1429

Introducing the New Editor of Arthritis & Rheumatism, David S. Pisetsky, MD, PhD

Joseph D. Croft, Jr

1430

In Memoriam: Joseph Lee Hollander, MD, 1910-2000

Robert Eisenberg, H. Ralph Schumacher, Terri H. Finkel, and George E. Ehrlich

1431

Review: Current Evidence for the Induction of Autoimmune Rheumatic Manifestations by Cytokine Therapy

Yiannis Ioannou and David A. Isenberg

1442

Erratum: Incorrect Listing of Author Affiliations in Article by D'Alfonso et al (Arthritis Rheum, January 2000)

1443

Occupational Physical Activities and Osteoarthritis of the Knee

David Coggon, Peter Croft, Samantha Kellingray, David Barrett, Magnus McLaren, and Cyrus Cooper

Like several earlier investigations, this case-control study of knee OA showed associations with occupational kneeling and squatting, with the risk being particularly high in subjects who were obese. The findings support the need for preventive measures in the work place and add weight to the evidence in support of compensation of knee OA as an occupational disease in people whose work requires them to kneel or squat for long periods.

1450

A Cotwin Control Study of the Relationship Between Hip Osteoarthritis and Bone Mineral Density

Leto Antoniades, Alexander J. MacGregor, Mathew Matson, and Tim D. Spector

This is the first study of the relationship between hip OA and BMD that adjusts for genetic factors by using twins. The study examined the association of OA with BMD using conditional logistic regression, adjusting for body mass index, lifetime physical activity, menopausal status, use of estrogen, and smoking. The study confirms the existence of an inverse relationship between OA and osteoporosis, and also provides evidence for the nature of this relationship, suggesting that local factors and shared genetic components may play important roles. Further research into the bone changes in OA and the genes responsible is likely to provide clues to its pathogenesis and focus therapeutic approaches.

1456

Adjacent Genes, for COL2A1 and the Vitamin D Receptor, are Associated with Separate Features of Radiographic Osteoarthritis of the Knee

Andre G. Uitterlinden, Huibert Burger, Cornelia M. van Duijn, Qiuju Huang, Albert Hofman, Jan C. Birkenhager, Johannes P. T. M. van Leeuwen, and Huibert A. P. Pols

Genetic epidemiologic methods were used in this study of 851 elderly men and women to assess the contribution of variation at the COL2A1 gene to susceptibility for ROA at the knee. The study was based on a previous observation in this population that variation at the VDR gene locus, located very close to the COL2A1 gene, was found to be associated with osteophytes. The study showed that both genes are involved in determining risk for ROA, but that they are implicated in different aspects of the disease: the COL2A1 genotype was found to be associated with narrowing of the joint space, while the VDR genotype was found to be associated with osteophytes. Combinations of risk alleles at both loci further increase the risk for ROA.

1465

A Comparison of Three Radiologic Scoring Systems for the Long-Term Assessment of Rheumatoid Arthritis: Findings of an Ongoing Prospective Inception Cohort Study of 132 Women Followed Up for a Median of Twelve Years

K. W. Drossaers-Bakker, E. Amesz, A. H. Zwinderman, F. C. Breedveld, and J. M. W. Hazes

This study shows that the progression in the scores of radiologic damage in RA is relentless, with a nearly linear trend over time, irrespective of the scoring system used. The Kellgren score appeared to be the most sensitive to change over time compared with the Sharp score as modified by van der Heijde and with the Sharp score with increased maximum scores. The Kellgren score was also the most efficient, in that it was less time consuming and required fewer patients to detect differences between study groups.

1473

Relationship Between Time-Integrated C-Reactive Protein Levels and Radiologic Progression in Patients with Rheumatoid Arthritis

Michael J. Plant, Arnold L. Williams, Margaret M. O'Sullivan, Peter A. Lewis, Edward C. Coles, and John D. Jessop

R A is a difficult condition to manage because of its heterogeneous nature and wide variation in outcome; radiologic damage is a marker of poor prognosis. This study shows that measurements of CRP over time correlate significantly with the degree of radiologic progression, and particularly with involvement of new joints. When the CRP level is within the normal range, new joint involvement is markedly decreased, and there is less disease progression in damaged joints. These findings add weight to the notion that disease-suppressive therapy should be initiated at an early stage.

1478

Determining Minimally Important Changes in Generic and Disease-Specific Health-Related Quality of Life Questionnaires in Clinical Trials of Rheumatoid Arthritis

Mark Kosinski, Sean Z. Zhao, Seema Dedhiya, Jane T. Osterhaus, and John E. Ware, Jr.

