239

Editorial: The Future Status of Pediatric Rheumatology in the United States: Strategic Planning for the Year 2000

American College of Rheumatology Blue Ribbon Committee for Academic Pediatric Rheumatology

243

Current Comment: Approaches for Identifying and Defining Environmentally Associated Rheumatic Disorders

Frederick W. Miller, Evelyn V. Hess, Daniel J. Clauw, Phillip A. Hertzman, Theodore Pincus, Richard M. Silver, Maureen D. Mayes, John Varga, Thomas A. Medsger, Jr., and Lori A. Love

250

Synovial Tissue in Rheumatoid Arthritis is a Source of Osteoclast Differentiation Factor

Ellen M. Gravallese, Cathy Manning, Alfie Tsay, Akifumi Naito, Chin Pan, Edward Amento, and Steven R. Goldring

It has been shown that osteoclasts contribute to bone erosion in RA. This study demonstrates that tartrate-resistant acid phosphatase-positive, cathepsin K-positive osteoclast precursor cells are present in areas of pannus invasion into bone and bone marrow. A newly described cytokine, osteoclast differentiation factor (ODF), has been shown to be essential for osteoclast differentiation in physiologic bone remodeling. Synovial tissues are a source of ODF, and both synovial fibroblasts and activated T cells from RA synovial tissue express messenger RNA for ODF. The results of this study suggest that ODF may be an important factor in stimulating osteoclast-mediated bone erosion in RA, and thus may be a potential therapeutic target in the prevention of bone loss in this disease.

259

Involvement of Receptor Activator of Nuclear Factor [Kappa]B Ligand/Osteoclast Differentiation Factor in Osteoclastogenesis from Synoviocytes in Rheumatoid Arthritis

Hiroshi Takayanagi, Hideharu Iizuka, Takuo Juji, Takumi Nakagawa, Aiichiro Yamamoto, Tsuyoshi Miyazaki, Yasuko Koshihara, Hiromi Oda, Kozo Nakamura, and Sakae Tanaka

Joint destruction in RA has never been completely controlled by any drug ever known. This is the first description of the involvement of receptor activator of nuclear factor [Kappa]B ligand/osteoclast differentiation factor, a newly discovered member of the tumor necrosis factor superfamily, in the mechanism of bone destruction in RA. The results of the study suggest the possibility of a new therapeutic strategy targeted at osteoclasts in arthritic bone destruction.

270

The Effects of Interferon-[beta] Treatment on Synovial Inflammation and Expression of Metalloproteinases in Patients with Rheumatoid Arthritis

Tom J. M. Smeets, Jean M. Dayer, Maarten C. Kraan, Johannes Versendaal, Rachel Chicheportiche, Ferdinand C. Breedveld, and Paul P. Tak

IFN[beta] treatment is emerging as a potentially effective form of therapy in various immune-mediated conditions. This report describes the effects of IFN[beta] on the cell infiltrate, cytokine profile, and expression of matrix metalloproteinases in the synovial tissue of RA patients. In vitro experiments were conducted to determine the effects of IFN[beta] on the production of matrix metalloproteinases, tissue inhibitor of matrix metalloproteinases, and prostaglandin E2 by human fibroblast-like synoviocytes. The results support the view that IFN[beta] therapy is potentially effective in RA.

275

Increased Expression of Extracellular Matrix Metalloproteinase Inducer in Rheumatoid Synovium

Yrjo T. Konttinen, Tian-Fang Li, Jami Mandelin, Mikko Liljestrom, Timo Sorsa, Seppo Santavirta, and Ismo Virtanen

This study investigated the expression of extracellular matrix metalloproteinase inducer (EMMPRIN) in synovium obtained from rheumatoid arthritis and osteoarthritis patients and showed an up-regulated expression in rheumatoid synovial membranes. Because EMMPRIN induces local production of MMPs 1, 2, and 3, it plays a role in joint destruction in rheumatoid arthritis and might therefore prove to be a useful target for new therapeutic approaches.

281

Synovial Fluid Levels of Tumor Necrosis Factor [alpha] and Oncostatin M Correlate with Levels of Markers of the Degradation of Crosslinked Collagen and Cartilage Aggrecan in Rheumatoid Arthritis But Not in Osteoarthritis

Daniel-Henri Manicourt, Pascal Poilvache, Anne Van Egeren, Jean-Pierre Devogelaer, Mary-Ellen Lenz, and Eugene J.-M. A. Thonar

This study compared synovial fluid SF levels of OSM, TNF[alpha], and interleukin-6 (IL-6) in patients with RA and OA and determined which correlated best with SF levels of antigenic keratan sulfate, a marker of aggrecan catabolism, and pyridinium crosslinks, markers of the degradation of mature collagen molecules. The findings suggest that catabolism of cartilage aggrecan and crosslinked collagens and up-regulation of OSM/IL-6 expression are closely coordinated in rheumatoid joints but not in osteoarthritic joints. TNF[alpha] may play a key role in coordinating the stimulation of these cell-dependent processes in RA.

