2499

Review: The Immunologic Homunculus in Rheumatoid Arthritis

Stefan Bla[germanB], Joachim-Michael Engel, and Gerd-Rudiger Burmester

2507

Review: Cryoglobulinemic Vasculitis

P. Lamprecht, A. Gause, and W. L. Gross

2517

The Arthritogenic T Cell Receptor and Its Ligand in a Model of Spontaneous Arthritis

Sara Mangialaio, Hong Ji, Anne-Sophie Korganow, Valerie Kouskoff, Christophe Benoist, and Diane Mathis

In this study, experiments using a transgenic mouse model of arthritis demonstrate that autoimmune reactivity of T lymphocytes can provoke an aggressive arthritis, without recognition of joint-specific antigens. This could provide a clue to possible models of pathogenesis in human rheumatoid arthritis.

2524

Identification of Multiple Loci Linked to Inflammation and Autoantibody Production by a Genome Scan of a Murine Model of Rheumatoid Arthritis

Jeffrey M. Otto, Gabriella Cs-Szabo, Jodi Gallagher, Sonja Velins, Katalin Mikecz, Edit I. Buzas, Jill T. Enders, Yefu Li, Bjorn R. Olsen, and Tibor T. Glant

Autoimmune diseases are polygenic disorders affected by both major histocompatibility (MHC)-associated and non-MHC-associated components. To dissect these genetic components in a heterogeneous human population is very difficult. However, through the use of inbred, homogeneous animal models, it becomes possible to identify the underlying genetics that contribute to autoimmune disorders. In this study, multiple loci associated with a mouse model of rheumatoid arthritis were identified.

2532

Suppressed Severity of Collagen-Induced Arthritis by In Vivo Transfection of Nuclear Factor [Kappa]B Decoy Oligodeoxynucleotides as a Gene Therapy

Tetsuya Tomita, Eiji Takeuchi, Naruya Tomita, Ryuichi Morishita, Motoharu Kaneko, Kei Yamamoto, Takanobu Nakase, Hiroshi Seki, Kazuyo Kato, Yasufumi Kaneda, and Takahiro Ochi

NF-[Kappa]B, a heterodimeric DNA binding protein, is a critical element in the regulation of many genes involved in inflammation, and its activation in synovium has been reported in both rheumatoid arthritis and experimental arthritis. In the present study, in vivo transfection into joint synovial cells of a sufficient quantity of decoy oligonucleotides containing the NF-[Kappa]B cis element effectively bound NF-[Kappa]B, thus preventing it from transactivating the gene expression of inflammatory cytokines, and thereby suppressing joint destruction. These results suggest that intraarticular transfection of NF-[Kappa]B decoy oligonucleotides may provide a useful approach for the treatment of inflammatory arthritis.

2543

Oncostatin M Induces Leukocyte Infiltration and Cartilage Proteoglycan Degradation In Vivo in Goat Joints

M. C. Bell, G. J. Carroll, H. M. Chapman, J. N. Mills, and Wang Hui

The results of this study indicate that OSM stimulates inflammation and modulates cartilage PG metabolism in vivo when injected into the joints of healthy goats. Some of the effects of OSM in vivo appear to be due, in part, to production and secretion of interleukin-1. These findings support the proposition that OSM contributes to the pathogenesis of inflammatory joint disease.

2552

Taurine Chloramine Inhibition of Cell Proliferation and Cytokine Production by Rheumatoid Arthritis Fibroblast-Like Synoviocytes

Ewa Kontny, Agnieszka Grabowska, Jacek Kowalczewski, Mariola Kurowska, Iwona Janicka, Janusz Marcinkiewicz, and W|flodzimierz Maslinski

FLS play an essential role in the destructive aspects and cytokine network of RA. The results of the present study demonstrate for the first time that Tau-Cl, a molecule formed in vivo in activated neutrophils by chlorination of the free amino acid taurine, inhibits important functions of RA FLS: cell proliferation, and cytokine-induced production of proinflammatory cytokines. Tau-Cl represents a potent physiologic factor to dampen crucial pathogenic functions of RA FLS, and thus may have therapeutic value.

2561

Fluoxetine and Amitriptyline Inhibit Nitric Oxide, Prostaglandin E2, and Hyaluronic Acid Production in Human Synovial Cells and Synovial Tissue Cultures

Ilana Yaron, Idit Shirazi, Rachel Judovich, David Levartovsky, Dan Caspi, and Michael Yaron

This study shows that amitriptyline and fluoxetine inhibit nitric oxide and prostaglandin E2 production by activated human synovial cells and tissue. These findings suggest a mechanism for the analgesic and antiinflammatory effect that some antidepressants may have when used in patients with chronic pain, such as in osteoarthritis, fibromyalgia, chronic inflammatory joint diseases, and cancer.

