1

Review: Gene Therapy for Rheumatic Diseases

C. H. Evans, S. C. Ghivizzani, R. Kang, T. Muzzonigro, M. C. Wasko, J. H. Herndon, and P. D. Robbins

17

Incidence and Risk Factors for Radiographic Knee Osteoarthritis in Middle-Aged Women: The Chingford Study

Deborah J. Hart, David V. Doyle, and Tim D. Spector

Although a number of risk factors have been associated with prevalent knee OA, this is the first study to examine causes of incident disease in middle-aged women. The results demonstrate that [approximate]3% of middle-aged women will develop radiologic knee OA every year, confirm the importance of obesity as the major modifiable risk factor for knee OA in middle-aged women, and provide evidence of a protective effect of estrogen replacement therapy. No clear evidence that smoking, physical activity, or knee injury are important risk factors was found. Knowledge of incidence rates will help in the planning of trials of preventive treatments or lifestyle interventions.

25

Does Laxity Alter the Relationship Between Strength and Physical Function in Knee Osteoarthritis?

Leena Sharma, Karen W. Hayes, David T. Felson, Thomas S. Buchanan, Gretchen Kirwan-Mellis, Congrong Lou, Yi-Chung Pai, and Dorothy D. Dunlop

Studies of strengthening interventions for knee OA have revealed an impact on patient function that is surprisingly modest given the role of muscle in joint function. Other factors may moderate the strength-function relationship in knee OA. In this study, the presence of varus-valgus laxity was associated with a reduction in the magnitude of the relationship between strength and functional status. This has implications for the expectations regarding the outcome of muscle-strengthening intervention, a major component of the usual treatment program for knee OA. These results raise the possibility that a therapeutic approach that accounts for an impairment in the passive restraint system may result in better functional outcomes.

33

Grip Strength and the Risk of Developing Radiographic Hand Osteoarthritis: Results From the Framingham Study

Christine E. Chaisson, Yuqing Zhang, Leena Sharma, William Kannel, and David T. Felson

Grip is a common task during which high muscle forces are sustained at certain hand joints. In this study, men and women with high maximal grip strength were found to be at increased risk of OA in various hand joint groups. This strong association with grip strength suggests that excessive muscle force may contribute to the pathogenesis of hand OA.

39

Changes in Serum Cartilage Marker Levels Indicate Altered Cartilage Metabolism in Families with the Osteoarthritis-Related Type II Collagen Gene COL2A1 Mutation

Jane F. Bleasel, A. Robin Poole, Dick Heinegard, Tore Saxne, Daniel Holderbaum, Mirella Ionescu, Paul Jones, and Roland W. Moskowitz

This study was performed in individuals with familial OA and revealed altered cartilage metabolism, demonstrated by elevated cartilage oligomeric matrix protein and keratan sulfate levels. Other markers, the 846 epitope of aggrecan and CPII (type II collagen propeptide), representative of cartilage synthesis were not altered, indicating dissociation of anabolism and breakdown. These results support a clinical role for such markers in the diagnosis of clinically silent or active OA, or in disease progression.

46

Trends in the Incidence and Mortality of Systemic Lupus Erythematosus, 1950-1992

Kristine M. Uramoto, Clement J. Michet, Jr., Julian Thumboo, Jayasimha Sunku, W. Michael O'Fallon, and Sherine E. Gabriel

Over the past 40 years, there has been a progressive increase in the number of individuals diagnosed with SLE. Over the same time period, life expectancy for people with this disease has improved significantly. These results are likely due to a combination of improved recognition of milder forms of SLE and the availability of more effective treatment options.

51

Prevalence and Risk Factors of Carotid Plaque in Women with Systemic Lupus Erythematosus

Susan Manzi, Faith Selzer, Kim Sutton-Tyrrell, Shirley G. Fitzgerald, Joan E. Rairie, Russell P. tracy, and Lewis H. Kuller

In this study, duplex carotid scans were shown to provide a noninvasive measurement of atherosclerosis in women with lupus who are at high risk for premature cardiovascular events, and several potentially modifiable risk factors were identified. This technique provides a method for examining the risk factors associated with atherosclerosis in these young women, and facilitates followup of the progression and/or regression of plaque over time in observational or interventional trials.

