2261

Review: Juvenile Rheumatoid Arthritis as a Complex Genetic Trait

David N. Glass and Edward H. Giannini

2269

Editorial: High-Dose Immunosuppressive Therapy for Rheumatoid Arthritis: Some Answers, More Questions

Peter A. McSweeney, Daniel E. Furst, and Sterling G. West

2275

Intensified-Dose (4 gm/m2) Cyclophosphamide and Granulocyte Colony-Stimulating Factor Administration for Hematopoietic Stem Cell Mobilization in Refractory Rheumatoid Arthritis

Maxime Breban, Maxime Dougados, Francoise Picard, Simona Zompi, Jean-Pierre Marolleau, Catherine Bocaccio, Fahrad Heshmati, Maryse Mezieres, Francois Dreyfus, and Didier Bouscary

Four patients with severe refractory RA received intensified-dose CYC (4 gm/m2) and G-CSF to harvest peripheral blood stem cells with a view toward potential autologous stem cell transplantation (ASCT). This reasonably safe and technically suitable procedure induced a dramatic short-term improvement of RA activity followed by a partial disease relapse for all patients. The authors suggest that the procedure be used as a first step in the initiation of ASCT in RA.

2281

Autologous Hematopoietic Stem Cell Transplantation in Refractory Rheumatoid Arthritis: Sustained Response in Two of Four Patients

Richard K. Burt, Constantinos Georganas, Jim Schroeder, Ann Traynor, Jakub Stefka, Friedrich Schuening, Frank Graziano, Shin Mineishi, Mary Brush, Maryanne Fishman, Colleen Welles, Steve Rosen, and Richard Pope

This study investigated the safety and efficacy of immune ablation with subsequent autologous hematopoietic stem cell transplantation (HSCT) in severe rheumatoid arthritis (RA). A lymphocyte depletion was performed on stem cells collected from 4 patients with refractory RA and poor prognostic factors, who were then treated with cyclophosphamide, antithymocyte globulin, and, in 1 case, total body irradiation. HSCT induced major clinical response and maintained significant benefit for 2 of the 4 patients. More aggressive T cell depletion of the autograft, use of a myeloablative regimen, or use of an allograft may be necessary to decrease relapse rates.

2286

A Phase I/II Dose Escalation Study of Intensified Cyclophosphamide and Autologous Blood Stem Cell Rescue in Severe, Active Rheumatoid Arthritis

J. A. Snowden, J. C. Biggs, S. T. Milliken, A. Fuller, and P. M. Brooks

The safety and efficacy of high-dose CYC therapy with autologous peripheral blood stem cell support was investigated in a dose escalation study of patients with severe, resistant RA. Patients receiving 100 mg/kg of CYC had only transient responses, but substantial improvements were sustained beyond 17-19 months for patients receiving 200 mg/kg of CYC. Although the procedure did not completely abolish disease activity, these encouraging results provide a baseline for future studies aimed at refining this intensive approach.

2293

Cost Effectiveness of Replacing Diclofenac with a Fixed Combination of Misoprostol and Diclofenac in Patients With Rheumatoid Arthritis

Ivar S\onb\o Kristiansen, Tore Kristian Kvien, and Erik Nord

Gastrointestinal complications are frequently encountered in RA patients taking nonsteroidal antiinflammatory drugs. The present study explores the health benefits and costs of prescribing misoprostol to avoid such complications. Using a variety of clinical data from randomized trials, the authors conclude that misoprostol is cost-effective only in high-risk groups who meet certain clinical criteria.

2303

Evaluation of Pannus and Vascularization of the Metacarpophalangeal and Proximal Interphalangeal Joints in Rheumatoid Arthritis by High-Resolution Ultrasound (Multidimensional Linear Array)

Matthias Hau, Hendrik Schultz, Hans-Peter Tony, Marc Keberle, Roland Jahns, Rainer Haerten, and Manfred Jenett

The extent of intraarticular vascularization and pannus in the MCP and PIP joints of patients with RA was evaluated by a newly developed high-resolution Multi-D linear array ultrasound method. For both parameters, there were significant differences between healthy controls and patients with active, moderately active, and inactive RA. High-resolution ultrasound might be helpful in the assessment of disease activity and, thus, influence therapeutic strategies in RA.