HQL instruments are widely used to study the safety and efficacy of pharmacologic agents in treating the pain and disability associated with rheumatoid arthritis. This report presents results from 2 clinical trials of RA, which will be useful to investigators in planning future trials by establishing the minimally important changes in HQL scores that are associated with changes in the severity of RA.

1488

Inhibition of Neutrophil Migration Soon After Initiation of Treatment with Leflunomide or Methotrexate in Patients with Rheumatoid Arthritis: Findings in a Prospective, Randomized, Double-Blind Clinical Trial in Fifteen Patients

Maarten C. Kraan, Ben M. de Koster, Jan G. R. Elferink, Wendy J. Post, Ferdinand C. Breedveld, and Paul P. Tak

Leflunomide, an immunomodulating agent, is a novel disease-modifying antirheumatic drug for the treatment of RA. Because neutrophils are the major cell population in synovial exudates, this study addressed the question of whether interference with neutrophil migration could be a possible explanation for the beneficial clinical effects of leflunomide therapy. The data show a rapid decrease in the migration of neutrophils after exposure to either leflunomide or methotrexate.

1496

Subtyping of Juvenile Idiopathic Arthritis Using Latent Class Analysis

Elaine Thomas, Jennifer H. Barrett, Rachelle P. Donn, Wendy Thomson, Taunton R. Southwood, and the British Paediatric Rheumatology Group

Classification criteria for JIA have been proposed and revised recently. However, the criteria are based on clinicians' perceptions of disease patterns and may not define biologically similar subgroups. To enable important research to be carried out, both in clinical trials for treatment and in outcome studies, it is essential to define groups of patients that are homogeneous. This report describes a novel approach to this end.

1504

Young Adults with Juvenile Arthritis in Remission Attain Normal Peak Bone Mass at the Lumbar Spine and Forearm

Margaretha Haugen, Gunhild Lien, Berit Flat\o, Janne Kvammen, Odd Vinje, Dag Sorskaar, and Oystein Forre

This study evaluated the impact of disease activity on acquired peak bone mass and bone turnover in young adult patients with either persistent JA or JA in remission. The study showed significantly lower bone mineral density (BMD) and significantly more osteopenia and osteoporosis in JA patients than in healthy subjects. These findings imply that most young adults with JA attain the same BMD as healthy subjects if the disease goes into remission, while young adults with active disease have increased risk for osteopenia and osteoporosis.

1511

Natural Immune Response Involving Anti-Endothelial Cell Antibodies in Normal and Lupus Pregnancy

Lais L. F. Mendonca, Munther A. Khamashta, Maria J. Cuadrado, Maria L. Bertolaccini, and Graham R. V. Hughes

This study determined levels of IgM- and IgG-AECA in sera from pregnant patients with systemic lupus erythematosus (SLE), normal pregnant women, and nonpregnant healthy controls. The results demonstrate that an immune response occurs during normal pregnancy, involving increased levels of IgG- and IgM-AECA. The existence of these AECA implies a role for them in the normal immune response, and probably influences the maternal acceptance of the fetoplacental graft. The lack of increased levels of IgM-AECA in pregnant patients with SLE suggests impaired immunologic regulation of the antigenic overloads imposed during the gestation period.

1516

Spectrum of Autoantibodies Against a Dynamin-Related Protein, Dymple

Yoshinao Muro, Takahiro Kamimoto, Yasushi Tomita, and Masatoshi Hagiwara

The frequency of autoantibodies against dymple, a mammalian dynamin-related protein, in connective tissue diseases was determined. Antidymple antibodies were found in a few patients with scleroderma and/or Sjogren's syndrome and in a patient with dermatomyositis. All 5 patients with antidymple antibodies were male, and 4 of them had interstitial pneumonitis. This autoantibody could be a marker for a newly recognized subset of connective tissue disease.

1520

Gallium-67 Scintigraphy in Macrophagic Myofasciitis

P. Cherin, F.-J. Authier, R. K. Gherardi, N. Romero, P. Laforet, B. Eymard, S. Herson, and N. Caillat-Vigneron, for the Groupe D'Etudes et de Recherche sur les Maladies Musculaires Acquises et Dysimmunitaires

MMF is a newly described condition involving characteristic changes that can be detected by deltoid muscle biopsy. It usually manifests as a weakly specific, chronic arthromyalgic syndrome that predominates in the lower limbs. This study shows that 67Ga scintigraphy is a noninvasive method that may make it easier to differentiate MMF from fibromyalgia and sarcoidosis.

