199

Review: Fine Specificity of the Autoimmune Response to the Ro/SSA and La/SSB Ribonucleoproteins

R. Hal Scofield, A. Darise Farris, Angela C. Horsfall, and John B. Harley

210

Overexpression of Human Homologs of the Bacterial DnaJ Chaperone in the Synovial Tissue of Patients with Rheumatoid Arthritis

Ursula Kurzik-Dumke, Christoph Schick, Rita Rzepka, and Inga Melchers

The HLA-DRB1 alleles strongly associated with RA share a common sequence motif, which is also found within the J domain of the Escherichia coli DnaJ molecule, the prototype of the chaperone family of J proteins. In this study, the expression of J proteins within the synovial tissue of patients with RA or osteoarthritis was analyzed with a serum specific for a conserved motif of J domains. Several new members of the family were detected. Interestingly, the most prominent protein band in RA samples represented the human homolog of a recently discovered tumor suppressor gene product in Drosophila.

221

Establishment and Characterization of Nurse Cell-Like Stromal Cell Lines from Synovial Tissues of Patients with Rheumatoid Arthritis

Eiji Takeuchi, Tetsuya Tomita, Tomoko Toyosaki-Maeda, Motoharu Kaneko, Hiroshi Takano, Hideo Hashimoto, Kazuomi Sugamoto, Ryuji Suzuki, and Takahiro Ochi

This study demonstrates the characteristics and functions of nurse cell-like stromal cell lines established from synovial tissues of patients with RA. Synovial nurse-like stromal cell lines had an ability to activate lymphocytes and to secrete inflammatory cytokines. The results suggest that they may play an important role in the pathogenesis of RA by providing maintenance of infiltrating lymphocytes and producing a large amount of cytokines.

229

Expression of B7 Costimulatory Molecules by Salivary Gland Epithelial Cells in Patients with Sjogren's Syndrome

Menelaos N. Manoussakis, Ioannis D. Dimitriou, Efstathia K. Kapsogeorgou, Georgia Xanthou, Spiros Paikos, Maria Polihronis, and Haralampos M. Moutsopoulos

This study demonstrates that ductal and acinar epithelial cells in the minor salivary glands of patients with SS express B7.1 and B7.2 costimulatory proteins, which indicates their aberrant activation status. High levels of spontaneous and sustained B7.1 expression were also detected in long-term cultures of salivary gland epithelial cell lines derived from patients with SS, which indicates the possible operation of intrinsic activation mechanisms in these cells.

240

Analysis of VH-D-JH Gene Trancss in B Cells Infiltrating the Salivary Glands and Lymph Node Tissues of Patients with Sjogren's Syndrome

Sylke Gellrich, Sascha Rutz, Astrid Borkowski, Sven Golembowski, Erika Gromnica-Ihle, Wolfram Sterry, and Sigbert Jahn

In SS, B lymphocytes have been found to infiltrate salivary glands, and the disease is frequently associated with benign and neoplastic lymphoproliferation. This raises a question as to whether clonal B cell expansion takes place in lymphocytic infiltrations of salivary glands under (auto- [?]) antigen stimulation. This study provides evidence, on the nucleotide sequence level, that an antigen-triggered clonal B cell expansion takes place in the salivary glands of patients with SS who do not have histologic evidence of lymphoma. It can be inferred that those B cell clones expand during disease progression, resulting in lymphomagenesis. Patients with autoimmune disease should be closely observed for the occurrence of lymphocytic neoplasias.

248

Inhibition of Transforming Growth Factor [gb] Production by Nitric Oxide-Treated Chondrocytes: Implications for Matrix Synthesis

R. K. Studer, H. I. Georgescu, L. A. Miller, and C. H. Evans

Cartilage loss is a critical factor in the pathophysiology of rheumatoid arthritis and osteoarthritis. Interleukin-1 (IL-1) is an inflammatory cytokine that decreases synthesis of the cartilagenous matrix and increases its loss. NO is produced in response to, and is responsible for, some of the IL-1 inhibition of proteoglycan and collagen synthesis by chondrocytes exposed to this cytokine. In contrast, TGF[gb]1 is an anabolic cytokine that can counteract the actions of IL-1 and NO. Understanding the relationships among IL-1, NO, and TGF[gb], and their actions on chondrocytes and other cells of the joint is critical to the design of effective interventions to correct the pathophysiology of arthritis.

