1663

Review: Remnants of Suicidal Cells Fostering Systemic Autoaggression: Apoptosis in the Origin and Maintenance of Autoimmunity

Patrizia Rovere, Maria Grazia Sabbadini, Fausto Fazzini, Attilio Bondanza, Valerie S. Zimmermann, Claudio Rugarli, and Angelo A. Manfredi

1672

Maffucci's Syndrome

Umit Seckin, Pinar Borman, and Kursat Ozoran

1673

Multipoint Linkage Analysis of a Candidate Gene Locus in Rheumatoid Arthritis Demonstrates Significant Evidence of Linkage and Association with the Corticotropin-Releasing Hormone Genomic Region

Mark S. Fife, Sheila A. Fisher, Sally John, Jane Worthington, Chandrabala J. Shah, William E. R. Ollier, Gabriel S. Panayi, Cathryn M. Lewis, and Jerry S. Lanchbury

A strong candidate gene for RA susceptibility is CRH (or, corticotropin-releasing factor), a primary regulator of the hypothalamic-pituitary-adrenal axis and a key element in the response to stress and inflammation. Findings of genetic analysis of the genomic region close to CRH indicate a role for associated DNA variation in the development of RA. These studies provide an avenue for further genetic characterization and offer potential for the development of novel therapeutic approaches.

1679

Mannose-Binding Lectin and Rheumatoid Arthritis in Southern Chinese

W. K. Ip, Y. L. Lau, S. Y. Chan, C. C. Mok, D. Chan, K. K. Tong, and C. S. Lau

RA is a common disease managed by clinical rheumatologists in both Asia and the West. This study identified a risk factor associated with RA, i.e. mannose-binding lectin (MBL) deficiency. It was further demonstrated that MBL deficiency is associated with a more severe form of RA, hence implicating a pathogenetic role of MBL. It will be important to consider using MBL as a factor for stratification of treatment groups in future studies.

753

Tumor Necrosis Factor [ga] 5`-Flanking Region, Tumor Necrosis Factor Receptor II, and HLA-DRB1 Polymorphisms in Japanese Patients with Rheumatoid Arthritis

Tsukasa Shibue, Naoyuki Tsuchiya, Tae Komata, Masaki Matsushita, Michiko Shiota, Jun Ohashi, Masatoshi Wakui, Kunio Matsuta, and Katsushi Tokunaga

The substantial role of TNF[ga] in the pathogenesis of RA is widely recognized. In this study, the contribution of the polymorphisms in the recently described TNFA upstream promoter region, TNFR2 and HLA-DRB1, were examined in patients with RA. Among the 3 genes, HLA-DRB1 was most strongly associated with RA. These results will help us to understand the genetic contribution of HLA and TNF[ga] to RA.

1688

Adenovirus-Mediated Gene Transfer of CTLA-4Ig Fusion Protein in the Suppression of Experimental Autoimmune Arthritis

Emilia Quattrocchi, Margaret J. Dallman, and Marc Feldmann

This study provides insight into the pathogenesis of autoimmune arthritis and the rationale for the further development of novel therapeutic approaches for treating human rheumatoid arthritis by investigating, in vivo, the effectiveness of blocking a T lymphocyte costimulatory pathway (B7-CD28) by way of adenovirus-mediated gene delivery of a soluble CTLA-4Ig fusion protein. The results demonstrate that this gene-transfer method is therapeutic in established collagen-induced arthritis and associated with a significant reduction in both cellular and humoral immune responses to the disease-inducing antigen.

1698

Soluble Complement Receptor 1 (CD35) Delivered by Retrovirally Infected Syngeneic Cells or by Naked DNA Injection Prevents the Progression of Collagen-Induced Arthritis

Hanna Dreja, Alex Annenkov, and Yuti Chernajovsky

The role of complement in tissue damage and as the link between the native and adaptive immune responses is well documented. In rheumatoid arthritis, complexes of antibodies and complement have been reported to participate in cartilage destruction. In this study, the complement system was targeted by delivering a truncated soluble (ts) form of CR1 in an animal model of arthritis. This treatment was shown to affect the complement system as well as T and B cell functions. Low-level but long-term expression of tsCR1 was protective and could decrease proinflammatory cytokine production, T cell proliferation, and anticollagen antibody levels.