2569

Antibodies to Type II Collagen and HLA Disease Susceptibility Markers in Rheumatoid Arthritis

Andrew D. Cook, Alex Stockman, Caroline A. Brand, Brian D. Tait, Ian R. Mackay, Kenneth D. Muirden, Claude C. A. Bernard, and Merrill J. Rowley

Previous studies on autoimmunity to type II collagen in RA have yielded conflicting and confusing results. This study explains such results based on associations of antibodies to native and denatured type II collagen with particular HLA-DR alleles. By comparison with the collagen-induced arthritis animal model, which is widely used for the study of RA, autoimmunity to type II collagen is implicated as a major component in the multifactorial pathogenesis of this disease.

2577

Identification of a Genetic Risk Factor for Systemic Juvenile Rheumatoid Arthritis in the 5`-Flanking Region of the TNF[alpha] Gene and HLA Genes

Yukiji Date, Naoko Seki, Shintaro Kamizono, Takafumi Higuchi, Tomoshige Hirata, Koichiro Miyata, Masahiko Ohkuni, Osamu Tatsuzawa, Shumpei Yokota, Kunitaka Joo, Kohji Ueda, Takehiko Sasazuki, Akinori Kimura, Kyogo Itoh, and Hirohisa Kato

This report describes the allele frequency of the 5`-flanking region of the TNF[alpha] gene and those of the HLA-A and HLA class II (DRB1, DRB3, DRB4, DRB5, DQA1, DQB1, DPA1, and DPB1) genes, determined by DNA typing using the polymerase chain reaction-sequence-specific oligonucleotide probe method in Japanese patients with JRA. The frequency of the polymorphic allele at positions -1,031, -863, or -857 of the TNF[alpha] gene in patients with systemic JRA, but not in those with polyarticular or pauciarticular JRA, was significantly higher than that in healthy controls. The allele frequency of DRB1*0405 and DQB1*0401 in systemic JRA, but not in the other JRA types, was also significantly higher than that in the controls. These alleles may thus have a role in the genetic predisposition to JRA.

2583

Linked Production of Antibodies to Mammalian DNA and to Human Polyomavirus Large T Antigen: Footprints of a Common Molecular and Cellular Process?

Geir Bredholt, Eli Olaussen, Ugo Moens, and Ole Petter Rekvig

Viruses have been suggested as risk factors in the development of systemic lupus erythematosus (SLE) or autoimmunity in SLE. The present findings indicate that polyomavirus reactivation or infection may provide a molecular basis sufficient for induction of anti-DNA antibodies in SLE, but also in other clinical conditions. These results are in accordance with previously published data demonstrating that experimental in vivo expression of polyomavirus T antigen is sufficient to initiate production of antibodies to DNA. Formation of T antigen and host nucleosome complexes most likely represents the structural basis for such processes.

2593

B Cells Lacking RP105, A Novel B Cell Antigen, in Systemic Lupus Erythematosus

Syuichi Koarada, Yoshifumi Tada, Osamu Ushiyama, Fumitaka Morito, Noriaki Suzuki, Akihide Ohta, Kensuke Miyake, Masao Kimoto, and Kohei Nagasawa

RP105 is an LRR (leucine-rich repeat) protein found on all mature mouse B cells, through which the B cells are activated to be resistant to apoptosis. This study demonstrated a significant increase in RP105-negative B cells in SLE patients, which reflected the activity of the SLE. The phenotype of RP105-negative B cells is consistent with activated or germinal-center B cells, which may be involved in the production of Ig.

2601

Single-Nucleotide Polymorphisms of T Cell Receptor [zeta] Chain in Patients with Systemic Lupus Erythematosus

Jianming Wu, Jeffrey C. Edberg, Andrew W. Gibson, Betty Tsao, and Robert P. Kimberly

Recent studies have suggested that genes encoded on human chromosome 1 may contribute to susceptibility to lupus. Among the relevant genes encoded on chromosome 1 is the TCR [zeta] chain, whose signaling functions are impaired in patients with SLE. This study identifies a novel splice variant of [zeta] chain and 2 coding-sequence single-nucleotide polymorphisms, but the occurrence of these variations in both SLE and normal subjects and their specific positions within the TCR[zeta] coding region make it improbable that they play important roles in the genetic susceptibility to SLE.