1527

Modification of Disease Outcome in Salmonella-Infected Patients by HLA-B27

Paivi Ekman, Juha Kirveskari, and Kaisa Granfors

In this study, the frequency of HLA-B27 was determined in Finnish Salmonella-infected patients and healthy controls, the excretion of Salmonella was monitored at monthly intervals, and symptoms of acute infection and possible joint involvement were evaluated. B27 positivity did not clearly affect disease susceptibility or excretion of Salmonella. However, the presence of B27 strongly correlated with the risk of developing postinfection joint symptoms, as well as with the severity and duration of surprisingly common joint symptoms during or after Salmonella infection. These findings emphasize the role of HLA-B27 in modulating the outcome of Salmonella infection, and imply that joint symptoms are more commonly triggered by Salmonella than previously considered.

1535

A Novel Missense Mutation (C30S) in the Gene Encoding Tumor Necrosis Factor Receptor 1 Linked to Autosomal-Dominant Recurrent Fever with Localized Myositis in a French Family

Catherine Dode, Thomas Papo, Claire Fieschi, Christophe Pecheux, Elisabeth Dion, Francoise Picard, Pierre Godeau, Jacques Bienvenu, Jean-Charles Piette, Marc Delpech, and Gilles Grateau

TRAPS (tumor necrosis factor receptor [TNFR]-associated periodic syndrome) is a distinct clinical and radiologic disease entity responsible for recurrent fever and migratory cellulitis-like processes with localized myositis. A novel TNFR1 mutation, C30S, which is located in the first extracellular N-terminal cysteine-rich domain of TNFR1, was identified in a French family affected by the disease. This mutation seems to affect the level of soluble TNFR1, since, during inflammatory attacks, soluble TNFR1 levels were abnormally low. Thus, specific clinical features and familial clustering with autosomal-dominant transmission are the diagnostic clues for TRAPS.

1542

Stiff Skin Syndrome

Maja DiRocco

Basic Science

1543

Detection of Chlamydia Pneumoniae in Giant Cell Vasculitis and Correlation with the Topographic Arrangement of Tissue-Infiltrating Dendritic Cells

Annette D. Wagner, Herve C. Gerard, Tanja Fresemann, Wolfgang A. Schmidt, Erika Gromnica-Ihle, Alan P. Hudson, and Henning Zeidler

Giant cell arteritis (GCA) is a fairly common vasculitis, and recent observations strongly suggest that it is an antigen-driven entity. The present study demonstrates that the intracellular respiratory pathogen C pneumoniae, which has been associated with vascular disease in other contexts, is present in the majority of temporal artery specimens from GCA patients, whereas it is essentially absent in congruent specimens from non-GCA patients. Although these results do not demonstrate that C pneumoniae is the causative agent in GCA, the observations clearly suggest that more study is warranted.

1552

Autocrine Stimulation by Insulin-Like Growth Factor 1 and Insulin-Like Growth Factor 2 Mediates Chondrocyte Survival in Vitro

Richard F. Loeser and Gouri Shanker

This study shows that production of IGFs by chondrocytes helps to maintain their survival in cell culture. Cells from older animals were more susceptible to cell death than those from younger animals when IGF action was blocked and cell death was stimulated. A loss in the responsiveness to IGFs in aging subjects and in patients with osteoarthritis may contribute to cell death in cartilage and subsequent loss of cartilage matrix.

1560

Mitochondrial Oxidative Phosphorylation is a Downstream Regulator of Nitric Oxide Effects on Chondrocyte Matrix Synthesis and Mineralization

Kristen Johnson, Alexander Jung, Anne Murphy, Alexander Andreyev, James Dykens, and Robert Terkeltaub

Biomechanical factors and inflammatory pathways, including cytokine-induced NO production and oxidative stress in chondrocytes, are believed to promote not only osteoarthritis (OA), but also pathologic calcification of articular cartilage in established OA. This study revealed that mitochondrial respiration, which supports ATP generation via oxidative phosphorylation, could be a central component of a common pathway that NO suppresses, to induce not only decreased matrix synthesis, but also increased mineralizing activity by chondrocytes. These findings suggest that NO-induced suppression of mitochondrial reserve, as the capacity for ATP generation via oxidative phosphorylation, may be a pathogenic factor in OA and secondary crystal deposition in degenerating articular cartilage.

1571

ATP Release by Mechanically Loaded Porcine Chrondrons in Pellet Culture

Ronald D. Graff, Eduardo R. Lazarowski, Albert J. Banes, and Greta M. Lee

Study of the mechanism(s) by which chondrocytes respond to mechanical load is important for understanding the role of mechanical loading in the maintenance of cartilage integrity and the development of osteoarthritis. This work describes basal release of ATP from chondron pellets at rest and enhanced release due to mechanical stimulation, and demonstrates the generation of pyrophosphate subsequent to ATP hydrolysis. ATP may play a role in chondrocyte signaling during dynamic loading, and may contribute to pyrophosphate generation and calcium pyrophosphate dihydrate crystal deposition in osteoarthritis.