1710

Cartilage Degradation and Invasion by Rheumatoid Synovial Fibroblasts is Inhibited by Gene Transfer of a Cell Surface-Targeted Plasmin Inhibitor

W. H. van der Laan, T. Pap, H. K. Ronday, J. M. Grimbergen, L. G. M. Huisman, J. M. TeKoppele, F. C. Breedveld, R. E. Gay, S. Gay, T. W. J. Huizinga, J. H. Verheijen, and P. H. A. Quax

This study examined the effects of gene transfer of a cell surface-targeted plasmin inhibitor on rheumatoid arthritis synovial fibroblast-dependent cartilage degradation in vitro, and investigated cartilage invasion in vivo using the SCID mouse coimplantation model. The results provide in vitro and in vivo evidence for the involvement of the plasminogen activation system in the degradation and invasion of articular cartilage by synovial fibroblasts of the pannus tissue in rheumatoid arthritis. The study also demonstrates effective inhibition of this destruction by gene transfer of the cell surface-targeted plasmin inhibitor.

1719

Anti-Interleukin-1 and Anti-CD44 Interventions Producing Significant Inhibition of Cartilage Destruction in an In Vitro Model of Cartilage Invasion by Rheumatoid Arthritis Synovial Fibroblasts

Michel Neidhart, Renate E. Gay, and Steffen Gay

A novel in vitro approach was used to study the mechanisms and modulation of joint destruction in RA. In a 3-dimensional system, native extracellular matrix was isolated from bovine embryonic tissues, pretreated with gel-foam collagen sponges, and then cultured with human and bovine chondrocytes. The effects of isolated synovial fibroblasts, macrophages (through their cytokines), and other agents (monoclonal antibodies and drugs) on the synovial fibroblast-cartilage interaction were tested using this system. Based on the findings, anti-IL-1- and anti-CD44-directed therapies may help prevent cartilage destruction in RA.

1729

Participation of Transglutaminase in the Activation of Latent Transforming Growth Factor [gb]1 in Aging Articular Cartilage

Ann K. Rosenthal, Claudia M. Gohr, Lisa A. Henry, and Min Le

This study demonstrates a novel role for the enzyme transglutaminase (TGase) in aging articular cartilage. TGase from aging chondrocytes participates in the activation of latent transforming growth factor [gb] (TGF[gb]). Because TGF[gb] promotes osteophyte formation and calcium pyrophosphate dihydrate crystal deposition in aging joints, understanding processes of latent TGF[gb] activation will lead to the identification of novel targets for new therapies for these common diseases.

1734

Human Chondrocytes Express Functional Chemokine Receptors and Release Matrix-Degrading Enzymes in Response to C-X-C and C-C Chemokines

Rosa Maria Borz|fi, Ilaria Mazzetti, Luca Cattini, Mariagrazia Uguccioni, Marco Baggiolini, and Andrea Facchini

Chondrocytes control the integrity of the extracellular matrix, and this function is influenced by cyokines in the joint microenvironment that can also modulate the synthesis of chemokines by cartilage. This study investigated whether human chondrocytes also have chemokine receptors and examined the effects of chemokines on chondrocyte activity. The results show that human chondrocytes can express chemokine receptors, and that chemokines can induce chondrocyte catabolic activity by releasing matrix metalloproteases and lysosomal glycosidases. Since osteoarthritic cartilage overexpresses some chemokine receptors compared with normal cartilage and releases more abundant amounts of matrix-degrading enzymes, the study provides a new perspective for understanding the pathophysiology of osteoarthritis.