61

Discrepancy Between Regional Cerebral Blood Flow and Glucose Metabolism of the Brain in Systemic Lupus Erythematosus Patients with Normal Brain Magnetic Resonance Imaging Findings

Chia-Hung Kao, Yung-Jen Ho, Jung-Liang Lan, Sheng-Ping Changlai, Ko-Kaung Liao, and Poon-Ung Chieng

Involvement of the brain is one of the most important complications of SLE. However, due to the lack of effective imaging, diagnosis of brain involvement in SLE patients is difficult. 99mTc-HMPAO-SPECT and 18F-FDG-PET were used to simultaneously detect regional cerebral blood flow and glucose metabolism of the brain in SLE patients. The results indicated that, in patients with normal brain MRI findings, decreases in glucose metabolism coupled with decreases in rCBF are associated with serious neuropsychiatric SLE presentations, while normal glucose metabolism with decreases in rCBF may be found in SLE patients with or without NPSLE.

69

Prevalence of Autoantibodies to Ribosomal P Proteins in Juvenile-Onset Systemic Lupus Erythematosus Compared with the Adult Disease

Morris Reichlin, Tena Faulkner Broyles, Osvaldo Hubscher, Judith James, Thomas A. Lehman, Rosa Palermo, Haraldine A. Stafford, Elizabeth Taylor-Albert, and Marianne Wolfson-Reichlin

This retrospective study revealed an increased prevalence of antibodies to ribosomal P protein (anti-P) in juvenile-onset SLE compared with adult-onset SLE, and antibody levels varied with indices of clinical disease activity, often in concordance with the levels of anti-double-stranded DNA (anti-dsDNA). Children with both anti-P and anti-dsDNA almost invariably had nephritis during their disease course. Future studies, particularly large-scale, prospective studies, could better illuminate the relationship of anti-P to anti-dsDNA antibodies and to clinical disease expression, especially nephritis.

76

Comparing Self-Reported Function and Work Disability in 100 Community Cases of Fibromyalgia Syndrome Versus Controls in London, Ontario: The London Fibromyalgia Epidemiology Study

Kevin P. White, Mark Speechley, Manfred Harth, and truls Ostbye

Fibromyalgia is one of the most common musculoskeletal illnesses, accounting for 10-30% of all new patients presenting to rheumatology clinics. To date, much of what we know about fibromyalgia stems from studies on subspecialty clinic patients, which may present a biased picture of the syndrome. This report presents the results of a controlled study of 100 randomly selected community cases of fibromyalgia, focusing on patients' self-reported function and work disability.

84

Salmonella-triggered Reactive Arthritis: Use of Polymerase Chain Reaction, Immunocytochemical Staining, and Gas Chromatography-Mass Spectrometry in the Detection of Bacterial Components from Synovial Fluid

Simo Nikkari, Kaisu Rantakokko, Paivi Ekman, Timo Mottonen, Marjatta Leirisalo-Repo, Mika Virtala, Leena Lehtonen, Jari Jalava, Pirkko Kotilainen, Kaisa Granfors, and Paavo Toivanen

In this study, 3 different PCR techniques and immunofluorescence staining were used to investigate whether microbial DNA and antigenic components, respectively, were present in cells of synovial fluid and peripheral blood from patients with Salmonella-triggered ReA. Presence of bacteria-derived muramic acid in synovial fluid was studied with gas chromatography-mass spectrometry. In 23 patients with Salmonella-triggered ReA, bacterial degradation products, but not bacterial DNA, were present in the inflamed joint. This finding may have an impact on the treatment of Salmonella-triggered ReA.

90

Amelioration of Collagen-Induced Arthritis and Suppression of Interferon-[gg], Interleukin-12, and Tumor Necrosis Factor [ga] Production by Interferon-[gb] Gene Therapy

Kostas A. triantaphyllopoulos, Richard O. Williams, Hitakshi Tailor, and Yuti Chernajovsky

The data obtained from this experimental model of arthritis outline the possible mechanisms by which IFN[gb] could act in the prevention or amelioration of an autoimmune disease such as rheumatoid arthritis. The pleiotropic antiinflammatory and immunosuppressive effects reported warrant the further investigation of this cytokine in the clinical setting of rheumatoid arthritis.

