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Editorial: Arthritis & Rheumatism in 2000

William P. Arend

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Current Comment: Basic Biology and Clinical Application of Specific Cyclooxygenase-2 Inhibitors

Leslie J. Crofford, Peter E. Lipsky, Peter Brooks, Steven B. Abramson, Lee S. Simon, and Leo B. A. van de Putte

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Response to Methotrexate Treatment is Associated with Reduced Mortality in Patients with Severe Rheumatoid Arthritis

Dietmar Krause, Barbara Schleusser, Gertraud Herborn, and Rolf Rau

This report of a prospective observational study describes the mortality, after a mean followup of 10 years, of 256 patients treated with MTX for longstanding severe RA. The standardized mortality ratio for patients not responding to MTX treatment was more than twice that for patients responding to MTX treatment. Mortality for patients who discontinued MTX treatment was even higher. These findings suggest that efficacious MTX treatment is associated with a reduction in mortality for patients with severe RA.

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Factors Predicting Response to Treatment in Rheumatoid Arthritis: The Importance of Disease Duration

Jennifer J. Anderson, George Wells, Arco C. Verhoeven, and David T. Felson

Treatment decisions and response expectations of both rheumatologists and their patients can be informed by the results of this study, which show that longer disease duration reduces the response to treatment. Moreover, rheumatologists can use the results as an aid to interpret clinical trial findings, which may vary because the trials include patient populations that differ with respect to distribution of patient factors, including disease duration, sex, prior use of disease-modifying antirheumatic drugs, disease functional class, and disease activity, all of which have effects on the likelihood of patient response to treatment.

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Characterizing the Quantitative Genetic Contribution to Rheumatoid Arthritis Using Data from Twins

Alexander J. MacGregor, Harold Snieder, Alan S. Rigby, Markku Koskenvuo, Jaakko Kaprio, Kimmo Aho, and Alan J. Silman

The 15% concordance rate quoted for RA in monozygotic twins is frequently misinterpreted as suggesting that the overall genetic contribution to the disease in the population is relatively small. In this study, quantitative genetic techniques are applied to the data from 2 nationwide studies of RA, one in Finland and the other in the United Kingdom, and show that 1) the majority (60%) of the population liability to disease is attributable to genetic factors, and 2) there are no important differences in the overall genetic contribution according to sex, age, age at disease onset, and clinically defined subgroup. These findings should encourage the continuing search for genetic influences in RA through linkage and association studies and provide a yardstick against which the relative importance of the quantitative contribution of candidate genes for disease can be assessed.

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Reduction of Chemokine Levels and Leukocyte Traffic to Joints by Tumor Necrosis Factor [alpha] Blockade in Patients with Rheumatoid Arthritis

Peter C. Taylor, A. Michael Peters, Ewa Paleolog, Peter T. Chapman, Michael J. Elliott, Richard McCloskey, Marc Feldmann, and Ravinder N. Maini

The importance of TNF[alpha] in the pathology of RA has been confirmed by the results of clinical trials of antibodies or soluble receptor fusion proteins that block biologic activity of this cytokine. Which of the multiple pathophysiologic activities of TNF[alpha], interrupted by TNF[alpha] blockade, are important in the amelioration of disease remains to be established. It is proposed that reduced inflammatory cell traffic to rheumatoid joints is a major mechanism of action of anti-TNF[alpha] therapy, and evidence is presented to support this hypothesis.

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Evidence of Central Nervous System Damage in Patients with Neuropsychiatric Systemic Lupus Erythematosus, Demonstrated by Magnetization Transfer Imaging

G. P. Th. Bosma, M. J. Rood, A. H. Zwinderman, T. W. J. Huizinga, and M. A. van Buchem

Neuropsychiatric SLE is clinically difficult to diagnose because of incomplete understanding of its pathogenesis and absence of diagnostic clinical tests. The results of this study demonstrate that magnetization transfer imaging might be an alternative and sensitive tool to detect brain injury, and might also be useful in studying the natural history of the disease.