1742

Up-Regulation of Cartilage Oligomeric Matrix Protein at the Onset of Articular Cartilage Degeneration in a Transgenic Mouse Model of Osteoarthritis

Heli Salminen, Merja Perala, Pilar Lorenzo, Tore Saxne, Dick Heinegard, Anna-Marja Saamanen, and Eero Vuorio

In this study, analysis of COMP production and deposition in a transgenic mouse model of OA demonstrated that up-regulation of COMP messenger RNA, redistribution of the protein, and increased serum COMP levels are characteristic of the early stages of articular cartilage degeneration. These data provide additional support for the notion that COMP is a marker useful for early OA in humans.

1749

Association of Giant Cell Arteritis and Polymyalgia Rheumatica with Different Tumor Necrosis Factor Microsatellite Polymorphisms

Derek L. Mattey, Ali H. Hajeer, Adele Dababneh, Wendy Thomson, Miguel A. Gonzalez-Gay, Carlos Garcia-Porrua, and William E. R. Ollier

Differentiation between GCA and PMR, often considered to be part of the same clinical continuum, is sometimes difficult, although it is important for deciding on suitable treatment. This study indicates that GCA and PMR (and late-onset rheumatoid arthritis) in a population from northwestern Spain have distinct patterns of TNF microsatellite and HLA-DRB1 associations. The TNF and HLA associations appear to influence susceptibility to these conditions in an independent manner.

1756

Suppression of Tumor Necrosis Factor [ga]-Induced Matrix Metalloproteinase 9 Production by the Introduction of a Super-Repressor Form of Inhibitor of Nuclear Factor [gk]B[ga] Complementary DNA into Immortalized Human Salivary Gland Acinar Cells: Prevention of the Destruction of the Acinar Structure in Sjogren's Syndrome Salivary Glands

Masayuki Azuma, Keiko Aota, Tetsuya Tamatani, Katsumi Motegi, Tsuyoshi Yamashita, Kouji Harada, Yoshio Hayashi, and Mitsunobu Sato

Although SS is one of the most common rheumatic diseases, the pathogenesis of the selective and progressive destruction of the acinar structure is not yet fully understood. Understanding the mechanism underlying this characteristic feature of SS salivary glands would inevitably contribute to the clinical improvement of patients with the disease. Because MMP-9 is regulated by nuclear factor [gk]B, the effect of a super-repressor form of srI[gk]B[ga] on the suppression of TNF[ga]-induced MMP-9 production in acinar cells was investigated in this study. TNF[ga]-induced MMP-9 activity was effectively suppressed by srI[gk]B[ga], resulting in the correction of the aberrant in vitro morphogenesis of acinar cells. These results may suggest the usefulness of gene delivery of srI[gk]B[ga] in the restoration of the acinar structure in the salivary glands of patients with SS.

1768

SR Proteins are Autoantigens in Patients with Systemic Lupus Erythematosus: Importance of Phosphoepitopes

Karla M. Neugebauer, Joan T. Merrill, Mark H. Wener, Robert G. Lahita, and Mark B. Roth

In this study, investigators sought to determine whether members of the highly phosphorylated SR protein family are autoantigens and, if so, to determine the frequency and molecular basis of antigen recognition. It was found that the SR protein family of pre-messenger RNA splicing factors is recognized by [approximate]50% of patients with SLE; that many patients' seroreactivity with SR proteins depends on phosphorylation, increasing or decreasing with phosphate removal; and that a posttranslational modification directly influences autoantigen recognition by autoantibodies. SR proteins have been implicated in the immune response to the spliceosome through their association with components such as the U1 small nuclear RNP, an important autoantigen complex in SLE and mixed connective tissue disease. However, evidence that SR proteins themselves are antigens was lacking prior to this study.

1779

Noninflammatory Phagocytosis of Monosodium Urate Monohydrate Crystals by Mouse Macrophages: Implications for the Control of Joint Inflammation in Gout

Darshna R. Yagnik, Philippa Hillyer, Diane Marshall, Cheryl D. W. Smythe, Thomas Krausz, Dorian O. Haskard, and R. Clive Landis

The findings of this study show that monosodium urate monohydrate crystals can be phagocytosed by mature macrophages without the production of proinflammatory cytokines or induction of endothelial cell adhesion molecule expression. This may be important for maintaining the asymptomatic state in hyperuricemia and in promoting the resolution of an acute attack of gout.

