1905

Special Article: Recommendations for the Medical Management of Osteoarthritis of the Hip and Knee: 2000 Update

American College of Rheumatology Subcommittee on Osteoarthritis Guidelines

1916

Review: The Role of the Chondrocyte in Osteoarthritis

Mary B. Goldring

1927

The Course of Radiologic Damage During the First Six Years of Rheumatoid Arthritis

Henricus M. J. Hulsmans, Johannes W. G. Jacobs, Desiree M. F. M. van der Heijde, Grietje A. van Albada-Kuipers, Yolanda Schenk, and Johannes W. J. Bijlsma

In this prospective investigation of the course of radiologic damage in 502 patients with early RA, radiographs were assessed annually for a maximum of 6 years. The study showed that radiologic damage progressed at a constant rate, that in advanced disease, monitoring the progression of previously existing damage was as important as assessing new abnormalities in previously undamaged joints, and that radiographs of the feet should be included in assessments of radiologic damage that are used in clinical intervention trials and daily practice. These findings are useful for optimum planning of therapeutic strategies for patients with early and advanced RA.

1941

The Antiinflammatory Drug Sulfasalazine Inhibits Tumor Necrosis Factor [alpha] Expression in Macrophages by Inducing Apoptosis

Richard J. T. Rodenburg, Anuradha Ganga, Peter L. E. M. van Lent, Leo B. A. van de Putte, and Walther J. van Venrooij

The antiinflammatory drug sulfasalazine is widely used in the treatment of rheumatoid arthritis and several other inflammatory diseases. This study shows that sulfasalazine inhibits the expression of the proinflammatory cytokine TNF[alpha] by macrophages. It is shown that this effect of sulfasalazine is a direct consequence of the induction of macrophage apoptosis and involves activation of caspase 8. The possible relevance of this finding to both the beneficial effects and side effects of sulfasalazine is discussed.

1951

Synovial Macrophage Depletion with Clodronate-Containing Liposomes in Rheumatoid Arthritis

Pilar Barrera, Arjen Blom, Peter L. E. M. van Lent, Louis van Bloois, Jos H. Beijnen, Nico van Rooijen, Maarten C. de Waal Malefijt, Leo B. A. van de Putte, Gert Storm, and Wim B. van den Berg

In animal models of RA, a selective and temporary depletion of synovial lining macrophages can be achieved by intraarticular administration of clodronate liposomes. This study is the first to assess the effects of clodronate liposomes in humans, and the results show that intraarticular administration of these liposomes in patients with advanced RA produces a selective decrease in lining macrophages and down-regulation of the expression of adhesion molecules in synovial tissue. The procedure is safe and well tolerated, and its therapeutic efficacy in early arthritis is currently under investigation.

1960

Efficacy and Safety of Alendronate for the Treatment of Osteoporosis in Diffuse Connective Tissue Diseases in Children: A Prospective Multicenter Study

Maria Luisa Bianchi, Rolando Cimaz, Maria Bardare, Francesco Zulian, Loredana Lepore, Antonella Boncompagni, Elena Galbiati, Fabrizia Corona, Giovanni Luisetto, Diego Giuntini, Paolo Picco, Maria Luisa Brandi, and Fernanda Falcini

Osteopenia/osteoporosis is increasingly reported as a complication in many chronic diseases of rheumatologic interest, even in children, and particularly those requiring long-term corticosteroid therapy. This is a major problem, especially considering that currently, the life expectancy of patients with many such diseases is much longer than ever before. The undertreatment of low bone mass in children may lead to severe problems in later years, such as a substantially higher number of bone fragility fractures which have dire consequences for the patients' quality of life as well as high economic costs. This study shows that bisphosphonates, alendronate in particular, offer a promising therapeutic option for osteoporosis, even in children.

1967

Should Postmenopausal Women with Rheumatoid Arthritis Who are Starting Corticosteroid Treatment be Screened for Osteoporosis? A Cost-Effectiveness Analysis

Daniel H. Solomon and Karen M. Kuntz

Corticosteroids are the mainstay of treatment for many rheumatic conditions, and management of their side effects is controversial. Corticosteroid-induced osteoporosis is especially problematic in older women with RA. This report describes the cost-effectiveness of different strategies for managing RA in postmenopausal women.

1976

Interleukin-10 Blockade Corrects Impaired In Vitro Cellular Immune Responses of Systemic Lupus Erythematosus Patients

Bernard R. Lauwerys, Nathalie Garot, Jean-Christophe Renauld, and Frederic A. Houssiau

Many SLE patients display in vitro impaired cellular immune responses against allo- or recall antigens. In this study, the role of IL-10 overexpression in this process was investigated by measuring the proliferation of SLE peripheral blood mononuclear cells against irradiated allogeneic dendritic cells in the absence or presence of antibodies blocking IL-10 activity, or in the absence or presence of IL-12. IL-10 blockade restored in vitro normal cellular immune responses against allogeneic targets, and IL-12 supplementation had similar effects, thereby indicating that dysregulation of the IL-10/IL-12 balance plays a critical role in the impaired cellular immune responses observed in SLE.