289

Therapy and Prevention of Arthritis by Recombinant Adeno-Associated Virus Vector with Delivery of Interleukin-1 Receptor Antagonist

Ru-Yu Pan, Show-Li Chen, Xiao Xiao, Dai-Wei Liu, Ho-Jeng Peng, and Yeou-Ping Tsao

This study evaluated the potential of rAAV-IL-1Ra for treating and preventing lipopolysaccharide (LPS)-induced arthritis. In the LPS-induced rat arthritis model, rAAV carrying IL-1Ra gene ameliorated both primary and recurrent arthritis and also prevented arthritis attack. Our findings suggest that rAAV is a potential tool for the gene therapy of arthritis.

298

123I-Antileukoproteinase Scintigraphy Reveals Microscopic Cartilage Alterations in the Contralateral Knee Joint of Rats With ``Monarticular'' Antigen-Induced Arthritis

Philipp Meyer, Harald Burkhardt, Ernesta Palombo-Kinne, Wilfried Grunder, Rolf Brauer, Klaus J. Stiller, Joachim R. Kalden, Wolfgang Becker, and Raimund W. Kinne

The findings of this study indicate that 123I-antileukoproteinase scintigraphy is a highly sensitive imaging method for detecting microscopic cartilage lesions in experimental arthritis, possibly superior to other conventional imaging procedures, including magnetic resonance microimaging (currently the ``gold standard'' for assessment of cartilage lesions). These results are of potential clinical interest, because detection of microscopic alterations of joint cartilage in humans with arthritis may allow early therapy aimed at preventing irreversible joint damage.

311

Cyclosporin A Prevents the Histologic Damage of Antigen Arthritis Without Inducing Fibrosis

Maria J. Benito, Olga Sanchez-Pernaute, Maria Jose Lopez-Armada, Purificacion Hernandez, Itziar Palacios, Jesus Egido, and Gabriel Herrero-Beaumont

CSA was introduced for the treatment of rheumatoid arthritis as an adjunct to methotrexate in refractory or severe cases, and hence, there is not yet enough information about its role as a disease-modifying antirheumatic drug. Furthermore, it has recently been suggested that deleterious effects of CSA are related to the induction of transforming growth factor [beta] (TGF[beta]) overexpression and fibrosis. This study provides new data regarding the benefits of CSA in synovitis and explores the relevance of TGF[beta] induction by the drug in joint inflammation.

320

Beneficial Effects of Tempol, A Membrane-Permeable Radical Scavenger, in a Rodent Model of Collagen-Induced Arthritis

Salvatore Cuzzocrea, Michelle C. McDonald, Helder Mota-Filipe, Emanuela Mazzon, Giuseppina Costantino, Domenico Britti, Giuseppe Mazzullo, Achille P. Caputi, and Christoph Thiemermann

The effects of tempol, a small molecule that permeates biologic membranes and scavenges reactive oxygen species, on CIA in Lewis rats were examined. Findings revealed that tempol treatment attenuated the degree of chronic inflammation and tissue damage associated with CIA in the rat. It is proposed that small molecules such as tempol, which permeate biologic membranes and function as intracellular radical scavengers, may be useful in the treatment of conditions associated with local or systemic inflammation.

329

Evidence for the Expression of a Second CD6 Ligand by Synovial Fibroblasts

Yeong-Shil Joo, Nora G. Singer, Judith L. Endres, Sujata Sarkar, Raimund W. Kinne, Rory M. Marks, and David A. Fox

Ligands for functionally important T cell surface structures are expressed on the membranes of other cells with which T cells interact, including in inflamed synovium. One ligand for the T cell molecule CD6 is known, and is designated activated leukocyte cell adhesion molecule (ALCAM) or CD166. In the present study, using immunologic and biochemical techniques, evidence for a second CD6 ligand on synovial fibroblasts, distinct from CD166/ALCAM and with an approximate size of 130 kd, was obtained.