1790

Clinical and Biologic Effects of Anti-Interleukin-10 Monoclonal Antibody Administration in Systemic Lupus Erythematosus

Luis Llorente, Yvonne Richaud-Patin, Carlos Garc|fia-Padilla, Emmanuel Claret, Juan Jakez-Ocampo, Mario H. Cardiel, Jorge Alcocer-Varela, Liliane Grangeot-Keros, Donato Alarcon-Segovia, John Wijdenes, Pierre Galanaud, and Dominique Emilie

This report describes the first administration of an IL-10-neutralizing monoclonal antibody (B-N10) to humans--SLE patients with active and steroid-dependent disease. B-N10 was given intravenously to 6 SLE patients for 21 consecutive days, with a followup period of 6 months. Neutralization of endogenous IL-10 improved the patients' clinical condition and biologic markers of disease activity. Since IL-10 may be involved in the pathogenesis of human SLE, neutralization of this cytokine is a potentially valuable therapeutic approach to managing the disease.

1801

Damage in Systemic Lupus Erythematosus and Its Association with Corticosteroids

Abraham Zonana-Nacach, Susan G. Barr, Laurence S. Magder, and Michelle Petri

This study evaluated the association between corticosteroid use by SLE patients and irreversible organ damage, by use of Cox proportional hazards regression analyses. The cumulative prednisone dose was associated with an increased risk of osteoporotic fractures, symptomatic coronary artery disease, and cataracts. High-dose prednisone ([lte]60 mg daily for [lte]2 months) was significantly associated with avascular necrosis and stroke, while intravenous pulse methylprednisolone was not. Damage prevention will require new therapeutic regimens that effectively treat specific SLE manifestations while minimizing both cumulative and high-dose prednisone exposure.

1809

Treatment of Poor-Prognosis Early Rheumatoid Arthritis: A Randomized Study of Treatment with Methotrexate, Cyclosporin A, and Intraarticular Corticosteroids Compared with Sulfasalazine Alone

S. M. Proudman, P. G. Conaghan, C. Richardson, B. Griffiths, M. J. Green, D. McGonagle, R. J. Wakefield, R. J. Reece, S. Miles, A. Adebajo, A. Gough, P. Helliwell, M. Martin, G. Huston, C. Pease, D. J. Veale, J. Isaacs, D. M. F. M. van der Heijde, and P. Emery

This study addresses the question of whether early, aggressive therapy (with cyclosporin A, methotrexate, and corticosteroids) beginning at presentation in patients with poor-prognosis RA can produce a major improvement in clinical outcome. Predictably, the early response was better in the aggressive-treatment group, but the number of good responders at the completion of the study was not significantly increased. The more aggressive approach did reduce the number of treatment failures. These results suggest that identification of poor responders and use of a selective ``step-up'' approach may be more appropriate than an unconditional introduction of combination therapy from the outset.

1820

Modulation of Inflammation and Metalloproteinase Expression in Synovial Tissue by Leflunomide and Methotrexate in Patients with Active Rheumatoid Arthritis: Findings in a Prospective, Randomized, Double-Blind, Parallel-Design Clinical Trial in Thirty-Nine Patients at Two Centers

Maarten C. Kraan, Richard J. Reece, Ella C. Barg, Tom J. M. Smeets, Jacqui Farnell, Ronald Rosenburg, Doug J. Veale, Ferdinand C. Breedveld, Paul Emery, and Paul P. Tak

Clinical trials of leflunomide and methotrexate have proven the efficaciousness of these agents with respect to joint inflammation and destruction in patients with active RA. Findings of this study document that changes in clinical parameters are reflected in a reduction in the cellular infiltrate and expression of adhesion molecules, proinflammatory cytokines, and matrix-degrading enzymes. Furthermore, a beneficial effect of both drugs on mediators of joint destruction was observed.

