473

Review: When Does Rheumatoid Arthritis Begin and Why Do We Need to Know?

Janet M. Kim and Michael H. Weisman

485

Review: Genetic Factors Predisposing to Spondylarthropathies

J. Martinez-Borra, Segundo Gonzalez, and C. Lopez-Larrea

493

Winners of the 1999 American College of Rheumatology Slide Competition

Catherine M. Meyer and the ACR Audiovisual Aids Subcommittee

495

Treatment with Leflunomide Slows Radiographic Progression of Rheumatoid Arthritis: Results from Three Randomized Controlled Trials of Leflunomide in Patients with Active Rheumatoid Arthritis

John T. Sharp, Vibeke Strand, Hoi Leung, Frank Hurley, and Iris Loew-Friedrich, on behalf of the Leflunomide Rheumatoid Arthritis Investigators Group

Three clinical studies were performed to evaluate the efficacy of leflunomide in comparison with MTX and SSZ, in slowing radiographic progression in RA. The results demonstrate that leflunomide, a recently approved disease-modifying antirheumatic drug (DMARD), joins a small group of DMARDs that have been demonstrated to slow radiographic progression in RA and confirm previous reports that MTX and SSZ retard joint destruction.

506

Clinical Improvement as Reflected in Measures of Function and Health-Related Quality of Life Following Treatment with Leflunomide Compared with Methotrexate in Patients with Rheumatoid Arthritis: Sensitivity and Relative Efficiency to Detect a Treatment Effect in a Twelve-Month, Placebo-Controlled Trial

Peter Tugwell, George Wells, Vibeke Strand, Andreas Maetzel, Claire Bombardier, Bruce Crawford, Catherine Dorrier, and Ann Thompson, on behalf of the Leflunomide Rheumatoid Arthritis Investigators Group

Treatment decisions need to reflect what is important to the patient. This report presents data that show that improvement in both disease-specific and generic measures of function and health-related quality of life following treatment with leflunomide or MTX is clinically meaningful in terms of evaluating therapies and comparing different disease states in patients with RA.

515

The Association of Variant Mannose-Binding Lectin Genotypes with Radiographic Outcome in Rheumatoid Arthritis

Niels A. Graudal, Hans O. Madsen, Ulrik Tarp, Arne Svejgaard, Anne Grethe Jurik, Hans K. Graudal, and Peter Garred

This study retrospectively determined MBL genotypes and plasma concentrations in RA patients selected from a major cohort followed up prospectively for up to 32 years. The study shows that RA patients who carry MBL variant alleles associated with a low concentration of MBL protein have poor outcomes. This indicates that MBL, a serum opsonine that activates complement, modulates the disease activity of RA. The determination of the MBL genotype may contribute significantly to the clinician's evaluation of the prognosis of patients with RA.

522

Bone Mineral Density and Frequency of Osteoporosis in Female Patients with Rheumatoid Arthritis: Results from 394 Patients in the Oslo County Rheumatoid Arthritis Register

Glenn Haugeberg, Till Uhlig, Jan A. Falch, Johan I. Halse, and Tore K. Kvien

Although osteoporosis is recognized as a well-known complication in RA, there have been no published data on the frequency of osteoporosis in a representative female RA population. The findings of this study are of special interest and importance for understanding the magnitude of the problem of reduced bone mineral density in RA, and for health care planning related to the prevention and management of osteoporosis in RA.

531

Total-Body Bone Mineral Content in Non-Corticosteroid-Treated Postpubertal Females with Juvenile Rheumatoid Arthritis: Frequency of Osteopenia and Contributing Factors

Carol J. Henderson, Bonny L. Specker, Rosa I. Sierra, Barbara N. Campaigne, and Daniel J. Lovell

Osteopenia and osteoporosis are known complications of JRA. In this study, 31% of white adolescent female JRA patients who were >-24 months post-menarche (i.e., at or near peak bone mass) and who had never received corticosteroids were found to be osteopenic. The contributions of a variety of parameters related to bone mineral status were evaluated. The results demonstrated that lean mass was protective of bone mineral content. The increased frequency of reduced bone mass combined with low lean mass may contribute to the risk of premature development of osteoporosis in postpubertal females with JRA.