2606

Autoantibodies Against Malondialdehyde-Modified Lipoprotein(a) in Antiphospholipid Syndrome

Fredeswinda I. Romero, Tatsuya Atsumi, Francisco J. Tinahones, Juan M. Gomez-Zumaquero, Olga Amengual, Munther A. Khamashta, and Graham R. V. Hughes

Recent evidence implicates oxidative phenomena in APS. This study measured autoimmune reactivity against malondialdehyde-modified lipoprotein(a) (MDA-Lp[a]) in sera from patients with APS, and is the first to establish the existence of autoantibodies to MDA-Lp(a). The presence of antibodies reacting not only against MDA-low-density lipoprotein but also against MDA-Lp(a) supports the hypothesis of a role for oxidative phenomena in the pathogenesis of APS and atherosclerosis.

2612

Association of the Glutathione S-Transferase M1 Homozygous Null Genotype with Susceptibility to Sjogren's Syndrome in Japanese Individuals

Akio Morinobu, Sugayo Kanagawa, Masahiro Koshiba, Susumu Sugai, and Shunichi Kumagai

GST enzymes, which catalyze the detoxification or inactivation of various drugs and xenobiotics, are thought to have a role in protection against oxidative stress. In this study, it was demonstrated that the GSTM1 homozygous null genotype was associated with both susceptibility to SS and SSA autoantibody production. These findings offer valuable information on the etiology and immune dysregulation of SS in terms of a genetic factor other than major histocompatibility complex genes.

2616

Genetic Basis of Autoimmune Sialadenitis in MRL/lpr Lupus-Prone Mice: Additive and Hierarchical Properties of Polygenic Inheritance

Miyuki Nishihara, Miho Terada, Junji Kamogawa, Yuichi Ohashi, Shiro Mori, Shuichi Nakatsuru, Yusuke Nakamura, and Masato Nose

An MRL strain of mice bearing a Fas-deletion mutant gene, lpr, develops autoimmune sialadenitis that resembles Sjogren's syndrome, for which MRL background genes are required. This study clarifies the mode of inheritance of sialadenitis in this strain of mice and identifies its susceptibility loci in order to simulate the genetic basis of Sjogren's syndrome.

2624

YKL-40 in Giant Cells and Macrophages from Patients with Giant Cell Arteritis

Julia S. Johansen, Bo Baslund, Charly Garbarsch, Michael Hansen, Michael Stoltenberg, Ib Lorenzen, and Paul A. Price

YKL-40 is secreted in vitro by activated macrophages at late stages of differentiation. Macrophages play an important role in the pathogenesis of GCA, and therefore YKL-40 may be of significance in GCA. In the present study, immunohistochemical analysis was used to demonstrate that macrophages and giant cells in temporal artery biopsy samples from patients with GCA stained positive for the YKL-40 antigen. Serum YKL-40 concentrations were elevated in patients with GCA and decreased to normal levels during prednisolone therapy.

2631

Chondroprogenitor Cells of Synovial Tissue

Keita Nishimura, Luis A. Solchaga, Arnold I. Caplan, Jung U. Yoo, Victor M. Goldberg, and Brian Johnstone

This report describes the analysis of the chondrogenic potential of cells within synovium. Chondrogenesis was induced both in explants of synovial tissue and in isolated synovial cells. The chondrocytic cells of rheumatoid pannus may be derived from these cells, rather than from articular chondrocytes as previously proposed. Metaplasia of these cells may be responsible for heterotopic cartilage formation within the joint, which is found in conditions such as synovial chondromatosis.

2637

Errata

Incorrect Listing of Pediatric Rheumatology Abstract Reviewers and Error in Author Index, September 1999 Abstract Supplement Supplement

2638

Systemic Sclerosis-Associated Pulmonary Hypertension: Short- and Long-Term Effects of Epoprostenol (Prostacyclin)

Elizabeth S. Klings, Nicholas S. Hill, Michael H. Ieong, Robert W. Simms, Joseph H. Korn, and Harrison W. Farber

Pulmonary hypertension secondary to systemic sclerosis is common, is associated with increased mortality, and has limited therapeutic options. In this study, epoprostenol, a synthetic form of prostaglandin I2, improved the short- and long-term hemodynamic parameters and clinical symptoms and affected mortality in patients with pulmonary hypertension secondary to SSc.