258

Expression of both P1 and P2 Purine Receptor Genes by Human Articular Chondrocytes and Profile of Ligand-Mediated Prostaglandin E2 Release

Mitchell Koolpe, David Pearson, and Hilary P. Benton

Inflammation in synovial joints is a complex process, and although much progress has been made in identifying mediators of cartilage damage such as interleukin-1, there are clearly still other unidentified components that contribute to disease progression. Extracellular purines have been widely implicated as inflammatory molecules in many cell systems, and multiple cell surface receptors that bind purine nucleotide and nucleoside ligands have been identified. The present study shows that human chondrocytes express members of both the P1 and P2 receptor families. The results also demonstrate that treatment of chondrocytes with P2Y2 receptor ligands significantly potentiates the prostaglandin release induced by interleukin-1.

268

Associations of Anti-[gb]2-Glycoprotein I Autoantibodies with HLA Class II Alleles in Three Ethnic Groups

Frank C. Arnett, Perumal Thiagarajan, Chul Ahn, and John D. Reveille

Associations of HLA class II alleles with antibodies to [gb]2GPI, an important cofactor in the antiphospholipid antibody syndrome, were studied. Genetic associations with certain class II major histocompatibility complex alleles were found, but there were differences in the anti-[gb]2GPI-associated alleles among different ethnic groups.

275

Autoantibodies to RNA Polymerases Recognize Multiple Subunits and Demonstrate Cross-Reactivity with RNA Polymerase Complexes

Masataka Kuwana, Yutaka Okano, Junichi Kaburaki, Thomas A. Medsger, Jr., and Timothy M. Wright

285

Association of Polymorphism at the Type I Collagen (COL1A1) Locus with Reduced Bone Mineral Density, Increased Fracture Risk, and Increased Collagen Turnover

R. W. Keen, K. L. Woodford-Richens, S. F. A. Grant, S. H. Ralston, J. S. Lanchbury, and T. D. Spector

Type I collagen is the major protein constituent of bone. This report highlights findings that a genetic variant of the COL1A1 gene is associated with reduced bone density at the spine, an increased risk of fracture, and an increased rate of turnover of type I collagen. These data give an increased understanding of the pathophysiologic processes underlying the genetic determination of osteoporosis, and may ultimately result in improved therapeutic options and diagnostic tools for this disease.

291

Fas and Fas Ligand Interaction Induces Apoptosis in Inflammatory Myopathies: CD4+ T Cells Cause Muscle Cell Injury Directly in Polymyositis

Tomoko Sugiura, Yohko Murakawa, Atsushi Nagai, Masahiro Kondo, and Shotai Kobayashi

In this study the presence of Fas/FasL-mediated apoptosis in the inflammatory myopathies was studied. In both polymyositis and dermatomyositis, muscle fibers as well as infiltrating mononuclear cells were susceptible to Fas/FasL-mediated apoptosis. Although CD8+ T cells are thought to play a central role in muscle injury in patients with polymyositis, the evidence indicates that CD4+ T cells, which express FasL predominantly, also cause muscle cell damage directly.

298

Applications Invited for Editor of Arthritis & Rheumatism, 2000-2005

299

Interferon-[ga] Does Not Improve Outcome at One Year in Patients with Diffuse Cutaneous Scleroderma: Results of a Randomized, Double-Blind, Placebo-Controlled Trial

Carol M. Black, Alan J. Silman, Ariane I. Herrick, Christopher P. Denton, Helen Wilson, Jason Newman, Lucie Pompon, and Xu Shi-Wen

The present study failed to demonstrate improvement in patients with early scleroderma after 12 months of treatment with interferon-[ga], and in fact, the side effects at the dosage used precluded further testing. Double-blind, randomized, placebo-controlled trials of potential antifibrotic therapies for scleroderma, such as interferon-[ga], are important for improving the management of this condition.