1982

Association of Autoantibodies Against the Phosphatidylserine-Prothrombin Complex with Manifestations of the Antiphospholipid Syndrome and with the Presence of Lupus Anticoagulant

Tatsuya Atsumi, Masahiro Ieko, Maria L. Bertolaccini, Kenji Ichikawa, Akito Tsutsumi, Eiji Matsuura, and Takao Koike

The clinical significance of autoantibodies against prothrombin has not been established. This report indicates that the clinical relevance depends on the method of antibody detection, and that antibodies against the phosphatidylserine-prothrombin complex, rather than antibodies against prothrombin alone, are closely associated with the antiphospholipid syndrome and with lupus anticoagulant. This study is the first to show the value of determining these antibodies in routine clinical practice.

1994

Chlorpromazine Induces Apoptosis in Activated Human Lymphoblasts: A Mechanism Supporting the Induction of Drug-Induced Lupus Erythematosus?

Thomas Hieronymus, Philipp Grotsch, Norbert Blank, Mathias Grunke, Dorin Capraru, Thomas Geiler, Silke Winkler, Joachim R. Kalden, and Hanns-Martin Lorenz

To build a basis for better treatment options in autoimmune diseases, a better understanding of the processes leading to autoimmunity is required. It has been suggested that a dysregulation of apoptosis, or programmed cell death, is involved in the pathogenesis of systemic lupus erythematosus. These studies describe the induction of apoptosis in activated lymphoblasts by chlorpromazine, a drug known to induce lupus. It is hypothesized that increased susceptibility of activated lymphocytes to apoptosis during chlorpromazine challenge might lead to the induction of DILE.

2005

HLA-DQA1*0501 is Associated with Diffuse Systemic Sclerosis in Caucasian Men

Nathalie C. Lambert, Oliver Distler, Ulf Muller-Ladner, Tracy S. Tylee, Dan E. Furst, and J. Lee Nelson

SSc most often affects women, with infrequent occurrence in men. Investigators in this study attempted to identify factors that contribute to the risk of SSc in men. It was found that a specific HLA-DQA1 allele was strongly associated with SSc in men, and that the contribution of this allele to the risk of SSc was significantly more pronounced in men than in women. These findings suggest that HLA susceptibility alleles should be systematically analyzed according to sex.

2011

Histopathologic Evidence that Sacroiliitis in Ankylosing Spondylitis is not Merely Enthesitis: Systematic Study of Specimens from Patients and Control Subjects

Robert J. Francois, Dugald L. Gardner, Etienne J. Degrave, and Eric G. L. Bywaters

Radiologic recognition of sacroiliitis is one of the main clues to the clinical diagnosis of AS. This report describes the first systematic controlled histopathologic study of sacroiliac joints in AS. The results suggest that synovitis and subchondral bone marrow changes play larger roles in pathogenesis than does enthesitis, and challenge the concept of enthesitis as the key to understanding the histopathology of AS.

2025

Prediction of Relapses in Wegener's Granulomatosis by Measurement of Antineutrophil Cytoplasmic Antibody Levels: A Prospective Study

M. M. Boomsma, C. A. Stegeman, M. J. van der Leij, W. Oost, J. Hermans, C. G. M. Kallenberg, P. C. Limburg, and J. W. Cohen Tervaert

This report describes the value of serial quantification of ANCA by antigen-specific enzyme-linked immunosorbent assays (ELISA) and indirect immunofluorescence techniques for monitoring disease activity in a large cohort of patients with WG. Serial measurement of ANCA levels as determined by ELISA is clearly valuable for the early prediction of relapses.

2034

An Autosomal Dominant Periodic Fever Associated with AA Amyloidosis in a North Indian Family Maps to Distal Chromosome 1q

Michael F. McDermott, Ebun Aganna, Graham A. Hitman, B. William Ogunkolade, David R. Booth, and Philip N. Hawkins

This is the first report of a north Indian family with autosomal dominant periodic fever, which was ssociated with arthralgia and rash and frequently with AA amyloidosis. Markers from known periodic fever susceptibility loci were investigated in affected and healthy members of the family. The clinical features in the family overlapped with those of the Muckle-Wells syndrome and familial cold urticaria, and the linkage of all 3 disorders to the same region of chromosome 1 suggests that they may share a similar etiopathogenesis. Inherited periodic fever syndromes are rare, but they serve as invaluable models for elucidating known and novel pathways involved in inflammation, as demonstrated recently in familial Mediterranean fever and familial Hibernian fever.

