1563

Review: Rheumatic Disease and Cystic Fibrosis

Peter A. Merkel

1572

Current Comment: ACR 20: Clinical or Statistical Significance?

Theodore Pincus and C. Michael Stein

1577

Interleukin-1[gb]-Converting Enzyme/Caspase-1 in Human Osteoarthritic Tissues: Localization and Role in the Maturation of Interleukin-1[gb] and Interleukin-18

Nathalie Saha, Florina Moldovan, Ginette Tardif, Jean-Pierre Pelletier, Jean-Marie Cloutier, and Johanne Martel-Pelletier

This study shows, for the first time, the involvement of ICE in human osteoarthritic cartilage and demonstrates that an increase in the level of this enzyme is responsible for increased production of the mature form of IL-1[gb] and IL-18 by these pathologic chondrocytes. Therefore, ICE could be included in the list of factrs that play a critical role in the regulation of proinflammatory cytokines in OA tissues.

1588

Expression of Cathepsin K Messenger RNA in Giant Cells and Their Precursors in Human Osteoarthritic Synovial Tissues

Robert A. Dodds, Janice R. Connor, Fred H. Drake, and Maxine Gowen

This study demonstrates that osteoarthritic synovial giant cells express high levels of cathepsin K mRNA, but lack expression of mRNA for cathepsins B, L, and S. A direct or indirect role of synovial cathepsin K in the degradation of cartilage matrix could potentially open new perspectives on the diagnosis and pharmacologic management of osteoarthritis.

1594

Analysis of the p53 Tumor Suppressor Gene in Rheumatoid Arthritis Synovial Fibroblasts

Frank Kullmann, Martin Judex, Ingrid Neudecker, Sandra Lechner, Hans-Peter Justen, Douglas R. Green, Dieter Wessinghage, Gary S. Firestein, Steffen Gay, Jurgen Scholmerich, and Ulf Muller-Ladner

Up-regulation of protooncogenes is frequently observed in rheumatoid synovial fibroblasts located at the sites of invasion into the adjacent articular cartilage and bone. To determine whether mutations in the tumor suppressor gene p53 may contribute to the transformed-appearing phenotype of RA synovial fibroblasts, p53 gene mutation analysis was performed. No specific mutation pattern could be detected, and the data also indicate that the majority of p53 mutations in RA synovium are not located within the genome of RA synovial fibroblasts. In addition, the presence or absence of mutations was compared in synovial fibroblasts from 2 institutions located on 2 continents.

1601

Macrophage Migration Inhibitory Factor in Rheumatoid Arthritis: Evidence of Proinflammatory Function and Regulation by Glucocorticoids

Michelle Leech, Christine Metz, Pamela Hall, Paul Hutchinson, Katerina Gianis, Malcolm Smith, Helen Weedon, Stephen R. Holdsworth, Richard Bucala, and Eric F. Morand

MIF is a cytokine with emerging importance in the immune inflammatory response. Antagonism of MIF markedly inhibits arthritis in animal models. This report is the first description of MIF in human RA synovium. Its regulation by cytokines and glucocorticoids is examined, and evidence of a role of synoviocyte-derived MIF in the induction of mononuclear cell tumor necrosis factor [ga] production is provided. These data suggest MIF as a new therapeutic target in RA.

1609

Selective Expression of Folate Receptor [gb] and its Possible Role in Methotrexate Transport in Synovial Macrophages from Patients with Rheumatoid Arthritis

Noriko Nakashima-Matsushita, Toshio Homma, Su Yu, Takemasa Matsuda, Nobuhiko Sunahara, Tadashi Nakamura, Michishi Tsukano, Manohar Ratnam, and Takami Matsuyama

The present study demonstrates that folate receptor [gb] is selectively expressed in RA synovial macrophages and plays a role in methotrexate transport. These findings could aid in the development of folate antagonists with fewer side effects than methotrexate.

1617

Linkage of a Marker in Intron D of the Estrogen Synthase Locus to Rheumatoid Arthritis

Sally John, Anne Myerscough, Stephen Eyre, Philip Roby, Ali Hajeer, Alan J. Silman, William E. R. Ollier, and Jane Worthington

RA is a complex disease in which both genes and environment are thought to be etiologically important. Evidence from both epidemiologic and laboratory-based research has suggested a role for steroid hormones in RA susceptibility and pathology. The identification of polymorphisms affecting steroid hormone synthesis may have profound implications with respect to prediction of disease susceptibility and outcome, response to treatment, and provision of new therapeutic targets. Genetic data from this study suggest that the gene encoding estrogen synthase is implicated in RA susceptibility.

