1071

Review: The Genetics Revolution and the Assault on Rheumatoid Arthritis

Michael F. Seldin, Christopher I. Amos, Ryk Ward, and Peter K. Gregersen

1080

Current Comment: Psoriatic Arthritis: A Unified Concept Twenty Years On

Dennis McGonagle, Philip G. Conaghan, and Paul Emery

1087

In Memoriam: James Sydney Stillman, MD, 1908-1998

Ronald Anderson, Matthew Liang, and Peter Schur

1088

Dominant-Negative p53 Mutations in Rheumatoid Arthritis

Zuoning Han, David L. Boyle, Yan Shi, Douglas R. Green, and Gary S. Firestein

The wild-type p53 gene and 2 p53 mutants previously found in rheumatoid arthritis synovium were transfected into HS68 dermal fibroblasts. Both mutants interfered with wild-type p53 function. Since p53 regulates apoptosis, proliferation, and cytokine production, the presence of p53 mutations can alter the function of synovial cells.

1093

Interleukin-1[gb], Interleukin-1 Receptor Antagonist, Interleukin-4, and Interleukin-10 Gene Polymorphisms: Relationship to Occurrence and Severity of Rheumatoid Arthritis

Alain Cantagrel, Frederique Navaux, Patrick Loubet-Lescoulie, Fathi Nourhashemi, Genevieve Enault, Michel Abbal, Arnaud Constantin, Michel Laroche, and Bernard Mazieres

In this study, 6 polymorphisms in 4 cytokine genes were investigated to test if these polymorphisms could identify susceptibility to or severity of RA. Allele frequencies and carriage rates in a normal population were compared with those in a prospective cohort of 108 patients with early RA, followed up over 2 years. Associations were found between RA and a polymorphic IL-4 gene sequence located in 5q31-33, and a polymorphism in IL-1[gb] exon 5 was shown to allow prediction, with a specificity of 91.8%, of erosive disease in 42.1% of patients.

1101

Polymorphic Haplotypes of the Interleukin-10 5` Flanking Region Determine Variable Interleukin-10 Transcription and are Associated with Particular Phenotypes of Juvenile Rheumatoid Arthritis

Esther Crawley, Richard Kay, James Sillibourne, Pritash Patel, Ian Hutchinson, and Patricia Woo

This report describes a correlation between genetic variation of the IL-10 5` flanking region and IL-10 gene expression and extended oligoarthritis in patients with JRA. Studies such as this may ultimately help in predicting the type of clinical course a new patient with JRA may follow and therefore enable appropriate modification of the treatment regimen.

1109

Association of the Course of Collagen-Induced Arthritis with Distinct Patterns of Cytokine and Chemokine Messenger RNA Expression

Sherry Thornton, Laura E. Duwel, Gregory P. Boivin, Yuhe Ma, and Raphael Hirsch

Using the CIA model, the present study identifies distinct patterns of cytokine and chemokine mRNA expression during the development and progression of autoimmune arthritis. These findings may have relevance to the pathophysiology of other autoimmune arthritides, such as rheumatoid arthritis.

1119

Hemoglobin Protects from Streptococcal Cell Wall-Induced Arthritis

Nancy L. McCartney-Francis, Xiao-Yu Song, Diane E. Mizel, Chris L. Wahl, and Sharon M. Wahl

Nitric oxide (NO) has been implicated in the pathogenesis of inflammatory arthritis, and inhibition of NO production reduces synovial inflammation and tissue injury. Systemic administration of hemoglobin, a scavenger of NO, to arthritic rats diminished inflammatory cell accumulation and tissue pathology in the joints. These data offer insight into the role of NO in inflammation and reveal a novel use of NO scavengers as potential therapeutic agents in chronic inflammatory diseases.

1128

Kinetics of Aggrecanase- and Metalloproteinase-Induced Neoepitopes in Various Stages of Cartilage Destruction in Murine Arthritis

Joyce B. J. van Meurs, Peter L. E. M. van Lent, Astrid E. M. Holthuysen, Irwin I. Singer, Ellen K. Bayne, and Wim B. van den Berg

This study shows the kinetic involvement of both MMP and aggrecanase during cartilage degradation in murine arthritis. Aggrecanase neoepitopes were present in normal cartilage, and in elevated amounts during the early stages of proteoglycan depletion and during cartilage repair. MMP neoepitopes were detected only when cartilage damage was well advanced.

1140

Specificity of Inhibition of Matrix Metalloproteinase Activity by Doxycycline: Relationship to Structure of the Enzyme

Gerald N. Smith, Jr., Elizabeth A. Mickler, Karen A. Hasty, and Kenneth D. Brandt

Doxycycline inhibits the activity of some, but not all, MMPs at concentrations near those achieved by oral dosing. Of the collagenases, MMP-1 (collagenase 1) is not inhibited significantly, while MMP-8 (collagenase 2) and MMP-13 (collagenase 3) are inhibited. Studies with full-length and truncated enzymes suggest that doxycycline disrupts the conformation of the hemopexin-like domain of MMP-13 and the catalytic domain of MMP-8.