541

Medium- and Long-Term Functional Outcomes in a Multicenter Cohort of Children with Juvenile Dermatomyositis

Adam M. Huber, Bianca Lang, Claire M. A. LeBlanc, Nina Birdi, Roxana K. Bolaria, Peter Malleson, Inez MacNeil, Jo-Anne Momy, Glenda Avery, and Brian M. Feldman

Juvenile dermatomyositis is a rare, chronic inflammatory disease of muscle and skin that affects children. This report presents data on functional outcomes in children with juvenile dermatomyositis, which reflect current management of this illness. Data which endeavor to identify risk factors that may predict a poorer functional outcome are also provided.

550

Ovulation Induction and In Vitro Fertilization in Systemic Lupus Erythematosus and Antiphospholipid Syndrome

Nerissa Guballa, Lisa Sammaritano, Sergio Schwartzman, Jill Buyon, and Michael D. Lockshin

Because of the possibility that hormones may induce flare or thrombosis, patients with SLE or primary APS undergoing ovulation induction and in vitro fertilization are potentially at risk. In this investigation, outcomes in 19 women with SLE or primary APS who underwent 68 cycles of OI were studied retrospectively. The results indicate that, although OI/IVF can be successful in patients with SLE and primary APS, rates of fetal and maternal complications are high.

557

Prevalence of Anti-Protein S Antibodies in Patients with Systemic Lupus Erythematosus

Kyung Soon Song, Young Sook Park, and Hyun Kyung Kim

An autoimmune anti-PS antibody has recently been identified, and autoimmune PS deficiency may be a common mechanism in SLE. However, neither the prevalence of anti-PS antibodies nor their clinical significance in association with plasma levels of PS in SLE is known. This study sought to ascertain the prevalence of circulating anti-PS antibodies in association with PS deficiency in patients with SLE. A prevalence rate of 25.9% for anti-PS antibody was found, which may be helpful in the management of SLE in association with thrombosis.

561

The Association Between Chronic Widespread Pain and Mental Disorder: A Population-Based Study

Sidney Benjamin, Stella Morris, John McBeth, Gary J. Macfarlane, and Alan J. Silman

In this population-based case-control study, subjects completed a questionnaire that included pain and psychiatric assessments. A subset of these subjects was assessed further using a structured psychiatric interview and detailed assessment of medical records to identify cases of mental disorder. Chronic widespread pain was found to be associated with an increased likelihood of having a mental disorder, particularly depressive and anxiety disorders. These findings have implications for the treatment of patients with chronic pain.

568

The Mechanism of the Effect of Obesity in Knee Osteoarthritis: The Mediating Role of Malalignment

Leena Sharma, Congrong Lou, September Cahue, and Dorothy D. Dunlop

Obesity is more strongly linked to OA at the knee than at other lower extremity joints. This study provides evidence that varus malalignment is one local factor that increases the impact of excess body weight on OA severity at the knee. Body mass index correlated with radiographic disease severity in those with varus knees but not in those with valgus knees. Much of the effect of body mass index on radiographic severity was explained by varus malalignment. Factors that contribute to progression may differ between varus and valgus knees. Alignment may influence risk of progression and responsiveness to treatment among obese subjects.

576

The Mechanism of Formation of Bony Spurs (Enthesophytes) in the Achilles Tendon

Mike Benjamin, Aminu Rufai, and Jim R. Ralphs

Although it is widely assumed that bony spurs develop in response to microdamage or inflammation at tendon or ligament entheses, it is also recognized that spurs are common in otherwise healthy individuals and are therefore not, in themselves, a sign of disease. The present study clearly demonstrates that spurs can develop without prior damage or inflammation, as an extension of normal enthesis development by vascular invasion along rows of enthesis fibrocartilage cells. It also suggests that during the reattachment of tendons/ligament to bone, the challenge that faces surgeons is to encourage bone to grow into the tendon, and not vice versa.

584

Erythema Nodosum: Etiologic and Predictive Factors in a Defined Population

Carlos Garcia-Porrua, Miguel A. Gonzalez-Gay, Manuel Vazquez-Caruncho, Luis Lopez-Lazaro, Mercedes Lueiro, Maria L. Fernandez, Javier Alvarez-Ferreira, and Ramon M. Pujol

EN is the most common cause of inflammatory nodules and usually occurs on the lower extremities. Although generally considered benign and self-limited, EN can be associated with various conditions. This study examined the spectrum of biopsy-proven EN in a defined population by reviewing the clinical symptoms and laboratory findings in patients with biopsy-proven EN, as well as their outcomes. The study also established the best set of clinical variables for identifying patients with secondary EN.