1621

No Support for HLA-DQ Encoded Susceptibility in Rheumatoid Arthritis

Niek de Vries, Claudia van Elderen, Henk Tijssen, Piet L. C. M. van Riel, and Leo B. A. van de Putte

Recent studies on collagen-induced arthritis in mice suggest that susceptibility to rheumatoid arthritis might be encoded at the HLA-DQ locus, rather than the HLA-DRB1 locus. Susceptibility effects of HLA-DQ alleles might be abrogated by self peptides of HLA-DRB1 molecules. If this hypothesis is true, it might open a road to immunologic intervention with HLA-DRB1 peptides. This study tested predictions based on this DR/DQ hypothesis and showed no evidence to support it in its present form.

1628

Treatment of Experimental Autoimmune Arthritis by Nasal Administration of a Type II Collagen-Cholera Toxoid Conjugate Vaccine

Andrej Tarkowski, Jia-Bin Sun, Rikard Holmdahl, Jan Holmgren, and Cecil Czerkinsky

To improve the efficacy of mucosal tolerization against CII-induced arthritis, CII has been covalently coupled with atoxic cholera toxin B subunit (CTB). In this study, it was shown that intranasal administration of microgram amounts of this conjugate can markedly suppress the development of collagen-induced arthritis in mice, even when given after the onset of clinically evident arthropathy. Protection was associated with decreased production of proinflammatory cytokines and CII-specific antibodies. These results suggest that intranasal vaccination with CTB-CII may offer an effective immunotherapeutic means for the control of chronic polyarthritis.

1635

Delayed Onset and Reduced Severity of Collagen-Induced Arthritis in Interleukin-6-Deficient Mice

Mitsuko Sasai, Yukihiko Saeki, Shiro Ohshima, Katsuhiro Nishioka, Toru Mima, Toshio Tanaka, Yoshinori Katada, Kazuyuki Yoshizaki, Masaki Suemura, and Tadamitsu Kishimoto

To investigate the roles of IL-6 in the pathogenesis of rheumatoid arthritis, clinical and immunologic findings were compared in IL-6-deficient (IL-6[minus]/[minus]) mice and IL-6 wild-type littermates with CIA. Delayed onset and reduced severity of CIA were observed in IL-6[minus]/[minus] mice. Additionally, the degree of histologic and radiologic changes was reduced in these animals. Both suppression of specific immune responses to type II collagen and a shift toward a Th2 cytokine profile might contribute in part to the attenuation of CIA in IL-6[minus]/[minus] mice. These results suggest that blockade of IL-6 may have potential therapeutic applications in rheumatoid arthritis.

1644

Th1/Th2 Balance of Peripheral T Helper Cells in Systemic Lupus Erythematosus

Mitsuteru Akahoshi, Hitoshi Nakashima, Yosuke Tanaka, Tsutomu Kohsaka, Shuji Nagano, Eiichi Ohgami, Yojiro Arinobu, Kunihiro Yamaoka, Hiroaki Niiro, Michiya Shinozaki, Hideki Hirakata, Takahiko Horiuchi, Takeshi Otsuka, and Yoshiyuki Niho

In this study, the intracellular cytokine detection method was used to determine the Th1:Th2 ratio among peripheral T helper cells in patients with SLE. This ratio did not differ in the overall SLE patient group compared with controls. However, among SLE patients with WHO class IV lupus nephritis, there was a strong predominance of Th1. The Th1/Th2 balance may play a role in lupus nephritis.

1649

Increased Number of Interleukin-10-Producing Cells in Systemic Lupus Erythematosus Patients and Their First-Degree Relatives and Spouses in Icelandic Multicase Families

Gerdur Grondal, Helga Kristjansdottir, Brynja Gunnlaugsdottir, Alfred Arnason, Ingrid Lundberg, Lars Klareskog, and Kristjan Steinsson

This study shows increased interleukin-10 production in systemic lupus erythematosus patients and their first-degree relatives and spouses in multicase families. The data indicate that not only genetic, but also environmental factors are involved in this aberration.