336

Decreased Expression of Interleukin-1[alpha], Interleukin-1[beta], and Cell Adhesion Molecules in Muscle Tissue Following Corticosteroid Treatment in Patients with Polymyositis and Dermatomyositis

Ingrid Lundberg, Anna-Karin Kratz, Helene Alexanderson, and Manuel Patarroyo

The effect of immunosuppressive treatment, and in particular, corticosteroid treatment, on the expression of IL-1[alpha], IL-[beta], cell adhesion molecules, and class I major histocompatibility complex antigen in muscle tissue was investigated in 11 patients with PM or DM, by performing immunohistochemical analyses of muscle biopsy specimens obtained before and after therapy. After 3-6 months of treatment, muscle function had improved, inflammatory infiltrates had decreased or disappeared completely, and there was a concomitant decrease in expression of the investigated molecules in the muscle tissue. These results indicate that changes in clinical symptoms of myositis can be related to distinct molecular changes seen on muscle biopsy, and that analysis of muscle biopsy specimens obtained on more than one occasion should be of value for further evaluation of the effects and mechanisms of action of therapies for myositis.

349

Identification of Intervals on Chromosomes 1, 3, and 13 Linked to the Development of Lupus in BXSB Mice

Michelle E. K. Haywood, Maxine B. Hogarth, Jason H. Slingsby, S. Jane Rose, Penny J. Allen, E. Mary Thompson, Michael A. Maibaum, Phillip Chandler, Kevin A. Davies, Elizabeth Simpson, Mark J. Walport, and Bernard J. Morley

This study analyzed 286 backcross mice for a range of phenotypic traits associated with the development of systemic lupus erythematosus (SLE) in BXSB mice and used extreme-phenotype and quantitative trait locus analysis to study the linkage of 93 microsatellite markers to disease. The study showed that SLE in the BXSB mouse model has a complex genetic basis and involves at least 5 distinct intervals located on chromosomes 1 and 3. The results also provide evidence that different intervals affect particular aspects of the SLE phenotype. An understanding of the genetic basis of SLE will help to elucidate the etiology of this complex autoimmune disease and may identify novel therapeutic approaches.

356

The Features of Arthritis Induced by CpG Motifs in Bacterial DNA

Guo-Min Deng and Andrej Tarkowski

This study investigated the features of arthritis induced by bacterial DNA that contain CpG motifs injected intraarticularly into the knee joints of mice. The findings of the study demonstrate that bacterial DNA that contain nonmethylated CpG motifs induces arthritis, suggesting an important pathogenic role of bacterial DNA in septic arthritis.

365

Detection of Viral Ribonucleic Acid and Histologic Analysis of Inflamed Synovium in Ross River Virus Infection

Muriel Soden, Helen Vasudevan, Brenda Roberts, Robert Coelen, Gary Hamlin, Subash Vasudevan, and Justin La Brooy

This study documents the histopathology of inflamed synovium in patients with persistent arthritis following Ross River virus infection, and demonstrates the presence of viral nucleic acid in the synovium 5 weeks after the onset of symptoms. These findings extend the knowledge of the immunopathology of this viral arthritis.

370

Comparison of the Effect of Rofecoxib (a Cyclooxygenase 2 Inhibitor), Ibuprofen, and Placebo on the Gastroduodenal Mucosa of Patients with Osteoarthritis: A Randomized, Double-Blind, Placebo-Controlled Trial

Christopher Hawkey, Loren Laine, Thomas Simon, Andre Beaulieu, Jose Maldonado-Cocco, Eduardo Acevedo, Aditi Shahane, Hui Quan, James Bolognese, and Eric Mortensen, for the Rofecoxib Osteoarthritis Endoscopy Multinational Study Group

Although treatment with nonsteroidal antiinflammatory drugs (NSAIDs) is effective in relieving the signs and symptoms of OA, NSAIDs are associated with injury of the gastroduodenal mucosa. These adverse drug reactions represent a significant source of morbidity and mortality and result in the utilization of substantial health care resources. This article reports the results of a large, randomized, multinational, placebo- and active-controlled study along with the results of a combined analysis of this study and a similar study. The study was designed to test the hypothesis that treatment over 6 months with rofecoxib, a specific inhibitor of prostaglandin synthesis by the COX-2 isozyme which spares COX-1 activity, would result in significantly decreased rates of gastroduodenal ulceration detected by endoscopy compared with the NSAID ibuprofen and that the rates would be comparable to the injury observed with placebo over 3 months.