1580

Response of Engineered Cartilage Tissue to Biochemical Agents as Studied by Proton Magnetic Resonance Microscopy

Kimberlee Potter, John J. Butler, Walter E. Horton, and Richard G. S. Spencer

This work demonstrates a new approach to tissue engineering of cartilage and to noninvasive biochemical characterization of the engineered tissue. The studies yield insights which may be of great importance in future clinical rheumatologic practice with reference to the development of tissue for cartilage transplantation and for noninvasive assessment of the transplanted tissue. The correlations between magnetic resonance imaging and biochemical data, if extended to the clinical arena, may also prove to be of significant help to clinicians in the diagnosis and treatment of cartilage degenerative diseases by methods other than tissue transplantation.

1591

Enhanced Expression and DNA Binding Activity of Two CCAAT/Enhancer-Binding Protein Isoforms, C/EBP[gb] and C/EBP[gd], in Rheumatoid Synovium

Katsuhiro Nishioka, Shiro Ohshima, Mitsuko Umeshita-Sasai, Norihiko Yamaguchi, Toru Mima, Shintaro Nomura, Norikazu Murata, Masatoshi Shimizu, Tadao Miyake, Kazuyuki Yoshizaki, Masaki Suemura, Tadamitsu Kishimoto, and Yukihiko Saeki

This study demonstrated that, among the C/EBP family transcription factors, the expression and DNA binding activity of C/EBP[gb] and -[gd] were enhanced in rheumatoid synovium, predominantly in synovial lining cells. C/EBP[gb] and -[gd] may therefore be involved in the pathogenesis of rheumatoid arthritis, especially synovial lining hyperplasia.

1597

Expression of Osteopontin Messenger RNA and Protein in Rheumatoid Arthritis: Effects of Osteopontin on the Release of Collagenase 1 from Articular Chondrocytes and Synovial Fibroblasts

Peter K. Petrow, Klaus M. Hummel, Jorg Schedel, Juliane K. Franz, Christoph L. Klein, Ulf Muller-Ladner, Jorg Kriegsmann, Pi-Ling Chang, Charles W. Prince, Renate E. Gay, and Steffen Gay

This study examined the expression of osteopontin (OPN) in the synovia of RA patients, as well as the effect of OPN on the production of collagenase 1 in rheumatoid synovial fibroblasts and articular chondrocytes. OPN mRNA and protein expression were shown in the synovium from RA patients. OPN expression was especially prominent at the interface of cartilage and invading synovium, and OPN was found to stimulate the secretion of collagenase 1 in articular chondrocytes. Given the apparent association of OPN with processes such as tumor invasion and metastasis, it might be suggested that OPN is associated with the aggressive and destructive behavior of synovial fibroblasts in RA.

1606

Lack of CD80 Expression by Fibroblast-Like Synoviocytes Leading to Anergy in T Lymphocytes

Valerie M. Corrigall, Elisabeth Solau-Gervais, and Gabriel S. Panayi

This study shows that the poor responsiveness of rheumatoid T cells to a range of stimulants may be due to their interaction with FLS, which fail to express a molecule, CD80, that is critical for full activation of T cells. The interaction between CD80-negative FLS and T lymphocytes leads to a negative signal being transmitted to the latter cells and consequent deficiency in function. These results should contribute to our understanding of the processes leading to inflammation in rheumatoid arthritis.

1616

Novel In Vitro Effects of Bucillamine: Inhibitory Effects on Proinflammatory Cytokine Production and Transendothelial Migration of T Cells

Yasuhiko Munakata, Satoshi Iwata, Jorg Dobers, Tomonori Ishii, Mamoru Nori, Hirotoshi Tanaka, and Chikao Morimoto

This study evaluates the novel effects of the antirheumatic drug, bucillamine, on T cell functions in vitro, which could lead to inhibition of inflammation in rheumatoid arthritis. Bucillamine inhibited the proliferative response and production of type 1 T helper and proinflammatory cytokines induced by the costimulation of T cells. Furthermore, bucillamine inhibited transendothelial migration of phytohemagglutinin-activated T cells, as well as the cell surface expression of CD44.