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Increased Soluble Vascular Cell Adhesion Molecule 1 Concentrations in Patients with Primary or Systemic Lupus Erythematosus-Related Antiphospholipid Syndrome: Correlations with the Severity of Thrombosis

Gilles Kaplanski, Patrice Cacoub, Catherine Farnarier, Valerie Marin, Regine Gregoire, Anne Gatel, Jean-Marc Durand, Jean-Robert Harle, Pierre Bongrand, and Jean-Charles Piette

Antiphospholipid antibodies induce in vitro endothelial expression of adhesion molecules and leukocyte adhesion. This study compared serum samples from patients with primary APS, SLE-APS, pure SLE, control patients with thrombosis, and healthy volunteers using enzyme-linked immunosorbent assays specific for 3 soluble cell adhesion molecules. The study showed that for patients with primary APS, sVCAM-1 concentrations were increased and correlated with severity of thrombosis and renal involvement. These findings support the hypothesis of endothelial activation in vivo, and suggest a role for monocyte/ endothelium interactions in the pathogenesis of primary APS.

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T Cells that are Autoreactive to [beta]2-Glycoprotein I in Patients with Antiphospholipid Syndrome and Healthy Individuals

Noriko Hattori, Masataka Kuwana, Junichi Kaburaki, Tsuneyo Mimori, Yasuo Ikeda, and Yutaka Kawakami

This study identifies autoreactive T cells responsive to [beta]2GPI in patients with APS. The results strongly suggest that [beta]2GPI-reactive CD4+ T cells have the ability to induce antiphospholipid antibody synthesis from autologous B cells in APS patients, indicating that these autoreactive T cells play a central role in the pathogenic process in APS.

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Presence of Antinucleosome Autoantibodies in a Restricted Set of Connective Tissue Diseases: Antinucleosome Antibodies of the IgG3 Subclass are Markers of Renal Pathogenicity in Systemic Lupus Erythematosus

Zahir Amoura, Sophie Koutouzov, Henri Chabre, Patrice Cacoub, Isabelle Amoura, Lucile Musset, Jean-Francois Bach, and Jean-Charles Piette

This study analyzed the prevalence of the antinucleosome autoantibody response in a cohort of 596 patients, 496 of whom had 1 of 13 different CTD. IgG antinucleosome antibody activity was found to be present exclusively in patients with SLE, scleroderma, or mixed connective tissue disease, indicating that IgG antinucleosome is a selective biologic marker of these 3 CTDs. Moreover, patients with active SLE exhibited a unique switch from IgG1 to IgG3, which was related to disease activity, flares, and, specifically, to nephritis. These findings suggest that determination of IgG antinucleosome reactivity is a useful tool in the differential diagnosis of CTD, and that antinucleosome antibodies of the IgG3 isotype are involved in the pathophysiologic process of SLE.

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Autoantibodies to DEK Oncoprotein in Human Inflammatory Disease

Xingwen Dong, Jingsong Wang, Fathima N. Kabir, Melody Shaw, Ann M. Reed, Leonard Stein, Luis E. C. Andrade, Virginia F. M. Trevisani, Michael L. Miller, Takao Fujii, Masashi Akizuki, Lauren M. Pachman, Minoru Satoh, and Westley H. Reeves

Autoantibodies to the DEK protooncogene product have been reported to be a marker for pauciarticular juvenile rheumatoid arthritis (JRA) with iridocyclitis. However, there are no published reports of systematic quantitative studies of the frequency and levels of these autoantibodies. This study found that anti-DEK antibodies are less specific for JRA than previously believed and that anti-DEK antibodies may be a marker for a subset of autoimmunity associated with interferon-[gamma] production rather than a particular disease subset.

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Oligoclonal Non-Neoplastic B Cell Expansion is the Key Feature of Type II Mixed Cryoglobulinemia: Clinical and Molecular Findings Do Not Support a Bone Marrow Pathologic Diagnosis of Indolent B Cell Lymphoma

Salvatore De Vita, Valli De Re, Daniela Gasparotto, Marco Ballare, Barbara Pivetta, Gianfranco Ferraccioli, Stefano Pileri, Mauro Boiocchi, and Angelo Monteverde

Patients with type II MC often exhibit pathologic features of indolent B cell lymphoma in the bone marrow, whereas a neoplastic disorder is not indicated by the clinical evidence in most cases. The disease is often classified as neoplastic by hematologists, hemopathologists, and oncologists, while the systemic vasculitis features (non-neoplastic) have usually been stressed in rheumatology publications. In the present work, studies were performed on target tissue lesions from well-characterized patients with type II MC. The results led to the conclusion that type II MC is a non-neoplastic B cell disorder occurring in the course of chronic infection-related inflammation.