2309

Risedronate Therapy Prevents Corticosteroid-Induced Bone Loss: A Twelve-Month, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study

Stanley Cohen, Robert M. Levy, Michael Keller, Eugene Boling, Ronald D. Emkey, Maria Greenwald, Thomas M. Zizic, Stanley Wallach, Kathryn L. Sewell, Barbara P. Lukert, Douglas W. Axelrod, and Arkadi A. Chines

This study shows that bone loss is rapid during the first 3-6 months after the initiation of corticosteroid therapy in men and women, and treatment with 500 mg of calcium alone is not sufficient to prevent bone loss. Oral risedronate at a dosage of 5 mg/day maintained bone mass in the hip and spine during 12 months of treatment. The findings indicate that early intervention with risedronate prevents bone loss and should be considered in patients beginning long-term corticosteroid treatment.

2319

Significant Loss of Bone Mass in Patients with Early, Active Ankylosing Spondylitis: A Followup Study

J. Gratacos, A. Collado, F. Pons, M. Osaba, R. Sanmart|fi, M. Roque, M. Larrosa, and J. Munoz-Gomez

Osteoporosis is a severe complication of AS that can cause vertebral fracture and contribute to spinal deformity. In this study, loss of bone mass was compared in AS patients with versus those without active disease. The results show a clear relationship between osteoporosis and inflammatory activity in AS. These findings clarify knowledge of the pathophysiology of this secondary osteoporosis and constitute a further step toward preventing late complications and performing future trials of therapies.

2325

Comparison of Sulfasalazine and Placebo for the Treatment of Axial and Peripheral Articular Manifestations of the Seronegative Spondylarthropathies: A Department of Veterans Affairs Cooperative Study

Daniel O. Clegg, Domenic J. Reda, and Mazen Abdellatif

A number of studies that evaluate the efficacy of SSZ in treating the seronegative spondylarthropathies (SNSA) have been reported. The results of these trials have been mixed. This study evaluates the combined results of a large, multicenter, randomized trial of SSZ versus placebo, which demonstrate that SSZ is more effective for the peripheral articular manifestations than the axial manifestations of SNSA.

2330

Prevention of Leg Length Discrepancy in Young Children with Pauciarticular Juvenile Rheumatoid Arthritis by Treatment with Intraarticular Steroids

David. D. Sherry, Leonard D. Stein, Ann M. Reed, Laura E. Schanberg, and Deborah W. Kredich

This study is the first to evaluate the long-term outcome variables, leg length discrepancy and thigh circumference differences, in children with pauciarticular juvenile rheumatoid arthritis who were or were not treated with intraarticular steroids. The findings lend support for early and continued treatment with intraarticular steroids.

2335

Comparison of Treatment with Fluorinated Glucocorticoids to the Natural History of Autoantibody-Associated Congenital Heart Block: Retrospective Review of the Research Registry for Neonatal Lupus

Susan Saleeb, Joshua Copel, Deborah Friedman, and Jill P. Buyon

In this retrospective study, it was observed that fluorinated glucocorticoids ameliorated incomplete atrioventricular block and hydropic changes in autoimmune-associated congenital heart block but did not reverse established third-degree block. While prospective studies are needed, these findings suggest that fluorinated steroids should be considered for fetuses with incomplete block or hydropic changes. It remains to be determined whether third-degree block is reversible if therapy is initiated immediately upon detection.

2346

Close Relationship Between Systemic Lupus Erythematosus and Thrombotic Thrombocytopenic Purpura in Childhood

Hermine I. Brunner, Melvin Freedman, and Earl D. Silverman

This study assesses the relationship between SLE and TTP in childhood. A large proportion of children with TTP will be diagnosed as having SLE. High-grade proteinuria at diagnosis of TTP was the best predictor of the presence or development of SLE.