1655

A Role for the Polymorphism at Position 247 of the [gb]2-Glycoprotein I Gene in the Generation of Anti-[gb]2-Glycoprotein I Antibodies in the Antiphospholipid Syndrome

Naoto Hirose, Roxanne Williams, Alan R. Alberts, Richard A. Furie, Elliot K. Chartash, Rita I. Jain, Cristina Sison, Robert G. Lahita, Joan T. Merrill, Elena Cucurull, Azzudin E. Gharavi, Lisa R. Sammaritano, Jane E. Salmon, Shiori Hashimoto, Tetsuji Sawada, Charles C. Chu, Peter K. Gregersen, and Nicholas Chiorazzi

Patients with APS develop thromboembolic events, recurrent fetal loss, or thrombocytopenia in the setting of autoantibodies that bind to complexes of phospholipids and a variety of phospholipid-binding proteins, such as [gb]2GPI. Since [gb]2GPI is a main target of antiphospholipid antibodies and is involved in platelet function, any alteration in the gene that affects the structure or levels of the circulating protein may modify its in vivo behavior. This study demonstrates that a polymorphism in the gene for [gb]2GPI, located at position 247, is highly associated with the presence of anti-[gb]2GPI antibodies in Asian patients with APS and can therefore be viewed as a major risk factor in this ethnic group.

1662

Tumor Necrosis Factor Receptor p55 Controls the Severity of Arthritis in Experimental Yersinia Enterocolitica Infection

Yi-Xue Zhao, Hongwei Zhang, Basil Chiu, Ursula Payne, and Robert D. Inman

This study dissects the early host defense mechanisms relating to Yersinia-associated arthritis by the use of mice rendered deficient in tumor necrosis factor receptor p55. The findings demonstrate that TNFp55-mediated macrophage microbicidal activity is a central event in the process of the arthritis. The finding that TNF is a necessary protective factor in Yersinia-associated arthritis sheds light on the immunopathogenesis of reactive arthritis.

1673

Correlation of Increased Susceptibility to Apoptosis of CD4+ T Cells with Lymphocyte Activation and Activity of Disease in Patients with Primary Sjogren's Syndrome

Margit Zeher, Peter Szodoray, Edit Gyimesi, and Zsuzsa Szondy

The data presented in this report suggest that in vivo activation of CD4+ lymphocytes is correlated with the activity of the disease in patients with primary Sjogren's syndrome. The results give a possible explanation for the observed increase in susceptibility to apoptosis of peripheral T cells and for the decrease in CD4+ cell number in patients with this disease.

1682

Sugar Printing Rheumatic Diseases: A Potential Method for Disease Differentiation Using Immunoglobulin G Oligosaccharides

Mando Watson, Pauline M. Rudd, Martin Bland, Raymond A. Dwek, and John S. Axford

The study demonstrates that serum immunoglobulin G sugars isolated from patients with a range of rheumatic diseases showed statistically significant differences in the relative proportions of their oligosaccharides. This finding may be useful in the early diagnosis of rheumatic diseases and provides insight into disease pathogenesis.

1691

Treatment of Early Seropositive Rheumatoid Arthritis with Minocycline: Four-Year Followup of a Double-Blind, Placebo-Controlled Trial

James R. O'Dell, Gail Paulsen, Claire E. Haire, Kent Blakely, William Palmer, Steven Wees, P. James Eckhoff, Lynell W. Klassen, Melvin Churchill, Deborah Doud, Arthur Weaver, and Gerald F. Moore

This report describes long-term results (mean 4 years followup) in RA patients who were treated with minocycline during the early part of their disease. Compared with patients who had received placebo rather than minocycline for 3 months during the early part of their disease, the patients who had received minocycline had a significantly higher frequency of improvement or remission. These results indicate that minocycline, given early in the disease, is effective in the treatment of RA.

1696

Association of HLA Alleles and Clinical Features in Patients with Synovitis of Recent Onset

Hani S. El-Gabalawy, Raphaela Goldbach-Mansky, David Smith, II, Thurraya Arayssi, Sherri Bale, Percio Gulko, Cheryl Yarboro, Ronald L. Wilder, John H. Klippel, and H. Ralph Schumacher, Jr.