592

Arthritis & Rheumatism and Arthritis Care and Research to be Available Online

593

Presence of Bacterial DNA and Bacterial Peptidoglycans in Joints of Patients with Rheumatoid Arthritis and Other Arthritides

Ineke M. van der Heijden, Bert Wilbrink, Ilja Tchetverikov, Ingrid A. Schrijver, Leo M. Schouls, Maarten P. Hazenberg, Ferdinand C. Breedveld, and Paul P. Tak

This article describes the presence of bacterial DNA and bacterial cell wall constituents in joint samples from a subset of patients with RA and other arthritides. It is hypothesized that common, ubiquitous microbial agents may enhance synovial inflammation in a nonspecific way. Variations in the bacterial load could provide one of the stimuli influencing the waxing and waning of arthritis in the genetically susceptible host.

599

Expression of Sentrin, A Novel Antiapoptotic Molecule, at Sites of Synovial Invasion in Rheumatoid Arthritis

Juliane K. Franz, Thomas Pap, Klaus M. Hummel, Michael Nawrath, Wilhelm K. Aicher, Yukio Shigeyama, Ulf Muller-Ladner, Renate E. Gay, and Steffen Gay

The present study investigated sentrin, a novel antiapoptotic molecule, and found it to be expressed in RA synovium but not in normal synovium. Most interestingly, sentrin expression was predominantly localized to invasive synovial fibroblast-like cells at sites of cartilage and bone degradation. Therefore, sentrin appears to contribute to the hyperplasia and invasive growth of RA synovium and may be a promising candidate for novel antirheumatic therapies.

608

Induction of Tumor Necrosis Factor [alpha] Production by Adhered Human Monocytes: A Key Role for Fc[gamma] Receptor Type IIIA in Rheumatoid Arthritis

Vikki M. Abrahams, Geraldine Cambridge, Peter M. Lydyard, and Jonathan C. W. Edwards

In this study, monoclonal antibodies to immunoglobulin receptors (Fc[gamma]R) on human macrophages were used to probe the mechanisms by which IgG rheumatoid factor-based immune complexes might induce cytokine production. Evidence was obtained for specific involvement of the receptor Fc[gamma] RIIIa in the production of the cytokines tumor necrosis factor [alpha] and interleukin-1[alpha], supporting previous evidence for a key role for this receptor in the pathogenesis of RA.

617

Reduced Expression of the Regulatory CD4+ T Cell Subset is Related to Th1/Th2 Balance and Disease Severity in Rheumatoid Arthritis

Kazuo Yudoh, Hiroaki Matsuno, Fujio Nakazawa, Tamon Yonezawa, and Tomoatsu Kimura

This study examined the role of the regulatory CD4+ T cell subset, which produces high levels of interleukin-10 (IL-10) and low levels of IL-4 and IL-2 and is able to down-regulate the T cell-mediated immune response involved in the pathogenesis of RA. The results suggest that the expression of this type of CD4+ T cell subset in peripheral blood and synovial tissue may be involved in Th1/Th2 balance and disease activity in RA. The analysis of CD4+ T cells producing high levels of IL-10 and low levels of IL-4 and IL-2 might provide important insights into understanding the pathologic immune response of RA as well as the development of a novel therapy that regulates the Th1/Th2 balance in patients with RA.

628

Myeloid-Related Proteins 8 and 14 are Specifically Secreted During Interaction of Phagocytes and Activated Endothelium and are Useful Markers for Monitoring Disease Activity in Pauciarticular-Onset Juvenile Rheumatoid Arthritis

Michael Frosch, Anke Strey, Thomas Vogl, Nico M. Wulffraat, Wietse Kuis, Cord Sunderkotter, Erik Harms, Clemens Sorg, and Johannes Roth

This study shows that MRP8 and MRP14, two calcium-binding proteins expressed by neutrophils and in the early differentiation stages of monocytes, are released by monocytes during interaction with inflammatory activated endothelial cells in vitro. Their expression pattern in synovial tissue, as well as their concentrations in serum and synovial fluid, of patients with pauciarticular-onset JRA indicate that MRP8 and MRP14 seem to be released during the inflammatory process within the joint and are useful markers to monitor local disease activity as well as response to therapy in JRA.