100

Biphasic Regulation of the Development of Murine Type II Collagen-Induced Arthritis by Interleukin-12: Possible Involvement of Endogenous Interleukin-10 and Tumor Necrosis Factor [ga]

Tsuyoshi Kasama, Jyunko Yamazaki, Ryosuke Hanaoka, Yusuke Miwa, Yoshimi Hatano, Kazuo Kobayashi, Masao Negishi, Hirotsugu Ide, and Mitsuru Adachi

This report contains novel data that demonstrate the differential regulation of murine collagen-induced arthritis by interleukin-12. In addition, IL-12-induced cross-talking of antiinflammatory mediators and proinflammatory cytokines was demonstrated as an important factor in the regulation of arthritis inflammation.

110

Modulation by Cytokines of Induction of Oral Tolerance to Type II Collagen

G. J. Thorbecke, R. Schwarcz, J. Leu, C. Huang, and W. J. Simmons

Feeding of type II collagen has not proved beneficiary in the treatment of rheumatoid arthritis, although oral tolerance to this protein can protect against induction of arthritis in mice. However, even in mice, many parameters defining the most effective conditions for induction of oral tolerance, and in particular the influence of various cytokines and/or drugs, have not yet been examined in sufficient detail. The present report describes an initial attempt to find conditions that may improve the chance of ameliorating already developing arthritis in mice through intragastric administration of type II collagen.

119

High-Resolution Three-Dimensional Magnetic Resonance Imaging for the Investigation of Knee Joint Damage During the Time Course of Antigen-Induced Arthritis in Rabbits

Janet Dawson, Sharon Gustard, and Nicolau Beckmann

This work demonstrates that the pathologic changes seen in 3-D MRI of arthritic joints can be correlated with pathologic changes seen histologically in the same joints. Applied in a clinical setting, this shows that 3-D MRI can be used to follow up over time both soft tissue inflammation and hard tissue destruction. MRI therefore represents an extremely important method for noninvasive assessment of the effectiveness of antiarthritic therapy on disease progression, with 3-D techniques facilitating the comparison of images acquired at different times.

129

Relationship of Matrix Metalloproteinases and their Inhibitors to Cartilage Proteoglycan and Collagen Turnover: Analyses of Synovial Fluid From Patients with Osteoarthritis

Naoki Ishiguro, Takayasu Ito, Hideo Ito, Hisashi Iwata, Hitenishi Jugessur, Mirela Ionescu, and A. Robin Poole

This study examines new assays designed to measure the proteinases, proteinase inhibitors, and fragments of cartilage matrix molecules that are involved in the degradation and synthesis of osteoarthritic joint tissue. By examining synovial fluid samples from osteoarthritis patients, information can be obtained about the balance and linkages between tissue destruction and repair. This type of approach may offer new insight into the pathologic process of osteoarthritis.

137

Retinoic Acid-Induced Type II Collagen Degradation Does Not Correlate with Matrix Metalloproteinase Activity in Cartilage Explant Cultures

Jo S. Price, Sherry Wang-Weigand, Richard Bohne, L. Didem Kozaci, and Anthony P. Hollander

This study attempts to elucidate the proteolytic mechanisms that contribute to collagen degradation in cartilage. A good understanding of these biochemical events is essential for the future development of new drugs to treat the damage to cartilage in the synovial joints of patients with arthritis.

148

Avocado/Soya Unsaponifiables Enhance the Expression of transforming Growth Factor [gb]1 and [gb]2 in Cultured Articular Chondrocytes

K. Boumediene, N. Felisaz, P. Bogdanowicz, P. Galera, G. B. Guillou, and J.-P. Pujol

Avocado/soya unsaponifiable extracts (ASU) are used in the treatment of osteoarthritis. ASU have been shown to improve clinical symptoms, but their mechanisms of action are not well understood. This in vitro study demonstrates that they can stimulate TGF[gb]1, TGF[gb]2, and plasminogen activator inhibitor 1 expression by articular chondrocytes, an effect which could explain their promoting action on matrix synthesis and their opposing effect on the interleukin-1-induced degradative process. This work provides the first possible explanation for the chondroprotective effect of ASU.