2356

Serum Cartilage Oligomeric Matrix Protein Reflects Osteoarthritis Presence and Severity: The Johnston County Osteoarthritis Project

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

This study characterized serum COMP levels in a large, radiographically defined, population-based sample of 148 individuals with no knee or hip OA and 143 individuals with knee OA of Kellgren/Lawrence grade [lte]2. This is the first study of a large, radiographically defined sample of control subjects (without OA) examined for this serum biomarker. COMP levels were examined for differences by sex, age, obesity, OA status, disease severity, and number of joints involved. It was found that in a population-based sample, serum COMP levels can distinguish an OA-affected subgroup from an unaffected subgroup and can reflect disease severity and multiple joint involvement in OA. These findings support the use of COMP levels as a surrogate measure of knee OA in population-based studies.

2365

Validity of a Vasculitis Activity Index for Systemic Necrotizing Vasculitis

Quinn E. Whiting-O'Keefe, John H. Stone, and David B. Hellmann

Defining disease activity in patients with systemic necrotizing vasculitis remains challenging. This report describes the validation of a new method of assessing vasculitis activity, the Vasculitis Activity Index (VAI). The VAI should be of interest to physicians caring for patients with these disorders.

2372

Correlates of the Disability Index of the Health Assessment Questionnaire: A Measure of Functional Impairment in Systemic Sclerosis

Philip J. Clements, Weng Kee Wong, Eric L. Hurwitz, Daniel E. Furst, Maureen Mayes, Barbara White, Fredrick Wigley, Michael Weisman, Walter Barr, Larry Moreland, Thomas A. Medsger, Jr., Virginia Steen, Richard Martin, David Collier, Arthur Weinstein, Edward Lally, John Varga, Steven Weiner, Brian Andrews, Micha Abeles, and James Seibold

In patients with recent-onset diffuse SSc, the 20-item patient-administered Disability Index of the Health Assessment Questionnaire (HAQ-DI) reflects objective physical and laboratory measures of SSc disease involvement (reduced fist closure and handspread, joint tenderness, older age, elevated platelet count, and female sex). Abnormal HAQ-DI scores may, therefore, support patient claims of functional impairment, help to focus physician attention on implementing measures to reduce functional impairment (especially in the hand), and be useful in reflecting the disease course over time.

2381

Type II Collagen Degradation in Spontaneous Osteoarthritis in C57Bl/6 and BALB/c Mice

Reinout Stoop, Peter M. van der Kraan, Pieter Buma, Anthony P. Hollander, R. Clark Billinghurst, A. Robin Poole, and Wim B. van den Berg

During OA, type II collagen degradation is thought to be of major importance in articular cartilage degeneration, but it is unclear whether this is a localized or a generalized process. This study shows that type II degradation in articular cartilage is restricted to sites of degeneration in spontaneous murine osteoarthritis.

2390

Degradation of Cartilage Type II Collagen Precedes the Onset of Osteoarthritis Following Anterior Cruciate Ligament Rupture

Jo S. Price, Simon H. Till, Derek R. Bickerstaff, Mike T. Bayliss, and Anthony P. Hollander

This study attempted to elucidate the relationship between cartilage collagen degradation and clinical OA in patients with rupture of the anterior cruciate ligament. The findings have important implications both for our general understanding of arthritis pathology and for potential approaches to treatment of cartilage degeneration in secondary OA.

2399

Mitogen-Activated Protein Kinase and Nuclear Factor [gk]B Together Regulate Interleukin-17-Induced Nitric Oxide Production in Human Osteoarthritic Chondrocytes: Possible Role of Transactivating Factor Mitogen-Activated Protein Kinase-Activated Protein Kinase (MAPKAPK)

Johanne Martel-Pelletier, Francois Mineau, Dragan Jovanovic, John A. Di Battista, and Jean-Pierre Pelletier

This study explores the different signaling pathways by which IL-17, a potent inflammatory cytokine, can induce the production of nitric oxide by human osteoarthritic chondrocytes. The findings yield important information about these pathways and point toward potential therapeutic strategies for controlling cell activation by IL-17.