306

Different Factors Influencing the Expression of Raynaud's Phenomenon in Men and Women

Liana Fraenkel, Yuqing Zhang, Christine E. Chaisson, Hildegard R. Maricq, Stephen R. Evans, Fred Brand, Peter W. F. Wilson, and David T. Felson

This cross-sectional evaluation of factors associated with RP suggests that certain risk factors differ systematically between men and women, with smoking and age being associated with RP in men only, and marital status and alcohol use being associated with RP in women only. These findings suggest that different mechanisms may contribute to the expression and/or pathophysiology of RP in each sex.

311

Disease Pattern in Cranial and Large-Vessel Giant Cell Arteritis

A. Brack, V. Martinez-Taboada, A. Stanson, J. J. Goronzy, and C. M. Weyand

GCA typically affects medium-sized arteries in a cranial distribution, resulting in ischemic complications such as blindness, stroke, and jaw claudication. GCA can also manifest as large vessel vasculitis, causing aortic arch syndrome. This case-control study shows that these 2 variants of GCA are significantly different in their clinical presentation and pathogenic mechanisms, and require different diagnostic approaches and probably also different therapeutic management.

318

Familial Antiphospholipid Antibody Syndrome: Criteria for Disease and Evidence for Autosomal Dominant Inheritance

Niti Goel, Thomas L. Ortel, Deeksha Bali, Joshua P. Anderson, Ian S. Gourley, Howard Smith, Colleen A. Morris, Muriel DeSimone, D. Ware Branch, Peter Ford, Donald Berdeaux, Robert A. S. Roubey, Donna D. Kostyu, Stephen F. Kingsmore, Tracy Thiel, Christopher Amos, and Michael F. Seldin

A semiquantitative analysis of clinical manifestations and laboratory studies was used to identify patients with primary APS and to determine affected family members. The clinical and laboratory evaluations suggested a set of criteria that could be utilized in precisely defining affected family members. Modeling studies that were performed on 7 multiplex families fulfilling these criteria strongly excluded nongenetic models and suggested an autosomal dominant mode of inheritance. Under this genetic model, genetic analyses of DNA typing results excluded linkage in the APS families with HLA and several candidate genes, including [gb]2-glycoprotein I, HLA, T cell receptor [gb] chain, Ig heavy chain, antithrombin III, Fas ligand, factor V, complement factor H, IgK, and Fas. Identification of a genetic basis for the development of antiphospholipid antibodies will improve our understanding of the pathophysiology associated with these antibodies and facilitate identification of individuals at risk of developing the associated clinical syndromes.

328

Estrogen Enhancement of Anti-Double-Stranded DNA Antibody and Immunoglobulin G Production in Peripheral Blood Mononuclear Cells from Patients with Systemic Lupus Erythematosus

Naoko Kanda, Tetsuya Tsuchida, and Kunihiko Tamaki

It has been suggested that estrogen may be involved in the pathogenesis of SLE. In this study, the in vitro effect of estrogen on the production of IgG anti-double-stranded DNA antibodies and total IgG in peripheral blood mononuclear cells from patients with SLE was examined. This work is important to clarify an immunoregulatory role of estrogen in human SLE.

338

Premature Morbidity from Cardiovascular and Cerebrovascular Diseases in Women with Systemic Lupus Erythematosus

Michael M. Ward

Cardiovascular and cerebrovascular diseases are important comorbid conditions in patients with SLE. In this population-based hospitalization study, women ages 18-44 with SLE had substantially increased risk of hospitalization due to acute myocardial infarctions and cerebrovascular accidents compared with age-matched control subjects. Women of all ages with SLE had increased risk of hospitalizations due to congestive heart failure.

