595

Editorial: A College for Its Teachers

David S. Pisetsky and Barbara White

599

The American College of Rheumatology Nomenclature and Case Definitions for Neuropsychiatric Lupus Syndromes

ACR Ad Hoc Committee on Neuropsychiatric Lupus Nomenclature

609

Review: Signal Transduction and Transcription Factors in Rheumatic Disease

Gary S. Firestein and Anthony M. Manning

622

Synovial Fluid CD146 (MUC18), a Marker for Synovial Membrane Angiogenesis in Rheumatoid Arthritis

Michel Neidhart, Rolf Wehrli, Pius Bruhlmann, Beat A. Michel, Renate E. Gay, and Steffen Gay

In this study, soluble CD146 was detected in the synovial fluid of patients with RA. The presence of soluble CD146 may predict vascular activity associated with RA.

631

IgG Anti-Endothelial Cell Autoantibodies from Patients with Systemic Lupus Erythematosus or Systemic Vasculitis Stimulate the Release of Two Endothelial Cell-Derived Mediators, Which Enhance Adhesion Molecule Expression and Leukocyte Adhesion in an Autocrine Manner

Dulce Carvalho, Caroline O. S. Savage, David Isenberg, and Jeremy D. Pearson

The present study demonstrates that purified IgG AECA from patients with SLE or systemic vasculitis can up-regulate leukocyte adhesion molecule expression on endothelial cells in vitro, with consequent increased leukocyte binding. This effect is due to the autocrine actions of interleukin-1 and a further novel mediator whose endothelial synthesis is induced by AECA. These results strengthen the evidence that AECA may be pathogenic in systemic diseases with a vasculitic component, and hence that their measurement may be of prognostic or therapeutic value.

641

Specific Targeting of Activated Endothelium in Rat Adjuvant Arthritis with a 99mTc-Radiolabeled E-Selectin-Binding Peptide

Kurt R. Zinn, Tandra R. Chaudhuri, Cheryl A. Smyth, Qi Wu, Hong-Gang Liu, Martin Fleck, John D. Mountz, and James M. Mountz

E-selectin is an adhesion molecule that is up-regulated on synovial endothelial cells in patients with arthritis. However, this assessment currently requires a synovial biopsy and histologic analysis. Noninvasive molecular nuclear medicine was applied to image the expression of E-selectin on activated endothelium during development of adjuvant-induced arthritis in rats. Early assessment of E-selectin up-regulation using molecular nuclear imaging methods may lead to identification and monitoring of this event for therapeutic intervention in humans.

650

Expression of the Activation Antigen CD97 and Its Ligand CD55 in Rheumatoid Synovial Tissue

Jorg Hamann, Jerome O. Wishaupt, Rene A. W. van Lier, Tom J. M. Smeets, Ferdinand C. Breedveld, and Paul P. Tak

Fibroblast-like synoviocytes (FLS) express decay-accelerating factor (CD55) at high levels. Recently, it was found that CD55 is a specific cellular ligand for the 7-span transmembrane receptor CD97. The results described in this study suggest that FLS are able to interact with macrophages via the CD97/CD55 receptor-ligand system. The CD97/CD55 receptor-ligand pair could account for the specific architecture of the intimal lining layer and might be of primary importance in maintaining and amplifying synovial inflammation.

659

Modulation of Hyaluronan Receptor (CD44) Function In Vivo in a Murine Model of Rheumatoid Arthritis

Katalin Mikecz, Kathryn Dennis, Mei Shi, and Jonathan H. Kim

It has been shown that an interaction between CD44 and hyaluronan is important for extravasation of leukocytes into inflammatory sites. By testing different anti-CD44 antibodies in vivo in a murine model of RA, this study identifies CD44 as a major mediator of cell-matrix interactions in the inflamed joint and, consequently, a target for therapeutic intervention in RA. In addition, this work reveals a unique mechanism by which CD44 function can be effectively down-regulated in vivo.

669

Different Mechanisms of Synovial Hyperplasia in Rheumatoid Arthritis and Pigmented Villonodular Synovitis: The Role of Telomerase Activity in Synovial Proliferation

Kazuo Yudoh, Hiroaki Matsuno, Takeshi Nezuka, and Tomoatsu Kimura

The results of this study suggest that telomerase activation in lymphocytes may be involved in the progression of synovitis and synovial proliferation in RA, and the enzyme activity in synoviocytes, but not in lymphocytes, may participate in hyperplasia of synovial villi in PVS. Analysis of telomerase activity might provide important insights not only in understanding the difference in the mechanisms of synovial hyperplasia or synovitis between RA and PVS, but also in the development of a novel therapy that regulates synovial tissue in these diseases.