638

A Comparative Study into the Mechanisms of Action of Anti-Tumor Necrosis Factor [alpha], Anti-CD4, and Combined Anti-Tumor Necrosis Factor [alpha]/Anti-CD4 Treatment in Early Collagen-Induced Arthritis

Lilia Marinova-Mutafchieva, Richard O. Williams, Claudia Mauri, Lesley J. Mason, Marita J. Walmsley, Peter C. Taylor, Marc Feldmann, and Ravinder N. Maini

This study consists of a comparison of the mechanisms of action of anti-TNF[alpha], anti-CD4, and combined anti-TNF[alpha]/anti-CD4 treatment in collagen-induced arthritis as a model for human rheumatoid arthritis. The results help to explain why some forms of immunotherapy are more effective than others at halting inflammatory processes.

645

Induction of Tolerance with Intranasal Administration of Human Cartilage gp-39 in DBA/1 Mice: Amelioration of Clinical, Histologic, and Radiologic Signs of Type II Collagen-Induced Arthritis

Leo A. B. Joosten, Christina J. J. Coenen-de Roo, Monique M. A. Helsen, Erik Lubberts, Annemieke M. H. Boots, Wim B. van den Berg, and Andre M. M. Miltenburg

This study is the first to demonstrate that human cartilage glycoprotein 39 (HC gp39), when administered in a semitherapeutic protocol, ameliorates murine collagen-induced arthritis through induction of bystander suppression. Both disease activity and joint destruction were suppressed by HC gp39 treatment. These data provide a strong case for the use of HC gp39-based immunotherapy in humans with rheumatoid arthritis, which which should be further investigated in future clinical trials.

656

Reversal of the Antiinflammatory Effects of Methotrexate by the Nonselective Adenosine Receptor Antagonists Theophylline and Caffeine: Evidence that the Antiinflammatory Effects of Methotrexate are Mediated Via Multiple Adenosine Receptors in Rat Adjuvant Arthritis

M. Carmen Montesinos, Josephine S. Yap, Avani Desai, Inmaculada Posadas, Christine T. McCrary, and Bruce N. Cronstein

Low-dose MTX is a mainstay in the treatment of inflammatory arthritis, although the mechanism of its antiinflammatory effects remains controversial. Prior studies have suggested that MTX increases adenosine release and that adenosine, acting at its receptors, mediates the antiinflammatory effects of MTX. The results of this study provide strong evidence that the antiinflammatory effects of low-dose MTX are mediated by adenosine and suggest that 2 commonly encountered adenosine receptor antagonists, theophylline and caffeine, may interfere with the therapeutic effects of MTX.

664

Comparison of the Degradation of Type II Collagen and Proteoglycan in Nasal and Articular Cartilages Induced by Interleukin-1 and the Selective Inhibition of Type II Collagen Cleavage by Collagenase

R. Clark Billinghurst, William Wu, Mirela Ionescu, Agnes Reiner, Leif Dahlberg, Jeffrey Chen, Harold van Wart, and A. Robin Poole

The destruction of the collagen network in articular cartilage, thought to signal the irreversible phase of cartilage degradation in arthritis, can be caused by cytokines such as IL-1. It is the cleavage of type II collagen fibrils by collagenases that is believed to initiate this process. This study examines the temporal relationships between proteoglycan catabolism and collagenase-generated cleavage, denaturation, and release of type II collagen in cytokine-induced cartilage degradation. The results show that the degradation of type II collagen in articular cartilage can be effectively arrested with a selective collagenase inhibitor, demonstrating that one or more specific collagenases are involved, and also point to the therapeutic potential of such an inhibitor in controlling the breakdown of articular cartilage in arthritis.

673

Selective Enhancement of Collagenase-Mediated Cleavage of Resident Type II Collagen in Cultured Osteoarthritic Cartilage and Arrest with a Synthetic Inhibitor that Spares Collagenase 1 (Matrix Metalloproteinase 1)

Leif Dahlberg, R. Clark Billinghurst, Paul Manner, Fred Nelson, Ginette Webb, Mirela Ionescu, Agnes Reiner, Michael Tanzer, David Zukor, Jeffrey Chen, Harold E. van Wart, and A. Robin Poole

It is important to establish whether the cleavage of type II collagen by collagenase and the degradation of proteoglycans is increased in arthritic cartilage, and whether this can be inhibited by synthetic proteinase inhibitors of the kind being developed to control cartilage degradation. This study provides evidence to indicate that collagenase activity is selectively enhanced in osteoarthritis, and that its therapeutic inhibition is possible.