347

Economic Consequences of the Progression of Rheumatoid Arthritis in Sweden

Gisela Kobelt, Kerstin Eberhardt, Linus Jonsson, and Bengt Jonsson

As a result of the scarcity of health care resources and the increasing interest in efficiency, one consideration in making treatment choices for a disease such as RA is cost-effectiveness. The simulation model presented in this report allows one to calculate the cost-effectiveness of treatments that affect the progression of RA beyond available clinical trial data. This model can therefore become a useful tool for clinical decision-making and for the development of clinical guidelines.

357

Dose-Loading with Hydroxychloroquine Improves the Rate of Response in Early, Active Rheumatoid Arthritis: A Randomized, Double-Blind Six-Week Trial with Eighteen-Week Extension

Daniel E. Furst, Herbert Lindsley, Bruce Baethge, Gary R. Botstein, Jacques Caldwell, Fredrick Dietz, Robert Ettlinger, Harvey E. Golden, George E. McLaughlin, Larry W. Moreland, W. Neal Roberts, Theodore W. Rooney, Bruce Rothschild, Marshall Sack, Anthony I. Sebba, Michael Weisman, Kathryn E. Welch, and David Yocum

This study tested the use of loading doses of HCQ in patients with early, active RA. The results indicated that patients receiving higher-dose HCQ for the first 6 weeks of treatment had a better and more rapid response to the medication than those who received a daily dosage of 400 mg. The use of loading doses could help to alleviate the slow onset of action of HCQ.

366

Genetic Influences on Cervical and Lumbar Disc Degeneration: A Magnetic Resonance Imaging Study in Twins

P. N. Sambrook, A. J. MacGregor, and T. D. Spector

This study, using MRI in twins, is the first to demonstrate a clear genetic influence on disc degeneration. The use of the sensitive technique of MRI scanning to determine the phenotype provides a model for future studies to allow a better understanding of the disease and make gene identification possible.

373

Association of the Inflammatory State in Active Juvenile Rheumatoid Arthritis with Hypo-High-Density Lipoproteinemia and Reduced Lipoprotein-Associated Platelet-Activating Factor Acetylhydrolase Activity

Alexandros D. Tselepis, Moses Elisaf, Sotiris Besis, Sonia-Athena P. Karabina, M. John Chapman, and Antigoni Siamopoulou

This study of 26 JRA patients and 22 controls revealed quantitative and qualitative alterations in plasma lipoproteins in the patients with JRA. These alterations were closely related to the inflammatory state of the disease. The results indicate that the active inflammatory phase of JRA is associated with partial loss of the antiinflammatory activity (platelet-activating factor acetylhydrolase) of both low- and high-density lipoproteins.

383

Histopathologic Features of Cerebral Vasculitis Associated with Mycobacterium tuberculosis

Francisco J. Blanco Garc|fia, Mercedes Sanchez Blas, and Mercedes Freire Gonzalez

384

Alternating Antineutrophil Cytoplasmic Antibody Specificity: Drug-Induced Vasculitis in a Patient with Wegener's Granulomatosis

Hyon K. Choi, Peter A. Merkel, Jan Willem Cohen Tervaert, Robert M. Black, Robert T. McCluskey, and John L. Niles

389

Increased Serum Levels of Antibodies Against Human Cytomegalovirus and Prevalence of Autoantibodies in Systemic Sclerosis

Michel Neidhart, Stephan Kuchen, Oliver Distler, Pius Bruhlmann, Beat A. Michel, Renate E. Gay, and Steffen Gay

393

Further Thoughts on the Immunomodulatory Role of Glucocorticoids: Comments on the Article by Buttgereit et al

Thomas Wilckens

395

Reply

Frank Buttgereit, Gerd-Rudiger Burmester, and Martin Wehling

396

Do We Need Pediatric Rheumatologists? The Hamburg, Germany Experience

Ivan Foeldvari

396

Estimates of the US Prevalence of Systemic Lupus Erythematosus: Comment on the Article by Lawrence et al

Wendell A. Wilson

12A

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