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The Effect of Mini-Dose Aspirin on Renal Function and Uric Acid Handling in Elderly Patients

D. Caspi, E. Lubart, E. Graff, B. Habot, M. Yaron, and R. Segal

Although aspirin is known to influence UA excretion, these effects have not been studied for modern, increasingly prevalent mini-dose regimens. Elderly patients use mini-dose aspirin more frequently and are more likely to develop adverse effects. This study evaluated prospectively the influence of mini-dose aspirin regimens on renal function and UA handling in 49 elderly inpatients. Even at a dosage of 75 mg/day, mini-dose aspirin caused significant changes in renal function and UA handling within 1 week in these patients, mainly in those with preexisting hypoalbuminemia.

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Evolution of Chronic Recurrent Multifocal Osteitis Toward Spondylarthropathy Over the Long Term

Olivier Vittecoq, Lamia Ait Said, Chantal Michot, Othmane Mejjad, Jean-Michel Thomine, Paul Mitrofanoff, Joel Lechevallier, Patrick Ledosseur, Alain Gayet, Philippe Lauret, and Xavier Le Loet

The long-term outcome of chronic recurrent multifocal osteitis (CRMO), a chronic inflammatory disease of bone, is poorly known. Three essential findings emerged from this study of CRMO over the long term: 1) the possibility, in certain cases, of an early diagnosis based on the association of clinical signs, without necessarily requiring invasive examinations, notably, a bone biopsy; 2) the classification of CRMO within the framework of spondylarthropathies because of the appearance, often late in its evolution, of classically observed lesions; and 3) the role of entheses in the genesis of CRMO lesions.

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Systemic Lupus Erythematosus Candidate Genes in the Italian Population: Evidence for a Significant Association with Interleukin-10

Sandra D'Alfonso, Marco Rampi, Daniela Bocchio, Gualtiero Colombo, Raffaella Scorza-Smeraldi, and Patricia Momigliano-Richiardi

This study analyzed the association with SLE, in the Italian population, of intragenic markers for each of 7 candidate genes, including either microsatellites or dimorphisms, by comparing gene frequencies of these gene markers for SLE patients and ethnically matched controls. The study showed that SLE patients had a significantly increased frequency of the 140-basepair allele of microsatellite IL10.G, located in the promoter region of the IL-10 gene. The identification of genes involved in SLE helps to clarify the etiopathogenic mechanism of the disease, and may be relevant for improving diagnostic approach and treatment or prevention strategies.

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TNF-308A and HLA-DR3 Alleles Contribute Independently to Susceptibility to Systemic Lupus Erythematosus

M. J. Rood, M. V. van Krugten, E. Zanelli, M. W. van der Linden, V. Keijsers, G. M. T. Schreuder, W. Verduyn, R. G. J. Westendorp, R. R. P. de Vries, F. C. Breedveld, C. L. Verweij, and T. W. J. Huizinga

This study provides evidence that TNF and HLA-DR3 alleles are independently involved in susceptibility to SLE. The identification of genetic factors that predispose to SLE or certain disease subsets will provide insight into the etiology and course of the disease.

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Analysis of Fas Ligand Gene Mutation in Patients with Systemic Lupus Erythematosus

Takeshi Kojima, Takahiko Horiuchi, Hiroaki Nishizaka, Takuya Sawabe, Masanori Higuchi, Shin-ichi Harashima, Shigeru Yoshizawa, Hiroshi Tsukamoto, Kohei Nagasawa, and Yoshiyuki Niho

A molecular defect of FasL has been reported in a patient with SLE; however, only 1 of the 4 exons of the FasL genome has been studied so far, probably because of a lack of information on the intron sequences. This is the first study analyzing the entire FasL genome for a mutation(s) or polymorphism(s) at the molecular level in patients with SLE. No defect was identified among the 143 SLE patients examined. It is therefore likely that a FasL defect is not a frequent cause of human SLE.

