrome May Frequently Develop from Rheumatoid Factor B Cells

Thierry Martin, Jean-Christophe Weber, Honey Levallois, Nathalie Labouret, Anne Soley, Severine Koenig, Anne-Sophie Korganow, and Jean-Louis Pasquali

908 Previous sequence analyses of the Ig variable-region genes provided indirect evidence that B cell receptor-mediated selection might play a role in the genesis of salivary gland lymphomas that occur in patients with SS, and that a unique antigen might be involved. This report describes the specificities of the Ig expressed by 2 monoclonal B cell non-Hodgkin's lymphomas that developed in the salivary glands of 2 patients with SS. The results directly demonstrate that neoplastic B cells express RF. The reasons that RF-expressing B cells are frequently involved in B cell tumors are discussed.

917

Gastrointestinal Health Care Resource Use and Costs Associated with Nonsteroidal Antiinflammatory Drugs Versus Acetaminophen: Retrospective Cohort Study of an Elderly Population

Elham Rahme, Lawrence Joseph, Sheldon X. Kong, Douglas J. Watson, and Jacques LeLorier

NSAIDs continue to be the treatment of choice in rheumatoid arthritis (RA) and severe osteoarthritis (OA). However, acetaminophen is preferred in mild-to-moderate OA. Unfortunately, NSAIDs have been associated with both major and minor GI adverse events. This study estimates both the rates of occurrence and the costs of GI side effects in patients taking NSAIDs compared with patients taking acetaminophen. This information can aid clinicians in weighing the relative risks and benefits of NSAIDs, acetaminophen, and the newer cyclooxygenase 2 antiinflammatory agents in the management of RA and OA.

925

Localization of a Gene for Familial Juvenile Hyperuricemic Nephropathy Causing Underexcretion-Type Gout to 16p12 by Genome-Wide Linkage Analysis of a Large Family

Naoyuki Kamatani, Maki Moritani, Hisashi Yamanaka, Fujio Takeuchi, Tatsuo Hosoya, and Mitsuo Itakura

Gout is one of the most important diseases encountered by almost all rheumatologists. Although some genetic causes of gout are known, they are all linked to overproduction of urate rather than underexcretion. This study analyzed a single large family affected with FJHN and localized a gene for underexcretion-type gout to a 9-cM region on chromosome 16p. These findings will be useful for the presymptomatic diagnosis of FJHN in some families and for testing of genetic heterogeneity of FJHN in general.

929

Errata: Errors in Articles by Bredholt et al (Arthritis Rheum, December 1999) and Genereau et al (Arthritis Rheum, December 1999) and in Table of Contents Listing of Clinical Image by Erkan et al (Arthritis Rheum, March 2000)

930

Multicentric Reticulohistiocytosis: Case Report with Immunohistochemical Analysis and Literature Review

Jennifer D. Gorman, Carol Danning, H. Ralph Schumacher, John H. Klippel, and John C. Davis, Jr.

939

Autoreactivity Against Matrilin-1 in a Patient with Relapsing Polychondritis

Jane Hoyt Buckner, Jiann-Jiu Wu, Robert A. Reife, Kuniaki Terato, and David R. Eyre

943

Diagnosis and Treatment of Retroperitoneal Fibrosis (Ormond's Disease)

Jeanne M. Poitras and Gregory J. Dennis

944

Patients Receiving Etanercept May Develop Antibodies that Interfere with Monoclonal Antibody Laboratory Assays

E. Russell, M. Zeihen, S. Wergin, and T. Litton

945

Possible Correction of Abnormal Rheumatoid Arthritis Synovial Cell Function by jun D Transfection In Vitro: Comment on the Article by Wakisaka et al

Stefan Sickinger and Raimund W. Kinne

945

Tsuyoshi Sakane and Noboru Suzuki

946

Role of HLA-DQ in Rheumatoid Arthritis Susceptibility: Comment on the Article by de Vries et al Eric Zanelli, Koen Vos, Ferdinand Breedveld, Rene de Vries, and Chella David 946

Monika A. Reuss-Borst, Almut Geyer, and Beate Berner

947

Niek de Vries, Claudia van Elderen, Henk Tijssen, Piet L. C. M. van Riel, and Leo B. A. van de Putte

949

MRI Bone Erosions and MRI Bone Lesions in Early Rheumatoid Arthritis: Comment on the Article by McGonagle et al

Mikkel \Ostergaard

950

Dennis McGonagle, Philip Conaghan, and Paul Emery

950

Autoantibodies to Human Nuclear Lamin B1 in Systemic Lupus Erythematosus: Comment on the Article by Senecal et al

Sladjana Andrejevic, Branka Bonaci-Nikolic, Mirjana Bukilica, and Milos M. Nikolic

951

Jean-Luc Senecal and Yves Raymond

951

High Frequency of t(14;18) Translocation in Sjogren's Syndrome: Comment on the Article by Gellrich et al

Imre Semsei, Margit Zeher, Istvan Takacs, Laszlo Urban, Gyula Szegedi, and Michael Bachmann

29A

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