683

Association of Antiphosphatidylserine/Prothrombin Autoantibodies with HLA Class II Genes

M. L. Bertolaccini, T. Atsumi, A. R. Caliz, O. Amengual, M. A. Khamashta, G. R. V. Hughes, and T. Koike

Associations of HLA class II alleles (DQB1*03 and DQB1*06) and lupus anticoagulant (LAC) have been reported. It is generally accepted that some LAC are directed toward [beta]2-glycoprotein I ([beta]2GPI) or prothrombin, and anti-[beta]2GPI antibody production has also been associated with HLA class II alleles (DQB1*0303 and DQB1*06). This study shows that the DQB1*0301/4;DQA1*0301/2;DRB1*04 haplotype might be responsible for antiprothrombin antibody production, which would partly explain the correlation between LAC and DQB1*03.

689

Quantitative Radioligand Assays Using De Novo-Synthesized Recombinant Autoantigens in Connective Tissue Diseases: New Tools to Approach the Pathogenic Significance of Anti-RNP Antibodies in Rheumatic Diseases

Ana Maria Yamamoto, Zahir Amoura, Catherine Johannet, Antonio L. C. Jeronimo, Henry Campos, Sophie Koutouzov, Jean-Charles Piette, and Jean-Francois Bach

Autoantibodies to nuclear RNPs are found in a number of rheumatic diseases. However, their clinical use has been hampered by the relatively low sensitivity and high variability as well as insufficient quantification of the assays used so far for their detection. This work describes a new sensitive and specific method for RNP antibody detection based on binding of these antibodies to de novo-synthesized antigens produced by in vitro transcription and translation reactions. This technique opens new perspectives to approach the pathogenic significance and the potential clinical correlations of these autoantibodies.

698

High-Resolution Computed Tomography in the Diagnosis and Management of Pulmonary Wegener's Granulomatosis in a Patient with Normal Chest Radiography Findings

Marina Anderson, B. Ronan O'Driscoll, Roger Chisholm, Ariane Herrick, and John Halsey

699

Pulmonary Edema Complicating Prostacyclin Therapy in Pulmonary Hypertension Associated with Scleroderma: A Case of Pulmonary Hemangiomatosis

Manish K. Gugnani, Chris Pierson, Richard Vanderheide, and Reda E. Girgis

703

New Manuscripts to be Sent to Dr. David Pisetsky as of April 1

704

Mixed Connective Tissue Disease Presenting with Pneumonitis and Pneumatosis Intestinalis

Cheryl Fernandes, Peter Bungay, B. Ronan O'Driscoll, and Ariane L. Herrick

707

Carpal Tunnel Syndrome from Accessory Lumbrical Muscles

Michael A. Malloy and David R. Finger

708

Fibromyalgia in Frida Kahlo's Life and Art

Manuel Martinez-Lavin, Mary-Carmen Amigo, Javier Coindreau, and Juan Canoso

709

Tuberculous Arthritis

Rika Draenert and Herbert Kellner

710

Bone Mineral Density and Juvenile Chronic Arthritis: Comment on the Article by Zak et al

Sarah Bartram, Helen Foster, and Roger Francis

710

Marek Zak, Susan Nielsen, Freddy Karup Pedersen, Christian Hassager, Daniel J. Lovell, and Carol J. Henderson

711

Cytokine-Producing T Cells in Systemic Lupus Erythematosus: Comment on the Article by Akahoshi et al

Monika A. Reuss-Borst, Almut Geyer, and Beate Berner

711

Mitsuteru Akahoshi, Hitoshi Nakashima, and Takeshi Otsuka

Psoriatic Arthritis-An Enthesopathy-Based Disorder? Comment on the Article by McGonagle et al

712

Patrick Costello, David Kane, Shane Curran, Barry Bresnihan, Oliver FitzGerald, and Robert Winchester

713

Dennis McGonagle, Philip G. Conaghan, and Paul Emery

714

Ehlers-Danlos Syndrome Presenting as Olecranon Bursitis

Doruk Erkan, Yusuf Yazici, and Steven K. Magid

21A

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