157

Enhancement of Phosphorylation and transcriptional Activity of the Glucocorticoid Receptor in Human Synovial Fibroblasts by Nimesulide, A Preferential Cyclooxygenase 2 Inhibitor

John A. Di Battista, Mengkun Zhang, Johanne Martel-Pelletier, Julio Fernandes, Nada Alaaeddine, and Jean-Pierre Pelletier

The work helps to explain some of the antiinflammatory effects and therapeutic efficacy of a new generation of COX-2 preferential nonsteroidal antiinflammatory drugs, in particular, nimesulide. In addition, it may help the clinician to make a more rational choice in selecting COX-2 inhibitors over conventional nonsteroidal antiinflammatory drugs.

167

[gb]2-Glycoprotein I is Necessary to Inhibit Protein C Activity by Monoclonal Anticardiolipin Antibodies

Masahiro Ieko, Kenji Ichikawa, Douglas A. triplett, Eiji Matsuura, Tatsuya Atsumi, Ken-Ichi Sawada, and Takao Koike

The influence of [gb]2GPI, or monoclonal anticardiolipin antibodies, on the activity of activated protein C (APC) was investigated using a chromogenic assay and soybean trypsin inhibitor to inhibit APC. [gb]2GPI, which is required for aCL to form a complex with phospholipids, inhibited APC activity. Monoclonal aCL further inhibited the APC activity, but only in the presence of [gb]2GPI.

175

Overlapping Peptide-Binding Specificities of HLA-B27 and B39: Evidence for a Role of Peptide Supermotif in the Pathogenesis of Spondylarthropathies

Yuji Sobao, Naoyuki Tsuchiya, Masafumi Takiguchi, and Katsushi Tokunaga

An association of HLA-B39 in Japanese patients with HLA-B27 negative spondylarthropathies has previously been reported. The similarity of HLA-B27 and B39 pocket B predicted that the antigenic peptides presented by these 2 molecules might overlap. The present study experimentally demonstrates that a subset of natural ligands of HLA-B27 is capable of binding to HLA-B39. This information may significantly contribute to the identification of antigenic peptides associated with spondylarthropathies.

181

Error in Spelling of Author's Name in Letter by Cid et al (Arthritis Rheum, November 1998)

182

Localized Bowel Vasculitis: Postoperative Cyclophosphamide or Not?

K. Raza, A. R. Exley, D. M. Carruthers, C. Buckley, L. A. Hammond, and P. A. Bacon

186

Induction Therapy with an Intravenous Loading Dose of Azathioprine for treatment of Refractory, Active Rheumatoid Arthritis

Eric L. Matteson, Carlos H. Orces, Joseph Duffy, James J. Lipsky, M. Gennett Pike, and William J. Sandborn

187

Lack of Occurrence of Severe Lupus Nephritis Among Anti-C1q Autoantibody-Negative Patients

Marten trendelenburg, Jutta Marfurt, Iris Gerber, Alan Tyndall, and Jurg A. Schifferli

189

Does Early and Aggressive treatment Improve the Prognosis in Psoriatic Arthritis? Comment on the Article by Wong et al

John Brockbank, Martin Leach, Mike Snaith, and Adewale Adebajo

189

Reply

Dafna D. Gladman and Vernon T. Farewell

190

Acute-Phase Response and Risk of Developing Ischemic Complications in Giant Cell Arteritis: Comment on the Article by Cid et al

T. Lehmann and M. Seitz

190

Reply

Maria C. Cid, Carme Font, Alejandro de la Sierra, Blanca Coll-Vinent, Alfons Lopez-Soto, Alvaro Urbano-Marquez, Josep M. Grau, Joaquim Oristrell, and Jaume Vilaseca

190

Clinical, Immunologic, and Immunogenetic Evidence that Mixed Connective Tissue Disease is a Distinct Entity: Comment on the Article by Smolen and Steiner

G. C. Sharp and R. W. Hoffman

191

Naming Names! Comment on the Article by Smolen and Steiner

David Isenberg and Carol Black

193

Reply

Josef S. Smolen and Gunter Steiner

196

Iloprost treatment in Systemic Sclerosis: Comment on the Concise Communication by Tedeschi et al

J. Braun, J. Sieper, G. Riemekasten, and F. Hiepe

197

Reply

Alberto Tedeschi, Pier Luigi Meroni, Nicoletta Del Papa, Carla Boschetti, and Antonio Miadonna

13A

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