Among patients with recent-onset synovitis, alleles containing the shared epitope (SE) were found in this study to be associated with rheumatoid factor-positive (RF+) rheumatoid arthritis (RA) and were a risk factor for the development of early radiographic erosions in both RF+ and RF[minus] RA. HLA-B27 was highly associated with enthesitis in a wide spectrum of patients, including a number who met the criteria for RF+ RA, and was found to be significantly associated with SE alleles in the patients with early arthritis, but not in the controls. These findings emphasize the complex degree of genetic interaction between allleles at several major histocompatibility loci, which may explain the variation in clinical phenotypes.

1706

The Relationship Between Synovitis and Bone Changes in Early Untreated Rheumatoid Arthritis: A Controlled Magnetic Resonance Imaging Study

Dennis McGonagle, Philip G. Conaghan, Philip O'Connor, Wayne Gibbon, Michael Green, Richard Wakefield, John Ridgway, and Paul Emery

The relationship between synovitis and erosions is critical in understanding the pathogenesis of RA. MRI was used to image patients with early untreated RA. The study showed that 68% of RA patients, but only 10% of controls, had bone edema. In RA patients, bone edema was seen almost exclusively in joints where synovitis was present. This suggests that synovitis is the primary abnormality and that bone changes are secondary.

1712

How Much Disability in Rheumatoid Arthritis is Explained by Rheumatoid Arthritis?

Agust|fin Escalante and Inmaculada del Rincon

This study used hierarchical regression models to determine the extent to which factors directly related to the RA disease process, and factors external to RA, contribute to disability among patients with the disease. The results indicate that demographic and psychosocial factors contribute substantially to the degree of disability in patients with RA.

1722

Outcomes of Total Hip and Knee Replacement: Preoperative Functional Status Predicts Outcomes at Six Months After Surgery

Paul R. Fortin, Ann E. Clarke, Lawrence Joseph, Matthew H. Liang, Michael Tanzer, Diane Ferland, Charlotte Phillips, Alison J. Partridge, Patrick Belisle, Anne H. Fossel, Nizar Mahomed, Clement B. Sledge, and Jeffrey N. Katz

This study raises the question as to when is the ideal window of time in the course of osteoarthritis (OA) of the knee or hip for total joint replacement that would provide maximal benefit (e.g., improvement in function and pain) at the lowest immediate cost. In patients with worse physical function preoperatively, surgery may be performed too late, resulting in worse postoperative function. Thus, earlier intervention in the course of the natural history of hip or knee OA allows for a better postoperative outcome at 6 months.

1729

Heritabilities of Radiologic Osteoarthritis in Peripheral Joints and of Disc Degeneration of the Spine

Casper Bijkerk, Jeanine J. Houwing-Duistermaat, Hans A. Valkenburg, Ingrid Meulenbelt, Albert Hofman, Ferdinand C. Breedveld, Huibert A. P. Pols, Cornelia M. van Duijn, and P. Eline Slagboom

This study, through data derived from a sibling pair study and a random population-based sample, examines the genetic component in radiologic OA of the knees, hips, and hands and of disc degeneration of the spine. The findings support the evidence of heritability of hand OA and generalized OA, and present evidence of heritability of disc degeneration of the spine. For knee and hip OA, no evidence of heritability was found.

1736

Prevention of Corticosteroid-Induced Osteoporosis: Results of a Patient Survey

Lenore M. Buckley, Mariella Marquez, Robert Feezor, David M. Ruffin, and Linda L. Benson

This survey study demonstrates that many patients receiving long-term corticosteroids do not receive adequate treatment to prevent bone loss, and that physician specialty is an important factor associated with bone density testing and preventive treatment. A broad educational effort aimed at physicians of varied specialties is needed to ensure that osteoporosis prevention becomes the standard of care for patients receiving long-term corticosteroid treatment.

1740

The Role of Vitamin D in Corticosteroid-Induced Osteoporosis: A Meta-Analytic Approach

Shreyasee Amin, Michael P. LaValley, Robert W. Simms, and David T. Felson

There is conflicting evidence regarding the efficacy of vitamin D for managing corticosteroid-induced osteoporosis, with published guidelines differing in their recommendations. A systematic search was conducted for published and unpublished studies of vitamin D's effficacy, where the outcome measure was change in lumbar spine bone mineral density. A moderately beneficial effect of vitamin D plus calcium versus either no therapy or calcium alone was found. Bisphosphonates were more effective than vitamin D, while calcitonin was similarly effective. It was concluded that, as a minimum, vitamin D plus calcium should be recommended for patients receiving long-term corticosteroids.