1624

Inhibition of Type 1 Collagen Gene Expression in Normal and Systemic Sclerosis Fibroblasts by a Specific Inhibitor of Geranylgeranyl Transferase I

Joel Rosenbloom, Biagio Saitta, Svetlana Gaidarova, Nora Sandorfi, Joan C. Rosenbloom, William R. Abrams, Andrew D. Hamilton, Said M. Sebti, Umberto Kucich, and Sergio A. Jimenez

In this study, inhibition of geranylgeranyl prenylation was shown to cause a potent and selective inhibition of expression of the genes encoding types I and III collagen in SSc fibroblasts, without affecting cellular viability. This approach should be further studied as a potential treatment for SSc and other fibrosing diseases.

1633

Distribution of Novel Polymorphisms of the Interleukin-8 and CXC Receptor 1 and 2 Genes in Systemic Sclerosis and Cryptogenic Fibrosing Alveolitis

Elisabetta Renzoni, Penny Lympany, Piersante Sestini, Panagiotis Pantelidis, Athol Wells, Carol Black, Ken Welsh, Chris Bunn, Chris Knight, Patrick Foley, and R. M. Du Bois

This study identified 7 novel single-nucleotide polymorphisms in the IL-8 and IL-8 receptor CXCR-1 and CXCR-2 genes, and compared their distribution among patients with systemic sclerosis (both with and without fibrosing alveolitis), patients with cryptogenic fibrosing alveolitis, and healthy control subjects. The findings indicate an association between 2 polymorphisms occurring close to each other in the CXCR-2 gene and systemic sclerosis. In this group of patients, the association appears to be independent of fibrosing alveolitis, but this observation needs to be confirmed by future studies.

1641

A Two-Stage, Genome-Wide Screen for Susceptibility Loci in Primary Raynaud's Phenomenon

Elene Susol, Alexander J. MacGregor, Jennifer H. Barrett, Helen Wilson, Carol Black, Ken Welsh, Alan Silman, Bill Ollier, and Jane Worthington

The genetic basis of primary RP is unknown. Preliminary evidence of linkage to 5 chromosomal areas is presented in this report. Confirmation of these results and the ultimate identification of the genes involved in primary RP will further the understanding of the etiologic mechanisms involved in not only primary RP (which may be targeted for novel therapies), but also other conditions in which vasospasm is implicated as an etiologic factor.

1647

Inhibitory Effects of Muscarinic Receptor Autoantibodies on Parasympathetic Neurotransmission in Sjogren's Syndrome

Sally A. Waterman, Tom P. Gordon, and Maureen Rischmueller

This study uses a functional assay to detect the presence of autoantibodies that act as antagonists at M3-muscarinic receptors on smooth muscle in patients with primary and secondary SS. The results suggest that the antagonistic effects of these antibodies play a role in the development of sicca symptoms and other features of autonomic dysfunction in these patients. The findings provide useful clinical information to aid in diagnosis, elucidation of unexplained symptoms, and development of new approaches to treatment of SS.

1654

Orbital Granuloma and Subglottic Tracheal Stenosis in Wegener's Granulomatosis

P. Lamprecht, E. Reinhold-Keller, W. L. Gross, and M. Reuter

1655

An Evaluation of an Angiotensin-Converting Enzyme Gene Polymorphism and the Risk of Arterial Thrombosis in Patients with the Antiphospholipid Syndrome

Nerys M. Lewis, Kazuaki Katsumata, Tatsuya Atsumi, M. Lourdes Sanchez, Fredeswinda I. Romero, M. Laura Bertolaccini, Andreas Funke, Olga Amengual, Munther A. Khamashta, and Graham R. V. Hughes

1657

Mannose-Binding Lectin Deficiency and Infections in Homozygous and Heterozygous Patients with Systemic Lupus Erythematosus: Comment on the Article by Garred et al

Arnor Vikingsson and Helgi Valdimarsson

1657

Reply

Peter Garred, Hans O. Madsen, Poul Halberg, Jorgen Petersen, Gitte Kronborg, Arne Svejgaard, Vagn Andersen, and Soren Jacobsen

1658

Improvement Criteria--Clinical and Statistical Significance: Comment on the Article by Pincus and Stein

Anke M. van Gestel and Piet L. C. M. van Riel

1659

Reply

Theodore Pincus and C. Michael Stein

1660

Pseudogout and Intraarticular Hyaluronate Injections: Comment on the Article by Disla et al

Leonardo Punzi, Margherita Pianon, Salvati Gian Piero, and Silvano Todesco

1661

Reply

Eddys Disla, Ricardo Infante, and Girolamo G. Cuppari

1662

Increased MDR1 P-Glycoprotein Expression in Methotrexate Resistance: Comment on the Article by Yudoh et al

Proton Rahman, Donna Hefferton, and Desmond Robb

19A

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