2041

Localization of a Gene for Familial Recurrent Arthritis

Carol A. Wise, Lynda B. Bennett, Virginia Pascual, Joseph D. Gillum, and Anne M. Bowcock

This report describes a family that presented with a dominantly inherited disorder originally diagnosed as juvenile idiopathic arthritis. This disorder has been named ``familial recurrent arthritis.'' A genome-wide linkage survey of the extended kindred localized the causative gene to human chromosome 15q22-24.

2045

Neuropsychiatric Systemic Lupus Erythematosus

Michael Zapor, Thomas Rennie, Frederick T. Murphy, and Daniel F. Battafarano

2046

Mesenchymal Cells Expressing Bone Morphogenetic Protein Receptors are Present in the Rheumatoid Arthritis Joint

L. Marinova-Mutafchieva, P. Taylor, K. Funa, R. N. Maini, and N. J. Zvaifler

Investigators in this study examined synovial fluids, single-cell suspensions of cultured fibroblast-like synoviocytes, and synovial tissues for the presence of cells of an early mesenchymal lineage, as judged by the expression of bone morphogenetic protein receptors (BMPR) in the joints of normal individuals as well as patients with osteoarthritis and rheumatoid arthritis (RA). BMPR type IA- and BMPR type II-expressing cells were found in the intimal lining and in scattered cells in the sublining of all RA synovial membranes, but not in any normal synovial samples, and strong staining for BMPR was identified on cells at the invasive front of the pannus and at sites of cartilage erosion. BMPR-positive cells may be essential to the pathogenesis of RA and other inflammatory forms of chronic synovitis.

2056

Suppression of Arthritis and Protection from Bone Destruction by Treatment with TNP-470/AGM-1470 in a Transgenic Mouse Model of Rheumatoid Arthritis

Michel de Bandt, Maggy Grossin, Anne-Joelle Weber, Martine Chopin, Carole Elbim, Marika Pla, Marie-Anne Gougerot-Pocidalo, and Murielle Gaudry

The clinicopathologic mechanisms surrounding the origin of RA are still unknown; the most uniformly recognized hypothesis is that foreign agents provoke immunologic reactions on a genetically determined background. Proinflammatory cytokines (e.g., tumor necrosis factor [alpha] and interleukin-1) play an early and important role in pannus proliferation and synovial destruction, but other early phenomena, such as angiogenesis, must also be considered, since without new vessels delivering inflammatory cells, nutrients, and proinflammatory mediators locally, pannus would not persist. This study demonstrates that in vivo administration of an angiogenesis inhibitor in a mouse model of RA reduces the arthritis and protects from bone destruction, a finding that opens new therapeutic possibilities for RA.

2064

Suppression of Streptococcal Cell Wall-Induced Arthritis by Human Chorionic Gonadotropin

Xiao-Yu Song, Li Zeng, Wenwen Jin, Carey M. Pilo, Mark E. Frank, and Sharon M. Wahl

In human autoimmune diseases, including rheumatoid arthritis (RA), a dramatic amelioration of symptoms may occur during pregnancy, followed by an exacerbation postpartum, and one of the hormones that increases sharply in early pregnancy and declines rapidly after parturition is HCG. This study demonstrates unique immunoregulatory properties of HCG in an in vivo experimental model of arthritis, and provides insight into the potential mechanism of remission or amelioration of RA during pregnancy.

2073

The Effects of Local Administration of Lactoferrin on Inflammation in Murine Autoimmune and Infectious Arthritis

C. Guillen, I. B. McInnes, D. Vaughan, A. B. J. Speekenbrink, and J. H. Brock

Accumulation of iron in the synovium of rheumatoid arthritis patients is known to participate in the mechanisms involved in tissue damage and chronic inflammatory responses. To date, no satisfactory means has been found to either prevent its accumulation or reduce its toxicity. This study shows that periarticular injection of lactoferrin, an iron-binding protein, suppresses local inflammation in mice with inflammatory or infectious arthritis. Lactoferrin may therefore be of therapeutic use in inflammatory arthritic diseases.

2081

Functional Estrogen Receptors in Adult Articular Cartilage: Estrogen Replacement Therapy Increases Chondrocyte Synthesis of Proteoglycans and Insulin-Like Growth Factor Binding Protein 2

Renee S. Richmond, Cathy S. Carlson, Thomas C. Register, Gouri Shanker, and Richard F. Loeser

Epidemiologic evidence suggests that ERT may reduce the risk of radiographic osteoarthritis in postmenopausal women. In this study, a possible mechanism of action was examined, by which estrogen could act through estrogen receptors (ERs) in adult articular cartilage. Functional ERs were demonstrated in chondrocytes, and ERT was noted to increase both the production of insulin-like growth factor binding protein 2 and the synthesis of proteoglycans by chondrocytes from treated animals, demonstrating that ERT can have an effect on adult articular cartilage metabolism.