2410

Staphylococcus Aureus Stimulates Inducible Nitric Oxide Synthase in Articular Cartilage

Daniel Jang, Riley J. Williams, Min Xia Wang, Ai Qun Wei, and George A. C. Murrell

Staphylococcus aureus is a common cause of septic arthritis. In this study heat-killed and sonicated S aureus stimulated inducible NO synthase expression and activity in bovine articular cartilage. S aureus also suppressed proteoglycan synthesis which was dependent on the presence of NO. These findings implicate NO as a local mediator in the cartilage loss that occurs in staphylococcal septic arthritis.

2418

Evidence for Neural Regulation of Inflammatory Synovial Cell Functions by Secreting Calcitonin Gene-Related Peptide and Vasoactive Intestinal Peptide in Patients with Rheumatoid Arthritis

Yuko Takeba, Noboru Suzuki, Atsushi Kaneko, Tomiaki Asai, and Tsuyoshi Sakane

This report describes the involvement of CGRP and VIP in the neural regulation of excessive synovial cell functions in patients with RA. The results suggest beneficial effects of CGRP and VIP on the pathologic processes of RA and thus, these peptides or their analogs may have clinical applications for treating patients with RA.

2430

Expression of the Thioredoxin-Thioredoxin Reductase System in the Inflamed Joints of Patients with Rheumatoid Arthritis

Madelon M. Maurice, Hajime Nakamura, Sonja Gringhuis, Takashi Okamoto, Shinichi Yoshida, Frank Kullmann, Sandra Lechner, Ellen A. M. van der Voort, Angela Leow, Johannes Versendaal, Ulf Muller-Ladner, Junji Yodoi, Paul P. Tak, Ferdinand C. Breedveld, and Cornelis L. Verweij

Elevated levels of TRX, an important regulator of the redox state of proteins, in the inflamed joints of RA patients in comparison with patients with other joint diseases were found in this study. In addition, the results indicate that oxidative stress and tumor necrosis factor [ga] contribute to increased TRX expression. Based on its growth-promoting and cytokine-inducing capacity, TRX is believed to play a role in the persistence of inflammation.

2440

Regulation of Synovial Cell Apoptosis by Proteasome Inhibitor

Atsushi Kawakami, Tomoki Nakashima, Hideaki Sakai, Ayumi Hida, Satoshi Urayama, Satoshi Yamasaki, Hideki Nakamura, Hiroaki Ida, Yasufumi Ichinose, Takahiko Aoyagi, Itaru Furuichi, Munetoshi Nakashima, Kiyoshi Migita, Yojiro Kawabe, and Katsumi Eguchi

In this study, apoptosis of synovial cells was induced by inhibition of proteasome function through the activation of caspase cascade. This process was modulated by pretreatment of synovial cells with cytokines. These results identify a new regulatory mechanism that modulates the growth of synovium in patients with rheumatoid arthritis.

2449

Termination of Human T Cell Tolerance to Histones by Presentation of Histones and Polyomavirus T Antigen Provided That T Antigen is Complexed with Nucleosomes

Kristin Andreassen, Ugo Moens, Hans Nossent, Tony N. Marion, and Ole Petter Rekvig

This report provides a model to explain how a non-self DNA binding protein, polyomavirus T antigen, may, when expressed in vivo, stimulate B cells specific to components of nucleosomes, and, particularly, to DNA, through a linked presentation of histones and T antigen by antigen-presenting cells. T cells responding to T antigen may terminate anergy of bystander-anergic, histone-specific T cells. These may subsequently expand into functional T helper cells. The present data are relevant to explain how antibodies to DNA, and also functional autoimmune, histone-specific T cells, may be generated by a physiologic process, which may be of diagnostic and potential pathophysiologic significance in systemic lupus erythematosus.

2461

A Chimeric Antibody with the Human [gg]1 Constant Region as a Putative Standard for Assays to Detect IgG [gb]2-Glycoprotein I-Dependent Anticardiolipin and Anti-[gb]2-Glycoprotein I Antibodies

Kenji Ichikawa, Akito Tsutsumi, Tatsuya Atsumi, Eiji Matsuura, Seiichi Kobayashi, Graham R. V. Hughes, Munther A. Khamashta, and Takao Koike

In this study, HCAL, a chimeric antibody with human [gg]1 constant regions and variable regions of a mouse monoclonal antibody derived from an antiphospholipid syndrome-prone mouse, was continuously secreted by a transfected mouse myeloma cell line. The binding of HCAL to [gb]2GPI immobilized on cardiolipin-coated plates or on oxygenated polystyrene plates was similar to the binding of standards for IgG aCL assays performed in different laboratories. HCAL will be useful as a standard for human IgG aCL or anti-[gb]2GPI antibody assays.