1831

The Prognostic Value of Anti-Cyclic Citrullinated Peptide Antibody in Patients with Recent-Onset Rheumatoid Arthritis

Eric-Jan J. A. Kroot, Ben A. W. de Jong, Miek A. van Leeuwen, Hilde Swinkels, Frank H. J. van den Hoogen, Martin van 't Hof, Leo B. A. van de Putte, Martin H. van Rijswijk, Walther J. van Venrooij, and Piet L. C. M. van Riel

Anti-CCP antibodies have been shown to have significant diagnostic value with extremely high specificity for RA. The present study of patients with recent-onset RA was undertaken to investigate whether these autoantibodies also have prognostic value in predicting long-term outcome. The results indicate that anti-CCP does have additional value for predicting radiologic damage.

1836

Use of Methotrexate and Glucocorticoids in the Treatment of Wegener's Granulomatosis: Long-Term Renal Outcome in Patients with Glomerulonephritis

Carol A. Langford, Cheryl Talar-Williams, and Michael C. Sneller

In this study of 21 patients with WG and active glomerulonephritis who were previously treated with low-dose methotrexate and glucocorticoids, the use of methotrexate was not associated with a decline in renal function over the long term. Although the decision whether to use methotrexate or daily cyclophosphamide for remission induction should be based on individual considerations, the presence of active glomerulonephritis should not preclude consideration of methotrexate and glucocorticoids for treatmene of patients who would otherwise be eligible to receive such therapy.

1841

Cost-Effectiveness of Prophylaxis Against Pneumocystis carinii Pneumonia in Patients with Wegener's Granulomatosis Undergoing Immunosuppressive Therapy

James B. Chung, Katrina Armstrong, J. Sanford Schwartz, and Daniel Albert

Prophylactic therapy for PCP with trimethoprim/sulfamethoxazole (TMP/SMX) is routine for patients with acquired immunodeficiency syndrome who are receiving chemotherapy for hematologic malignancies or immunosuppressive therapy for organ transplantation, but is not widely used in patients undergoing immunosuppressive treatment for WG. This study shows that PCP prophylaxis with TMP/SMX in patients with WG is cost-saving as well as life-saving. These results have implications for managing not only patients with WG receiving immunosuppressive therapies, but also patients with other systemic rheumatic diseases that require immunosuppression.

1849

Randomized, Placebo-Controlled, Crossover Trial of Low-Dose Oral Methotrexate in Children with Extended Oligoarticular or Systemic Arthritis

P. Woo, T. R. Southwood, A. M. Prieur, C. J. Dore, J. Grainger, J. David, C. Ryder, N. Hasson, A. Hall, and I. Lemelle

The results of this study indicate that MTX given orally once a week is effective in the short-term therapy of the extended oligoarticular and systemic forms of juvenile idiopathic arthritis. Additional studies are needed to assess the long-term efficacy of this treatment in these potentially disabling forms of juvenile idiopathic arthritis.

1858

Long-Term Outcome and Prognosis in Oligoarticular-Onset Juvenile Idiopathic Arthritis

Severine Guillaume, Anne-Marie Prieur, Joel Coste, and Chantal Job-Deslandre

This longitudinal study was performed on a large cohort of 207 patients with oligoarticular-onset juvenile idiopathic arthritis and revealed that this disease may not be as benign as previously thought. Factors predictive of a severe disease course, which might help in early recognition of high-risk patients and would thus warrant more aggressive therapeutic strategies, were identified.

1866

Magnetic Resonance Imaging Detection of Occult Skin and Subcutaneous Abnormalities in Juvenile Dermatomyositis: Implications for Diagnosis and Therapy

Alexa B. Kimball, Ronald M. Summers, Maria Turner, Elizabeth M. Dugan, Jeanne Hicks, Frederick W. Miller, and Lisa G. Rider

In this study, STIR MRI of the proximal thighs and buttocks was obtained and cutaneous manifestations and other measures of disease activity were assessed in 26 children meeting criteria for probable or definite juvenile DM. STIR MRI detected cutaneous, subcutaneous, and fascial edema abnormalities in the majority of juvenile DM patients, and these abnormalities were usually not predicted by standard methods of assessing myositis disease activity, suggesting that MRI from many tissue layers are useful adjuncts in assessing juvenile DM disease activity. Dystrophic calcification, an often-disabling complication of juvenile DM, developed over a 9-month observation period in sites of subcutaneous edema seen on STIR MRI in 5 of 26 patients. When MRI of the thighs are obtained to assess disease activity in myositis patients, they should also be evaluated for skin, subcutaneous tissue, and fascial abnormalities to assess extramuscular disease, which may alter treatment plans.