2646

Losartan Therapy for Raynaud's Phenomenon and Scleroderma: Clinical and Biochemical Findings in a Fifteen-Week, Randomized, Parallel-Group, Controlled Trial

Magdalena Dziadzio, Christopher P. Denton, Roy Smith, Kevin Howell, Andrew Blann, Emma Bowers, and Carol M. Black

Angiotensin II is a candidate mediator of both vascular and fibrotic pathologies in scleroderma. This study evaluated the efficacy of losartan, an antagonist of angiotensin II receptor type 1, in Raynaud's phenomenon and scleroderma. The results provide preliminary evidence of its clinical and biochemical effectiveness.

2656

Autoantibodies to the Extracellular Matrix Microfibrillar Protein, Fibrillin 1, in Patients with Localized Scleroderma

Frank C. Arnett, Filemon K. Tan, Yosef Uziel, Ronald M. Laxer, Bernice R. Krafchik, Stephen Antohi, and Constantin Bona

In this study, serum autoantibodies to fibrillin 1, the major component of microfibrils in connective tissues and the gene that is mutated in Marfan's syndrome, were found in 26-30% of patients with localized scleroderma. The discovery of an autoimmune response to fibrillin 1 in both systemic and localized scleroderma opens new avenues of research into the pathogenesis of these diseases.

2660

Prediction of Five-Year Survival Following Presentation with Scleroderma: Development of a Simple Model Using Three Disease Factors at First Visit

C. Bryan, C. Knight, C. M. Black, and A. J. Silman

In this study of 280 patients with scleroderma, data on major laboratory and clinical variables were collected prospectively, and deaths occurring during the followup period were recorded. The results demonstrate that a few, simply collected variables at first presentation of scleroderma can be used to predict, with reasonable accuracy, the 5-year mortality in patients with this disease.

2666

A Staged Approach to the Treatment of Wegener's Granulomatosis: Induction of Remission with Glucocorticoids and Daily Cyclophosphamide Switching to Methotrexate for Remission Maintenance

Carol A. Langford, Cheryl Talar-Williams, Karyl S. Barron, and Michael C. Sneller

Thirty-one patients with Wegener's granulomatosis were treated with a staged approach using daily cyclophosphamide and glucocorticoids to induce disease remission, followed by methotrexate for remission maintenance. This regimen resulted in disease remission for all 31 patients, with few disease relapses and minimal toxicity. These findings support this approach as an acceptable alternative therapy for patients with active Wegener's granulomatosis, including those with severe disease.

2674

Temporal Artery Biopsy: A Diagnostic Tool for Systemic Necrotizing Vasculitis

Thierry Genereau, Olivier Lortholary, Marie-Antoinette Pottier, Ulrique Michon-Pasturel, Thierry Ponge, Benoit de Wazieres, Eric Liozon, Laurent Pinede, Eric Hachulla, Pascal Roblot, Jacques-Henri Barrier, Serge Herson, and Loic Guillevin, for the French Vasculitis Study Group

The localization of systemic necrotizing vasculitis by temporal artery biopsy may be a confusing finding. Such a localization was made in 27 patients who are described in depth in this report, and its frequency was assessed among elderly patients undergoing temporal artery biopsy for suspected giant cell arteritis. Careful analysis including temporal artery biopsy should help clinicians to diagnose many arterial diseases and help to guide the choice of therapy.

2682

Patterns of Disease Activity in Systemic Lupus Erythematosus

Susan G. Barr, Abraham Zonana-Nacach, Laurence S. Magder, and Michelle Petri

While SLE has traditionally been described as having unpredictable flares and remissions, this study showed that persistent disease activity was more common. Understanding the lifetime burden of lupus disease activity is important, because it appears to be a key predictor of both morbidity and mortality. Furthermore, clinical trials should use outcome measures capable of capturing changes in chronic lupus activity, rather than measuring differences in flare rates alone.

2689

Determinants of Enhanced Thromboxane Biosynthesis in Patients with Systemic Lupus Erythematosus

Domenico Ferro, Stefania Basili, Salvatore Roccaforte, Manuela Di Franco, Francesco Cipollone, Giovanni Ciabattoni, and Giovanni Davi

This study demonstrates that in vivo platelet activation can be observed in SLE patients when antiphospholipid antibody (aPL) positivity and endothelial perturbation coexist, whereas aPL per se do not cause platelet activation. Endothelial perturbation may directly elicit platelet activation or may favor platelet activation through stimulation of the clotting system. The analytical approach used in this study may help identify SLE patients at increased risk of thrombosis as potential candidates for antiplatelet therapy.