2471

Immunoglobulin Variable Genes and Epitope Recognition of Human Monoclonal Anti-Ro 52-kd in Primary Sjogren's Syndrome

Kamal E. E. Elagib, Pia Tengner, Michael Levi, Roland Jonsson, Keith M. Thompson, Jacob B. Natvig, and Marie Wahren-Herlenius

Little is known about how autoantibodies directed to the Ro/SSA ribonucleoprotein are generated, and there is no consensus as to whether they are of importance for the pathogenesis of Sjogren's syndrome and systemic lupus erythematosus. The 2 monoclonal antibodies in this study were derived from screening patients with primary Sjogren's syndrome, and indeed are the first human Ro/SSA autoantibodies characterized on a clonal level. They are both Ro 52 specific, and their epitope specificity and gene usage have been determined. These autoantibodies may be useful tools to study the potential to induce disease and for diagnostic as well as scientific purposes.

2482

Possible Association of Fibromyalgia with a Polymorphism in the Serotonin Transporter Gene Regulatory Region

Martin Offenbaecher, Brigitta Bondy, Silvia de Jonge, Karin Glatzeder, Marc Kruger, Peter Shoeps, and Manfred Ackenheil

Fibromyalgia is a syndrome of unknown etiology which is believed to be linked to disturbed serotonin metabolism. It has recently been shown that a functional polymorphism in the promotor region of the serotonin transporter is associated with psychiatric disorders in which abnormal serotonergic function is considered to be a major etiologic factor. In the present study, these alleles were analyzed in patients with fibromyalgia. The results demonstrate an increased frequency of the S/S genotype in FM patients compared with healthy controls.

2489

Hepatitis C Virus Infection, Sjogren's Syndrome, and Non-Hodgkin's Lymphoma

Albert Selva-O'Callaghan, Dolores Rodriguez-Pardo, Lluis Sanchez-Sitjes, Laia Matas-Pericas, Roser Solans-Laque, Josep Angel Bosch-Gil, and Miguel Vilardell-Tarres

2491

Endothelial Apoptosis in Scleroderma: Comment on the Article by Black et al

Tihomir Stefanec

2491

Lipoprotein(a) Levels and Atherosclerosis in Rheumatoid Arthritis: Comment on the Article by Asanuma et al

M. J. Banks and G. D. Kitas

2492

Reply

Yu Asanuma and Shinichi Kawai

2492

Absence of Human Retrovirus 5 in French Patients with Rheumatoid Arthritis: Comment on the Article by Griffiths et al

Philippe Gaudin, Francois Moutet, Philip W. Tuke, and Jeremy A. Garson

2493

Reply

David J. Griffiths and Patrick J. W. Venables

2494

Specificity of Antineutrophil Cytoplasmic Antibody: Comment on the Article by Choi et al

Sueli B. Maciel, Morton A. Scheinberg, and Vijay Kumar

2495

Comparison of Dutch and US Patients' Perceptions of the Effects of Wegener's Granulomatosis on Health, Function, Income, and Interpersonal Relationships: Comment on the Article by Hoffman et al

M. M. Boomsma, C. A. Stegeman, and J. W. Cohen Tervaert

2496

Reply

Gary S. Hoffman and Kent Kwoh

2497

Reporting of Bone Mineral Density Values as T-Scores or Z-Scores: Comment on the Article by Sowers et al

John A. Shepherd and Sven Prevrhal

2497

Reply

MaryFran Sowers

2497

Rarity of Reported Cases of Vasculitis in Africa: Comment on the Article by Bae et al

A. O. Adebajo and R. A. Watts

2498

Radiographic Progression of Rheumatoid Arthritis Over Twenty Years

Inmaculada del Rincon and Jose F. Roldan

23A

ACR Announcements