678

Systemic Viral Interleukin-10 Gene Delivery Prevents Cartilage Invasion by Human Rheumatoid Synovial Tissue Engrafted in SCID Mice

Christian Jorgensen, Florence Apparailly, Francois Canovas, Claudie Verwaerde, Claude Auriault, Chantal Jacquet, and Jacques Sany

Immunotherapy in rheumatoid arthritis may be achieved through cytokine gene transfer. The findings of this study demonstrate the biologic effects of viral IL-10 systemic gene transfer through adenoviral vectors in the SCID-hu preclinical model of rheumatoid arthritis. IL-10 prevented cartilage invasion by synovial tissue engrafted in SCID mice.

686

Expression of Murine HOXD9 During Embryonic Joint Patterning and in Human T Lymphotropic Virus Type I TAX Transgenic Mice with Arthropathy Resembling Rheumatoid Arthritis

Nguyen Dinh Khoa, Tomoko Hasunuma, Tetsuji Kobata, Tomohiro Kato, and Kusuki Nishioka

This study examined expression of murine 5` HOXD genes, members of the homeobox family, during development of synovial joints and in human T lymphotropic virus type I tax transgenic mice with arthropathy resembling rheumatoid arthritis. The findings suggest that HOXD9 is not only involved in normal joint development, but may also be involved in the development of arthritis. Specific expression of HOXD9 and its possible regulatory mechanisms in arthritic joints might be linked to synovial hyperplasia during arthritis.

697

Autoantibodies in Primary Sjogren's Syndrome are Directed Against Proteasomal Subunits of the [ga] and [gb] Type

Eugen Feist, Ulrike Kuckelkorn, Thomas Dorner, Helge Donitz, Sonja Scheffler, Falk Hiepe, Peter-M. Kloetzel, and Gerd-R. Burmester

The antiproteasome response in primary Sjogren's syndrome is directed against several [ga] and [gb] subunits, including those which carry the proteolytic active sites of the proteasome complex. The results of this study indicate that the proteasome complex may play an important role as an autoantigen in primary Sjogren's syndrome. This could give new insights into the pathogenesis of systemic autoimmunity and may link the proteasome, a well-characterized mechanism of the immune defense, to mechanisms of humoral autoimmunity.

703

T Cell Receptor [gb]-Chain Third Complementarity-Determining Region Gene Usage is Highly Restricted Among Sm-B Autoantigen-Specific Human T Cell Clones Derived from Patients with Connective Tissue Disease

Beth L. Talken, Margaret-Mary Holyst, David R. Lee, and Robert W. Hoffman

In this study, it was observed that there are very limited gene segments used in the recognition of the Sm autoantigen by T cells, and that only a specific segment of the autoantigen is recognized when presented complexed with HLA-DR molecules on antigen-presenting cells. These observations have important implications for the design of future therapeutic approaches that would be directed to disrupt these specific T cell receptor-autoantigen interactions.

710

Inhibition of Tumor Necrosis Factor [ga]-Induced Prostaglandin E2 Production by the Antiinflammatory Cytokines Interleukin-4, Interleukin-10, and Interleukin-13 in Osteoarthritic Synovial Fibroblasts: Distinct Targeting in the Signaling Pathways

Nada Alaaeddine, John A. Di Battista, Jean-Pierre Pelletier, Kayghobad Kiansa, Jean-Marie Cloutier, and Johanne Martel-Pelletier

The proinflammatory cytokine TNF[ga] is an important catabolic factor in osteoarthritis. This study shows that the antiinflammatory cytokines IL-4, IL-10, and IL-13 are able to abrogate the TNF[ga]-induced production of PGE2 and provide a significant contribution to the mechanisms in the TNF[ga] signaling pathways.

719

Differential Patterns of Response to Doxycycline and Transforming Growth Factor [gb]1 in the Down-Regulation of Collagenases in Osteoarthritic and Normal Human Chondrocytes

Boris V. Shlopov, Gerald N. Smith, Jr., Ada A. Cole, and Karen A. Hasty

In this study, levels of fibroblast collagenase, neutrophil collagenase, and collagenase 3 were measured in chondrocytes from lesional and nonlesional areas of OA cartilage, and the effect of doxycycline, TGF[gb]1, and phorbol myristate acetate treatment on these levels was assessed. Incubation of OA chondrocytes with doxycycline at pharmacologically achievable doses resulted in decreased levels of mRNA and protein for all 3 collagenases. These findings suggest that doxycycline may regulate collagenase synthesis in OA chondrocytes, and may be an effective treatment in this disease.

728

A Prospective Analysis of Cognitive Function and Anticardiolipin Antibodies in Systemic Lupus Erythematosus

John G. Hanly, Connie Hong, Stephanie Smith, and John D. Fisk

Abnormalities in cognitive function, identified by standardized neuropsychological assessment, are a recognized manifestation of central nervous system lupus. The etiology of cognitive impairment in SLE is unknown. In this study, the association between anticardiolipin antibodies and change in cognitive function over 5 years was evaluated in 51 female SLE patients. The results indicate that persistent elevation of IgG and IgA anticardiolipin antibodies is associated with progressive deterioration in some aspects of cognitive function.