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Antiphospholipid Antibodies Affect Trophoblast Gonadotropin Secretion and Invasiveness by Binding Directly and Through Adhered [beta]2-Glycoprotein I

N. Di Simone, P. L. Meroni, N. Del Papa, E. Raschi, D. Caliandro, S. De Carolis, M. A. Khamashta, T. Atsumi, G. R. V. Hughes, G. Balestrieri, A. Tincani, P. Casali, and A. Caruso

Antiphospholipid antibodies are a family of autoantibodies with different antigen specificities that are associated with thrombosis and recurrent fetal loss. However, most pregnancy failures in patients with the antiphospholipid syndrome cannot be explained merely by the presence of thrombotic events in the placenta. The results of the present study indicate that aPL recognition of anionic PL and adhered [beta]2GPI on trophoblasts might play a role in defective placentation in these patients.

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Lack of Evidence for an Involvement of Epstein-Barr Virus Infection of Synovial Membranes in the Pathogenesis of Rheumatoid Arthritis

Gerald Niedobitek, Renate Lisner, Bernd Swoboda, Nick Rooney, Hans Georg Fassbender, Thomas Kirchner, Thomas Aigner, and Hermann Herbst

EBV is a candidate etiologic agent in the pathogenesis of RA. Using in situ hybridization and immunohistochemistry, this study shows that EBV infection in synovial membranes from patients with RA is restricted to rare B lymphocytes, while other cell types, including synovial lining cells, are EBV negative. These results support the view that EBV infection of cells within the synovial membrane does not contribute to the pathogenesis of RA.

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The Diagnostic Properties of Rheumatoid Arthritis Antibodies Recognizing a Cyclic Citrullinated Peptide

Gerard A. Schellekens, Hendrik Visser, Ben A. W. de Jong, Frank H. J. van den Hoogen, Johanna M. W. Hazes, Ferdinand C. Breedveld, and Walther J. van Venrooij

Diagnostic tests with high specificity for RA are desirable because treatment is shifting toward earlier and more aggressive antirheumatic therapy. The test presented here is extremely specific for RA and can be performed in a reliable and relatively easy enzyme-linked immunosorbent assay format. This test might therefore be very useful for diagnostic purposes in patients who do not have definite signs of RA.

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Tumor Necrosis Factor [alpha] Promotes the Expression of Stem Cell Factor in Synovial Fibroblasts and Their Capacity to Induce Mast Cell Chemotaxis

Hans P. Kiener, Roland Hofbauer, Makiyeh Tohidast-Akrad, Sabine Walchshofer, Kurt Redlich, Peter Bitzan, Stylianos Kapiotis, Gunter Steiner, Josef S. Smolen, and Peter Valent

Mast cells (MC) reportedly accumulate in the synovium in rheumatoid arthritis (RA) and osteoarthritis (OA) and may be involved in the process of inflammation. However, the mechanisms of MC accumulation are not known. This study shows that synovial fibroblasts (SFB) express and release stem cell factor (SCF) and thereby induce MC chemotaxis. Furthermore, tumor necrosis factor [alpha], a cytokine that is highly up-regulated in RA, augments SCF expression in SFB, as well as the capacity of SFB to induce MC chemotaxis. Thus, SFB-derived SCF may play an important role in the accumulation of MC in RA.

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Disease-Modifying Activity of SB 242235, A Selective Inhibitor of p38 Mitogen-Activated Protein Kinase, in Rat Adjuvant-Induced Arthritis

Alison M. Badger, Don E. Griswold, Rasesh Kapadia, Simon Blake, Barbara A. Swift, Sandy J. Hoffman, George B. Stroup, Edward Webb, David J. Rieman, Maxine Gowen, Jeffrey C. Boehm, Jerry L. Adams, and John C. Lee

SB 242235 is a potent and selective p38 MAP kinase inhibitor. The compound is active in the adjuvant arthritic rat, where it inhibits inflammation and has significant joint-protective effects as measured by changes in bone mineral density, magnetic resonance imaging, micro-computed tomography, and histology. These studies indicate that cytokine-suppressing, low molecular weight p38 inhibitors may be orally active, disease-modifying agents in the treatment of rheumatoid arthritis.