2698

Interaction Between Tumor Necrosis Factor Microsatellite Polymorphisms and the HLA-DRB1 Shared Epitope in Rheumatoid Arthritis: Influence on Disease Outcome

Derek L. Mattey, Andrew B. Hassell, Peter T. Dawes, William E. R. Ollier, and Ali Hajeer

Identification of RA patients at risk of developing severe disease may allow more aggressive therapy to be appropriately targeted at an early stage. This study investigated whether interactions between tumor necrosis factor microsatellite a (TNFa) polymorphisms and the HLA-DRB1 shared epitope are associated with measures of disease severity in RA, and whether such associations are the same in male and female patients. The results suggest that the association of the shared epitope with disease severity is influenced by an interaction with the TNFa6 microsatellite polymorphism, and that this interaction appears to be acting predominantly in female patients.

2705

Lack of Borrelia Burgdorferi DNA in Synovial Samples From Patients with Antibiotic Treatment-Resistant Lyme Arthritis

David Carlson, Jesus Hernandez, Bradley J. Bloom, Jenifer Coburn, John M. Aversa, and Allen C. Steere

Borrelia burgdorferi DNA was not detected in synovial samples from 26 patients with Lyme arthritis who underwent arthroscopic synovectomies following antibiotic treatment for a mean total duration of 8 weeks. These results indicate that synovial inflammation may persist in some patients with Lyme arthritis after the apparent eradication of the spirochete from the joint with antibiotic therapy.

2710

Health Insurance Characteristics and Health Care Evaluations Among Persons with Rheumatic Diseases in California

Appendix A Characteristics of Health Insurance
Appendix B Evaluation of Health Care for Rheumatic Conditions

Patricia P. Katz, Edward H. Yelin, Amye Leong, and Dean R. Sonneborn

Many regulatory or accreditation bodies are now requiring surveys of patients satisfaction or patient evaluations. This study provides information to physicians about characteristics of health insurance plans that may influence patient evaluations of physician care, access to and convenience of care, and health plan coverage.

2719

Subchondral Insufficiency Fracture of the Femoral Head: A Differential Diagnosis in Acute Onset of Coxarthrosis in the Elderly

Takuaki Yamamoto and Peter G. Bullough

Acute-onset coxarthrosis in the elderly has generally been regarded as idiopathic. This report stresses the importance of including subchondral insufficiency fracture in the differential diagnosis, since the management in such a case may be quite different from that of most cases of coxarthrosis.

2724

Tuberculosis of the Wrist

E. Michael Shanahan, Sinead D. Hanley, Robin G. Gibney, and Oliver FitzGerald

2727

IgA-Class Anti-[beta]2-Glycoprotein I in Women with Unexplained Recurrent Spontaneous Abortion

Hideto Yamada, Akito Tsutsumi, Kenji Ichikawa, Emi Hirayama Kato, Takao Koike, and Seiichiro Fujimoto

2728

Evidence for the Participation of Anti-Ribosomal P Antibodies in Lupus Nephritis

Morris Reichlin and Marianne Wolfson-Reichlin

2729

Enhanced Interleukin-6 Messenger RNA Expression by Neuronal Cells in a Patient with Neuropsychiatric Systemic Lupus Erythematosus

Shunsei Hirohata and Kinya Hayakawa

2731

Is Chiari Malformation Associated with Increased Levels of Substance P and Clinical Symptoms in Persons with Fibromyalgia?

Laurence A. Bradley and Graciela S. Alarcon

2732

32CCR5 and Rheumatoid Arthritis: Comment on the Article by Gomez-Reino et al

Patrick J. W. Venables and Ali Hajeer

2732

Juan J. Gomez-Reino and Jose L. Pablos

2733

Roles of Nucleosomes in Systemic Lupus Erythematosus: Comment on the Article by Amoura et al

Stanley L. Lee

2734

Zahir Amoura, Jean-Charles Piette, Jean-Francois Bach, and Sophie Koutouzov

2734

Laxity in Healthy and Osteoarthritic Knees: Comment on the Article by Sharma et al

Jean H. Gillies, Diane L. MacLeod, and Jeffrey K. H. Vallance

2735

Leena Sharma, Congrong Lou, Dorothy D. Dunlop, Gretchen Kirwan-Mellis, David Weinrach, David T. Felson, and Thomas S. Buchanan

2736

Hypertrophic Osteoarthropathy

Sebastian Schnarr, Michael Galanski, Klaus F. Gratz, and Henning Zeidler

2737

Reviewers

2741

Contents, Volume 42, 1999

2768

Indexes

13A

ACR Announcements