1752

Granulocyte Colony-Stimulating Factor Treatment for Cyclophosphamide-Induced Severe Neutropenia in Wegener's Granulomatosis

Bernhard Hellmich, Armin Schnabel, and Wolfgang L. Gross

Severe neutropenia is an important adverse effect of cyclophosphamide treatment of systemic vasculitides and a risk factor for potentially life-threatening infections. Caution has been advocated in the use of G-CSF in vasculitis patients with severe neutropenia since the resulting increase in neutrophil count and neutrophil activity may cause a flare of the vasculitis. The present study shows that recombinant human G-CSF can shorten the duration of cyclophosphamide-induced severe neutropenia in a clinically significant manner without inducing a disease flare.

1757

DNA Typing of Maternal HLA in Congenital Complete Heart Block: Comparison with Systemic Lupus Erythematosus and Primary Sjogren's Syndrome

Gualtiero Colombo, Antonio Brucato, Elena Coluccio, Silvana Compasso, Cristina Luzzana, Franco Franceschini, Marzia Quinzanini, and Raffaella Scorza

This study investigated which maternal HLA allele or haplotype is primarily associated with isolated CCHB in offspring. Although very frequent in the mothers, HLA-DRB1*03011;DQA1*0501;DQB1*0201 seemed not to be primary CCHB-associated genes, but were involved in a Sjogren's syndrome-like anti-Ro/La response.

1765

Malignant Lymphoma in Primary Sjogren's Syndrome: A Multicenter, Retrospective, Clinical Study by the European Concerted Action on Sjogren's Syndrome

Michalis Voulgarelis, Urania G. Dafni, David A. Isenberg, Haralampos M. Moutsopoulos, and the Members of the European Concerted Action on Sjogren's Syndrome

This report presents the results from a multinational, multicenter study conducted in 9 European centers, designed to characterize malignant non-Hodgkin's lymphoma (MNHL) in primary SS, its evolution, prognosis, and survival. The results presented are based on the largest congregation of MNHL cases in patients with SS to date and should be of particular interest to rheumatologists treating patients with autoimmune disorders.

1773

Hodgkin's Disease and B Cell Lymphoproliferation in Rheumatoid Arthritis Patients Treated with Methotrexate: A Kinetic Study of Lymph Node Changes

Guillaume Chevrel, Francoise Berger, Pierre Miossec, Michel Blanc, Jose Jeanneret, Claude Felman, and Jacques Tebib

1777

Long-Term Remission with Allogenic Bone Marrow Transplantation in Systemic Lupus Erythematosus

Meir Gur-Lavi

1777

Diagnosis of Whipple's Disease by Molecular Analysis of Synovial Fluid

U. Lange and J. Teichmann

1779

Do Infliximab and Methotrexate Act Synergistically in the Treatment of Rheumatoid Arthritis? Comment on the Article by Maini et al

Michael M. Rezaian

1779

Reply

Ravinder N. Maini, Marc Feldmann, and Thomas Schaible

1781

Blindedness in Clinical Trials of Therapies for Rheumatoid Arthritis: Comment on the Article by Bresnihan et al

Wallace V. Epstein

1782

Reply

Barry Bresnihan, Jose Maria Alvaro-Gracia, Mark Cobby, Michael Doherty, Zlatko Domljan, Paul Emery, George Nuki, Karel Pavelka, Rolf Rau, Blaz Rozman, Iain Watt, Bryan Williams, Roger Aitchison, Dorothy McCabe, and Predrag Musikic

1782

Epstein-Barr Virus Infection May Be an Environmental Risk Factor for Systemic Lupus Erythematosus in Children and Teenagers

John B. Harley and Judith A. James

1783

Sequence Features of Monoclonal Antiphospholipid Antibodies: Comment on the Article by Ikematsu et al

Anisur Rahman, David Latchman, and David Isenberg

1784

Clinical Images: Osseous and Subcutaneous Tophus

Fulton F. Velez, Juan-Manuel Anaya, and Jorge Delgado

15A

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