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Cell Adhesion Molecules in the Development of Inflammatory Infiltrates in Giant Cell Arteritis: Inflammation-Induced Angiogenesis as the Preferential Site of Leukocyte-Endothelial Cell Interactions

Maria C. Cid, Mireia Cebrian, Carme Font, Blanca Coll-Vinent, Jose Hernandez-Rodriguez, Jordi Esparza, Alvaro Urbano-Marquez, and Josep M. Grau

The expression pattern of adhesion molecules in GCA lesions suggests that adventitial microvessels and neovessels within the inflammatory infiltrates are the main site of leukocyte-endothelial cell interactions that lead to the development of vascular infiltrates and indicates a crucial role for inflammation-induced angiogenesis in maintaining and amplifying vessel inflammation. Analysis of leukocyte-endothelial cell ligand pairs suggests that different interactions are preferentially used at distinct regions of the temporal artery.

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Autocrine Regulation of Collagenase 3 (Matrix Metalloproteinase 13) During Osteoarthritis

Boris V. Shlopov, Marina L. Gumanovskaya, and Karen A. Hasty

This work describes cytokine and cytokine receptor expression in chondrocytes from OA lesional and nonlesional sites, to correlate these data with the increased collagenase production in OA lesions that has been previously observed. The activated phenotype of OA chondrocytes can be mimicked by treatment with tumor necrosis factor [alpha] and reversed by treatment with transforming growth factor [beta]. Activation of protective cytokines can be used as a target for OA therapy.

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Osteogenic Protein 1 Stimulates Cell-Associated Matrix Assembly by Normal Human Articular Chondrocytes: Up-Regulation of Hyaluronan Synthase, CD44, and Aggrecan

Yoshihiro Nishida, Cheryl B. Knudson, Wolfgang Eger, Klaus E. Kuettner, and Warren Knudson

The loss of extracellular matrix from articular cartilage, particularly proteoglycan, is an important event in the pathogenesis of osteoarthritis. In this study, normal human chondrocytes were cultured with or without OP-1 treatment, and changes in the relative expression of messenger RNA for HA synthases, CD44, and aggrecan were determined by competitive quantitative reverse transcriptase-polymerase chain reaction. OP-1, known to stimulate the synthesis of aggrecan as well as type II collagen, also stimulated the synthesis of HA and CD44, two other molecules required for the retention of aggrecan. These findings suggest that OP-1 can serve as a model for therapeutic agents that promote repair in human articular cartilage.

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The Reactions of Articular Cartilage to Experimental Wounding: Role of Apoptosis

Simon R. Tew, Alvin P. L. Kwan, Anthony Hann, Brian M. Thomson, and Charles W. Archer

The poor reparative ability of cartilage poses numerous problems in relation to both degenerative joint disease and traumatic joint insult. Although it is known that when cartilage is damaged, there is a cell death response previously described as ``necrosis,'' the present work shows that some of this cell death is apoptosis, that is, a genetically controlled event. Since most apoptotic responses can be inhibited, it is likely that strategies to promote better reparative tissue integration, which is a recurrent problem, can be achieved.

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Subacute Bacterial Endocarditis with Positive Cytoplasmic Antineutrophil Cytoplasmic Antibodies and Anti-Proteinase 3 Antibodies

Hyon K. Choi, Peter Lamprecht, John L. Niles, Wolfgang L. Gross, and Peter A. Merkel

232

Chronic Seropositive Polyarthritis Associated with Hepatitis B Virus-Induced Chronic Liver Disease: A Sequel of Virus Persistence

Antal Csepregi, Bernadette Rojkovich, Elemer Nemesanszky, Gyula Poor, Maria Hejjas, and Margit Horanyi

234

Rheumatoid Arthritis Remission/Relapse and the Health Assessment Questionnaire: Comment on the Article by Barrett et al

J. Lee Nelson

234

Reply

Alan J. Silman and Jennifer H. Barrett

234

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

D. Schmidt and P. Vaith

235

Reply

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

236

Th2-Type Cytokines and the Fas Way to Pulmonary Fibrosis: Comment on the Article by Atamas et al

Fabrizio Spinozzi, Elisabetta Agea, Anna Russano, Onelia Bistoni, Gabrio Bassotti, Fernando M. deBenedictis, and Alberto Bertotto

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Reply

Sergei P. Atamas and Barbara White

238

Inflammatory Arterial Stenosis: Followup with Color Doppler Sonography

Peter Kern, Joachim R. Kalden, and Bernhard Manger

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