735

A Longitudinal Study of Anticardiolipin Antibody Levels and Cognitive Functioning in Systemic Lupus Erythematosus

S. Menon, E. Jameson-Shortall, S. P. Newman, M. R. Hall-Craggs, R. Chinn, and D. A. Isenberg

Patients with lupus are often cognitively impaired. This longitudinal study explores whether levels of anticardiolipin, anti-DNA, and C3 are associated with such impairment. The results strongly suggest that persistent elevations of anticardiolipin antibody levels, but not elevation of double-stranded DNA antibody levels or decreases in C3 levels, are linked to cognitive impairment, as judged by a wide-ranging set of neuropsychological tests.

742

Cytokine Profiles in Wegener's Granulomatosis: Predominance of Type 1 (Th1) in the Granulomatous Inflammation

Elena Csernok, Andreas Trabandt, Antje Muller, Guchoan C. Wang, Frank Moosig, Jens Paulsen, Armin Schnabel, and Wolfgang L. Gross

The findings of this study provide new information on the T cell cytokine profile in patients with WG which suggests that T cells play a role in the pathogenesis of WG. The data indicate that the type-1 cytokine pattern (Th1) predominates in the granulomatous inflammation of WG.

751

Wegener's Granulomatosis Associated with Renal Cell Carcinoma

Efstratios Tatsis, Eva Reinhold-Keller, Karen Steindorf, Alfred C. Feller, and Wolfgang L. Gross

This study examined the occurrence, types, and frequencies of malignancies in 477 patients with WG. Among 14 cases of simultaneous occurrence of cancer and WG, 5 cases of renal cell carcinoma could be identified, suggesting that malignancy, especially renal cell carcinoma, is in some cases a trigger for the development of WG. In practice, intense scrutiny of the patients at the time of diagnosis of WG is needed to exclude a concurrent malignant disease.

757

Quantifying the Exact Role of HLA-DRB1 Alleles in Susceptibility to Inflammatory Polyarthritis: Results from a Large, Population-Based Study

Wendy Thomson, Beverley Harrison, Bill Ollier, Nicola Wiles, Tony Payton, Jennifer Barrett, Deborah Symmons, and Alan Silman

Previous studies have not been able to clarify whether the influence of HLA-DRB1 on rheumatoid arthritis was related to disease susceptibility or to disease severity and progression. These data on a unique population-based incident cohort suggest only weak effects on susceptibility, with the exception of a clearly distinct influence of HLA-DRB1*0404.

763

Fertility and Pregnancy Outcome in Women with Systemic Sclerosis

Virginia D. Steen and Thomas A. Medsger, Jr.

This study compared fertility and pregnancy outcomes in women with scleroderma who had disease onset during the childbearing years, compared with women with rheumatoid arthritis and healthy controls. For most parameters, rates of infertility or adverse pregnancy outcomes were not increased among women with scleroderma, although the rate of premature births and delivery of small full-term infants was slightly increased among scleroderma patients whose pregnancy occurred after the onset of disease. These results indicate that fertility and pregnancy outcome are generally acceptable among women with scleroderma, and that if women with scleroderma have a well-timed pregnancy and are closely monitored, the risk of adverse outcome for the mother or baby is low.

769

Transitions in Employment, Morbidity, and Disability Among Persons Ages 51-61 with Musculoskeletal and Non-Musculoskeletal Conditions in the US, 1992-1994

Edward H. Yelin, Laura S. Trupin, and Douglas S. Sebesta

This study uses a national probability sample of the US population, ages 51-61, to present estimates of the incidence and prevalence of all forms of musculoskeletal conditions, and describes the proportion of persons with these conditions who experience the onset of disability and, of these, the proportion who enter and leave employment over a 2-year period. This information can help clinicians provide accurate prognostic information to their patients with musculoskeletal conditions.

780

Pneumocystis carinii Pneumonia in Patients with Connective Tissue Diseases: The Role of Hospital Experience in Diagnosis and Mortality

Michael M. Ward and Fiona Donald

Pneumonia due to Pneumocystis carinii is uncommon among patients with connective tissue disease. In this population-based study of all patients hospitalized in California from 1983 to 1994, 223 cases were reported in patients with connective tissue diseases. Patients admitted to hospitals that treated a greater number of patients with Pneumocystis carinii pneumonia were more likely to be diagnosed with this condition than patients who were admitted to less experienced hospitals, suggesting that diagnostic suspicion is important in the correct identification of infected patients.