1874

The Association Between Varus-Valgus Alignment and Patellofemoral Osteoarthritis

Sadaf Elahi, September Cahue, David T. Felson, Laszlo Engelman, and Leena Sharma

Knee OA is a leading cause of chronic pain and disability. Although patellofemoral (PF) involvement is a determinant of functional status, natural history studies continue to emphasize the tibiofemoral compartments, and little is known about possible risk factors for PF OA. It is likely that alterations in the PF mechanical environment play a key role in OA development. This study demonstrated that lateral PF OA was more common than medial PF OA and also provided evidence of associations between varus or valgus malalignment and medial or lateral PF OA, respectively.

1881

Evaluating the Predictive Value of Osteoarthritis Diagnoses in an Administrative Database

Leslie R. Harrold, Robert A. Yood, Susan E. Andrade, John I. Reed, Jackie Cernieux, Walter Straus, Mary Weeks, Barbara Lewis, and Jerry H. Gurwitz

There is an increasing body of literature examining the costs and outcomes of OA based on data derived from administrative and clinical databases. Rheumatologists and the health care systems in which they work are using this information to better understand patterns of clinical practice and resource utilization. This study demonstrates that relying on information contained in administrative databases for health services and epidemiologic research on OA may lead to both case misclassification and underascertainment.

1886

Increased [ga]2-Adrenergic Constriction of Isolated Arterioles in Diffuse Scleroderma

N. A. Flavahan, S. Flavahan, Q. Liu, S. Wu, W. Tidmore, C. M. Wiener, R. J. Spence, and F. M. Wigley

The mechanisms underlying the pathogenesis of diffuse systemic sclerosis (SSc; cleroderma) are unknown. The present study demonstrates that SSc dermal arterioles from clinically uninvolved skin display a selective increase in the activity of smooth muscle [ga]2-adrenergic receptors. This may contribute to the vasospasm and ischemic injury occurring in the SSc disease process. Increased understanding of the role of these receptors in regulating the vascular system in SSc might provide a novel therapeutic approach to treating this devastating disease.

1891

Thrombosis in Patients with Connective Tissue Diseases Treated with Specific Cyclooxygenase 2 Inhibitors: A Report of Four Cases

Leslie J. Crofford, Jim C. Oates, W. Joseph McCune, Samardeep Gupta, Mariana J. Kaplan, Francesca Catella-Lawson, Jason D. Morrow, Kevin T. McDonagh, and Alvin H. Schmaier

1897

Churg-Strauss Syndrome: Localization of Eosinophil Major Basic Protein in Damaged Tissues

Elisabeth Peen, Paulette Hahn, Gregory Lauwers, Ralph C. Williams, Jr., Gerald Gleich, and Gail M. Kephart

1900

Protein-Losing Gastroenteropathy in Systemic Lupus Erythematosus: Diagnosis with 99mTc-Human Serum Albumin Scintigraphy

Masayuki Miyata, Minako Yoshida, Mitsuru Saka, and Reiji Kasukawa

1901

Anticitrulline Antibody Assay Specificity for Rheumatoid Arthritis: Comment on the Article by Schellekens et al

Jean-Marie Berthelot and Alain Saraux

1903

D. Krause, B. Schleusser, G. Herborn, and R. Rau

1903

The Role of Nuclear Medicine in the Evaluation of Neuropsychiatric Systemic Lupus Erythematosus: Comment on the Article by Sibbitt et al Paolo Colamussi and Marcello Govoni

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

1904

Wilmer L. Sibbitt, Jr., William M. Brooks, and Randy R. Sibbitt

23A

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