2091

Mechanotransduction via Integrins and Interleukin-4 Results in Altered Aggrecan and Matrix Metalloproteinase 3 Gene Expression in Normal, but Not Osteoarthritic, Human Articular Chondrocytes

S. J. Millward-Sadler, M. O. Wright, L. W. Davies, G. Nuki, and D. M. Salter

Mechanical stimuli are known to be important both in maintaining the integrity of normal articular cartilage and, when abnormal, in the pathogenesis of OA. Evidence is accumulating that integrins are involved in the recognition of mechanical stimuli by chondrocytes and in the transduction of these signals into cellular responses. This study demonstrates that mechanical stimulation alters levels of aggrecan and MMP-3 mRNA in chondrocytes from normal, but not OA, cartilage. These molecular changes are dependent on both integrins and the action of the chondroprotective cytokine IL-4. Abnormalities of mechanotransduction leading to aberrant chondrocyte activity in diseased articular cartilage may be important in the progression of OA.

2100

Modulation of Collagenase 3 in Human Osteoarthritic Cartilage by Activation of Extracellular Transforming Growth Factor [beta]: Role of Furin Convertase

Florina Moldovan, Jean-Pierre Pelletier, Francois Mineau, Martine Dupuis, Jean-Marie Cloutier, and Johanne Martel-Pelletier

Collagenase 3 is an enzyme known to be responsible for collagen matrix degradation in OA, and activated latent TGF[beta] mediates the up-regulation of collaganese 3. This study provides novel information regarding the topographic localization of the small latent TGF[beta] complex and TGF[beta] receptors in normal and OA cartilage. The findings suggest a possible mechanism of in situ activation of latent TGF[beta] in the cartilage matrix, involving furin convertase with or without mannose-6 phosphate/insulin-like growth factor 2 receptor.

2110

Reduction in the Chondrocyte Response to Insulin-Like Growth Factor 1 in Aging and Osteoarthritis: Studies in a Non-Human Primate Model of Naturally Occurring Disease

Richard F. Loeser, Gouri Shanker, Cathy S. Carlson, Jean F. Gardin, Brent J. Shelton, and William E. Sonntag

Although the development of OA is directly associated with aging, the mechanism for this association has not been clearly defined. This study shows that with increasing age, chondrocytes exhibit a decline in their ability to respond to stimulation by IGF-1, an important cartilage growth factor. There is also a decline in IGF-1 response by chondrocytes from cartilage with OA changes, but the mechanism appears to differ from that of the age-related decline. These results may help to explain the reduced repair capacity of chondrocytes with aging and OA.

2121

Differences in Type II Collagen Degradation Between Peripheral and Central Cartilage of Rat Stifle Joints After Cranial Cruciate Ligament Transection

Reinout Stoop, Pieter Buma, Peter M. van der Kraan, Anthony P. Hollander, R. Clark Billinghurst, A. Robin Poole, and Wim B. van den Berg

This study investigated the kinetics of type II collagen degradation during experimental OA in a rat CCL<cont;opposite inside back cover; see inside for expanded table of contents>

2132

Special Article: Recommendations for the Medical Management of Osteoarthritis of the Hip and Knee: 2000 Update

American College of Rheumatology Suenes

Samarendra N. Seal, Rene M. A. Hoet, Jos M. H. Raats, and Marko Z. Radic

An improved understanding of the genetics, induction, and molecular features of anti-DNA IgG autoantibodies may produce valuable insights into the origin, prognosis, and treatment of systemic lupus erythematosus (SLE). In this study, anti-double-stranded DNA IgG antibodies obtained from the bone marrow of a patient with SLE were captured by amplification of their V genes, cloned in bacteriophage, and screened by phage display. The antibodies showed diverse V-gene use, cationic V-gene junctions, and somatic mutations suggestive of antigen selection in vivo.

2138

Poem

Thursdays

Molly Meyers

2139

Sjogren's Syndrome Occurring After Hepatitis B Vaccination

Eric Toussirot, Anne Lohse, Daniel Wendling, and Christiane Mougin

2140

Error in text of article by Said-Nahal et al (Arthritis Rheum, June 2000)

2141

Apolipoprotein(a) Deposition in Atherosclerotic Coronary Arteries of a Patient with Systemic Lupus Erythematosus: Comment on the Article by Romero et al

Yu Asanuma and Shinichi Kawai

2142

Tatsuya Atsumi, Olga Amengual, Munther A. Khamashta, Fredeswinda I. Romero, and Graham R. V. Hughes

25A

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