790

Assessment of Bone Mineral Density in Adults with a History of Juvenile Chronic Arthritis: A Cross-Sectional Long-Term Followup Study

Marek Zak, Christian Hassager, Daniel J. Lovell, Susan Nielsen, Carol J. Henderson, and Freddy K. Pedersen

Significantly decreased BMD has been shown to be present in prepubertal, pubertal, and young adult patients who have been diagnosed with JCA during childhood. In this study, hip and spine bone densitometry was performed in 65 patients with a history of or persistent JCA and in age- and sex-matched controls. The results indicate that adults with a diagnosis of JCA have significantly lower BMD in the hip and lumbar spine when compared with age- and sex-matched healthy controls.

799

Elevated Parathyroid Hormone 44-68 and Osteoarticular Changes in Patients with Genetic Hemochromatosis

Yves Pawlotsky, Philippe Le Dantec, Romain Moirand, Pascal Guggenbuhl, Anne-Marie Jouanolle, Michel Catheline, Jean Meadeb, Pierre Brissot, Yves Deugnier, and Gerard Chales

This clinical, radiologic, and biologic study provides original data on an increase in the serum concentration of parathyroid hormone midfragments containing the 44-68 region in patients with genetic hemochromatosis. The increase correlated significantly with chondrocalcinosis and subchondral arthropathies, but there was no corresponding increase in the intact molecule 1-84. The findings and the similarity between the osteoarticular changes associated with hyperparathyroidism and those associated with genetic hemochromatosis suggest that parathyroid fragments containing the 44-68 region could play a role in the pathogenesis of chondrocalcinosis and subchondral arthropathies. No obvious influence of the Cys282-Tyr mutation on osteoarticular changes was observed in this study.

806

Diabetic Neuropathic Arthropathy

Irmtraut Koop, Dieter Loreck, and Andreas Krause

807

Marked and Sustained Improvement Two Years After Autologous Stem Cell Transplantation in a Girl with Systemic Sclerosis

Alberto Martini, Rita Maccario, Angelo Ravelli, Daniela Montagna, Fabrizio De Benedetti, Federico Bonetti, Stefania Viola, Marco Zecca, Cesare Perotti, and Franco Locatelli

812

Whipple's Arthritis: Direct Detection of Tropheryma whippelii in Synovial Fluid and Tissue

J. Desmond O'Duffy, W. Leroy Griffing, Chin-Yang Li, Manal F. Abdelmalek, and David H. Persing

818

Altered Distribution of Fc[gg] Receptor IIIA Alleles in a Cohort of Korean Patients with Lupus Nephritis

Jane E. Salmon, Sonia Ng, Dae-Hyun Yoo, Tae-Hwan Kim, Seong Yoon Kim, and Gwan Gyu Song

819

Sustained Response to Doxycycline Therapy in Two Patients with SAPHO Syndrome

S. C. Ballara, Q. H. Siraj, R. N. Maini, and P. J. W. Venables

822

Immunogenetic Profile of Patients with Psoriatic Arthritis Varies According to the Age at Onset of Psoriasis

Proton Rahman, Catherine T. Schentag, and Dafna D. Gladman

824

Necrotizing Vasculitis Confined to the Nerves: Comment on the Concise Communication by Rosenbaum et al

R. Handa, P. Aggarwal, and J. P. Wali

824

Necrotizing Vasculitis of the Peripheral Nervous System: Nonsystemic or Clinically Undetectable?

X. Puechal and G. Said

825

Reply

James T. Rosenbaum, Lynn Adams Bell, and Richard Rosenbaum

825

Predictors of Visual Loss and Cerebrovascular Accidents in Giant Cell Arteritis: Comment on the Article by Gonzalez-Gay et al

Emilio B. Gonzalez

826

Reply

Vicente Rodr|figuez-Valverde, Miguel Delgado-Rodriguez, Ricardo Blanco, Victor M. Mart|finez-Taboada, Miguel A. Gonzalez-Gay, M. Figueroa, and Esther Uriarte

827

Does Normal Erythrocyte Sedimentation Rate Rule Out Polymyalgia Rheumatica? Comment on the Article by Helfgott and Kieval

Aysen Sivri

828

Reply

Simon M. Helfgott and Raphael I. Kieval

828

Fibromyalgia and Physical and Emotional Trauma: How are They Related? Comment on the Article by Aaron et al

Robert Ferrari and O. Kwan

829

Reply

Leslie A. Aaron, Laurence A. Bradley, Graciela S. Alarcon, Michelle Y. Martin, and Kristin R. Alberts

830

Opioids and Rheumatic Disease Pain: Comment on the Article by Ytterberg et al

Stephen G. Gelfand

831

Reply

Maren L. Mahowald

831

Is Malignant Infiltration Necessary for Development of Leukemic Arthritis? Comment on the Article by Rudwaleit et al

Sonja Praprotnik and Matija Tomsic

832

Reply

Martin Rudwaleit and Jurgen Braun

15A

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