378

Preference for Nonsteroidal Antiinflammatory Drugs Over Acetaminophen by Rheumatic Disease Patients: A Survey of 1,799 Patients with Osteoarthritis, Rheumatoid Arthritis, and Fibromyalgia

Frederick Wolfe, Sean Zhao, and Nancy Lane

This study examined preferences for acetaminophen versus NSAIDs among patients with rheumatoid arthritis, osteoarthritis, and fibromyalgia. There was a statistically significant preference for NSAIDs among the 3 groups, with fewer than 14% preferring acetaminophen. If safety and cost are not at issue, then there would be little reason to recommend acetaminophen over NSAIDs; however, if safety and cost are at issue, then the American College of Rheumatology's recommendation that acetaminophen be tried first seems correct, since 38.2% found acetaminophen to be as effective or more effective than NSAIDs.

386

Scores for Functional Disability in Patients with Rheumatoid Arthritis are Correlated at Higher Levels with Pain Scores than with Radiographic Scores

Tuulikki Sokka, Annaliisa Kankainen, and Pekka Hannonen

Anatomic damage of joints and deterioration of functional capacity are typical long-term consequences of RA. In fact, disability is assumed to be determined by joint damage. The findings of this study indicate that pain, rather than radiographic evidence of small joint damage, explains functional loss, while approximately half of the variation in functional capacity remains unexplained.

390

Recipients of Hip Replacement for Arthritis are Less Likely to be Hispanic, Independent of Access to Health Care and Socioeconomic Status

Augustin Escalante, Rolando Espinosa-Morales, Inmaculada del Rincon, Ramon A. Arroyo, and Steven A. Older

This report describes the results of a population-based study of ethnic background among recipients of elective hip replacements in Bexar County, Texas, compared with that of hospitalized persons with a similar level of access to health care. Its main finding is that recipients of hip replacements are less likely to be Hispanic. Given that hip replacement is a beneficial and cost-effective intervention for arthritis, it is important for practicing rheumatologists and orthopedic surgeons to know that Hispanics may not undergo elective hip replacement as frequently as do non-Hispanics.

400

Association of Mild Acetabular Dysplasia with an Increased Risk of Incident Hip Osteoarthritis in Elderly White Women: The Study of Osteoporotic Fractures

Nancy E. Lane, Paula Lin, Lisa Christiansen, L. Robert Gore, Elizabeth N. Williams, Marc C. Hochberg, and Michael C. Nevitt

The epidemiology of hip osteoarthritis is not well known. This study demonstrated that mild abnormalities in hip geometry increased the risk of developing incident osteoarthritis of the hip in elderly white women. Therefore, mild structural abnormalities in the hip can accelerate the development of hip osteoarthritis even in the elderly.

405

Drug-Associated Antineutrophil Cytoplasmic Antibody-Positive Vasculitis: Prevalence Among Patients with High Titers of Antimyeloperoxidase Antibodies

Hyon K. Choi, Peter A. Merkel, Alexander M. Walker, and John L. Niles

In this study, the prevalence of the prior use of hydralazine, propylthiouracil, and other drugs suspected of causing APV in 30 patients with high titers of anti-MPO antibodies was 33% exposure to hydralazine, 10% to propylthiouracil, and 17% to penicillamine, allopurinol, or sulfasalazine. These data strongly suggest that a sizable proportion of cases of APV with high titers of anti-MPO antibodies is medication associated.

414

Epidemiology of Systemic Vasculitis: A Ten-Year Study in the United Kingdom

Richard A. Watts, Suzanne E. Lane, Graham Bentham, and David G. I. Scott

The systemic vasculitides are uncommon conditions, the epidemiology of which is poorly documented. This study shows that the incidence increases markedly with age, peaking in the 65-74-year age group, and that the incidence may be slowly increasing with time. The age-specific increase in incidence should alert physicians that these conditions occur relatively more frequently in the elderly.

420

The Lupus Erythematosus Cell Phenomenon: Comparative Analysis of Antichromatin Antibody Specificity in Lupus Erythematosus Cell-Positive and -Negative Sera

Georg Schett, Robert L. Rubin, Gunter Steiner, Hannelore Hiesberger, Sylviane Muller, and Josef Smolen

This study demonstrates that high levels of anti-histone H1 antibodies and a positive LE cell phenomenon are closely related immunopathologic features in SLE patients, and may be indicators of a more severe and active disease with major organ involvement. This correlation suggests that the time-consuming LE cell preparation test could be replaced by anti-histone H1 testing.

429

Cross-Reactivity of Antiidiotypic Antibodies with DNA in Systemic Lupus Erythematosus

Elvira R. Eivazova, James M. McDonnell, Brian J, Sutton, and Norman A. Staines

Antibodies that react with double-stranded DNA (dsDNA) are characteristically associated with SLE. This report describes the properties of a set of such autoantibodies, initially identified by their reactivity with idiotypes of DNA-binding autoantibodies. They arise naturally in SLE and are induced by immunization with synthetic idiopeptides that represent parts of the idiotype. The antiidiotypic antibodies cross-react with DNA, and the results indicate that some DNA autoantibodies can arise through an immune reaction against epitopes of autoantibodies that act as natural mimotopes (surrogate antigens) for DNA. This could explain the production, in lupus, of antibodies against dsDNA, which, by itself, is a poor immunogen.

440

Validation of the Sapporo Criteria for Antiphospholipid Syndrome

Michael D. Lockshin, Lisa R. Sammaritano, and Sergio Schwartzman

This test of the Sapporo criteria for APS demonstrates that the criteria are both specific and sensitive for distinguishing primary and secondary APS patients from patients with systemic lupus erythematosus and lupus-like disease. Hence, the Sapporo criteria can be used for clinical studies of APS.

444

Systemic Sclerosis Sine Scleroderma: Demographic, Clinical, and Serologic Features and Survival in Forty-Eight Patients

Hadi Poormoghim, Mary Lucas, Noreen Fertig, and Thomas A. Medsger, Jr.

This study divided patients with SSc into those with no skin thickening (sine scleroderma) and those with skin thickening only distal to elbows or knees and/or of the face (limited cutaneous involvement), and compared them with regard to demographic characteristics, clinical, laboratory, and serologic features, and survival rates. No significant differences were found between the groups for most of the study parameters. SSc sine scleroderma should be included in the spectrum of SSc with limited cutaneous involvement and should not be considered a separate disorder.

452

Association of Transforming Growth Factor [beta]1 Genotype with Spinal Osteophytosis in Japanese Women

Yoshiji Yamada, Hiroyasu Okuizumi, Akimitsu Miyauchi, Yasuyuki Takagi, Kyoji Ikeda, and Atsushi Harada

A T[arrow right]C polymorphism at nucleotide 29 of the TGF[beta]1 gene was shown to be a genetic determinant of intervertebral disc degeneration, with the C allele being a risk factor for genetic susceptibility to radiographic spinal osteophytosis, in postmenopausal Japanese women. Genotype analysis of this gene may therefore prove beneficial for the prevention and management of spinal osteophytosis, as well as osteoporosis, for which the T allele was previously shown to be a risk factor.

461

Rheumatoid Arthritis Exacerbation Caused by Exogenous Interleukin-12

Elena Peeva, Ari D. Fishman, Gisele Goddard, Scott Wadler, and Peter Barland

464

The Changing Face of Rheumatoid Arthritis Therapy: Results of Serial Surveys

Ted R. Mikuls and James O'Dell

465

Diurnal Rhythm of Salivary Cortisol Levels in Patients with Recent-Onset Rheumatoid Arthritis

J. Caroline Dekkers, Rinie Geenen, Guido L. R. Godaert, Lorenz J. P. van Doornen, and Johannes W. J. Bijlsma

467

Wegener's Granulomatosis Presenting as Pancoast Tumor

Monika A. Reuss-Borst, Volker Becker, Burkhard Sattler, Clemens Grupp, and Gerhard A. Muller

468

Exacerbation of Systemic Lupus Erythematosus After Hepatitis B Vaccination: Comment on the Article by Battafarano et al and the Letter by Senecal et al

Jean Francis Maillefert, Christian Tavernier, Jean Sibilia, and Eric Vignon

468

Reply

Daniel F. Battafarano, Raymond J. Enzenauer, Steven A. Older, and Arthur M. Krieg

469

Absence of p53 Mutation in Japanese Patients with Rheumatoid Arthritis: Comment on the Article by Han et al

Hidero Kitasato, Renzo Okamoto, and Shinichi Kawai

469

Reply

Gary S. Firestein, Nathan J. Zvaifler, and Douglas R. Green

470

Severity of Rheumatoid Arthritis in Portuguese Patients: Comment on the Article by Drosos et al and on the Letter by Ronda et al

J. E. Fonseca, H. Canhao, F. Costa Dias, M. J. Leandro, C. Resende, J. C. Teixeira da Costa, J. A. Pereira da Silva, and M. Viana Queiroz

471

Reply

Alexandros A. Drosos, Gabriel S. Panayi, and Haralampos M. Moutsopoulos

472

Leg Pain and Clubbing

Yusuf Yazici, Doruk Erkan, and Stephen A. Paget

13A

ACR Announcements