1147

Collagenase 3 Production by Human Osteoarthritic Chondrocytes in Response to Growth Factors and Cytokines is a Function of the Physiologic State of the Cells

Ginette Tardif, Jean-Pierre Pelletier, Martine Dupuis, ChangShan Geng, Jean-Marie Cloutier, and Johanne Martel-Pelletier

This study demonstrates that the up-regulation of cartilage collagenase 3, one of the most powerful collagenases involved in human OA, is likely to be preferentially driven by transforming growth factor [gb] over other cytokines and growth factors. These data bring new information on the mechanisms involved in the degeneration of OA cartilage.

1159

Treatment with Calcitonin Suppresses the Responses of Bone, Cartilage, and Synovium in the Early Stages of Canine Experimental Osteoarthritis and Significantly Reduces the Severity of the Cartilage Lesions

Daniel-Henri Manicourt, Roy D. Altman, James M. Williams, Jean-Pierre Devogelaer, Anne Druetz-Van Egeren, Mary Ellen Lenz, Daniel Pietryla, and Eugene J.-M. A. Thonar

The results of the present study strongly suggest that bone, synovium, and cartilage all are involved in the state of hypermetabolism that develops in a knee joint following a traumatic joint injury. The findings support the contention that posttraumatic OA is not merely the failure of a single tissue, the cartilage, but the failure of an organ, the joint. Importantly, the results also show that treatment with calcitonin after the injury inhibits the hypermetabolic changes and the extent of cartilage lesions, and may therefore have benefits for humans who recently have had a traumatic knee joint injury.

1168

Production of Type 2 Cytokines by CD8+ Lung Cells is Associated with Greater Decline in Pulmonary Function in Patients with Systemic Sclerosis

Sergei P. Atamas, Vladimir V. Yurovsky, Robert Wise, Fredrick M. Wigley, Carol J. Goter Robinson, Patricia Henry, William J. Alms, and Barbara White

In this study, freshly isolated bronchoalveolar lavage (BAL) cells from SSc patients were more likely to show a type 2 pattern of cytokine messenger RNA (mRNA) than control BAL cells, and CD8+ T cells were the primary source. Patients whose BAL cells showed type 2 cytokine mRNA had a significant decline in forced vital capacity after the BAL, compared with patients whose BAL cells showed type 1 cytokine mRNA. These observations suggest that CD8+ T cells contribute to lung fibrosis in SSc patients through the production of type 2 cytokines.

1179

An Immunodominant Epitope on DNA Topoisomerase I is Conformational in Nature: Heterogeneity in Its Recognition by Systemic Sclerosis Sera

Masataka Kuwana, Junichi Kaburaki, Thomas A. Medsger, Jr., and Timothy M. Wright

An immunodominant epitope recognized by anti-DNA topoisomerase I (topo I) autoantibodies in systemic sclerosis sera was analyzed using 2 different forms of recombinant topo I fragments and synthetic peptides. Ninety-eight of 100 anti-topo I-positive sera reacted with 4 distinct epitopes formed by amino acid residues 489-573 of topo I. The recognition pattern of this region was heterogeneous and influenced by ethnic background.

1189

Polymorphism of [gb]2-Glycoprotein I at Codons 306 and 316 in Patients with Systemic Lupus Erythematosus and Antiphospholipid Syndrome

Francisca C. Gushiken, Frank C. Arnett, Chul Ahn, and Perumal Thiagarajan

The majority of antiphospholipid antibodies associated with a hypercoagulable state in patients with autoimmune disorders bind to a complex epitope consisting of [gb]2-glycoprotein I ([gb]2GPI) bound to anionic phospholipids. Mutations of the [gb]2GPI gene could affect its phospholipid binding properties and be causally related to thrombosis. In these studies, 2 mutations of the [gb]2GPI gene were investigated in a large series of patients with systemic lupus erythematosus and antiphospholipid syndrome. It was found that in patients with SLE, a mutation in exon 8 may predispose to thromboembolic complications.

1194

High-Dose Versus Low-Dose D-Penicillamine in Early Diffuse Systemic Sclerosis: Analysis of a Two-Year, Double-Blind, Randomized, Controlled Clinical Trial

Philip J. Clements, Daniel E. Furst, Weng-Kee Wong, Maureen Mayes, Barbara White, Fredrick Wigley, Michael H. Weisman, Walter Barr, Larry W. Moreland, Thomas A. Medsger, Jr., Virginia Steen, Richard W. Martin, David Collier, Arthur Weinstein, Edward Lally, John Varga, Steven Weiner, Brian Andrews, Micha Abeles, and James R. Seibold

This double-blind, randomized, controlled study of D-Pen showed that the course of changes in the skin score, the occurrence of renal crisis and other organ involvement, and the occurrence of death were not different between the low-dose (125 mg every other day) and the high-dose (1,000 mg every day) groups of SSc patients with recent-onset, diffuse cutaneous scleroderma. Toxicity warranting withdrawal occurred 4 times more commonly in the high-dose group. Both groups had significant improvement in skin thickness. On the basis of the data accrued, low-dose penicillamine cannot be dismissed as being ineffective, but there was no advantage to using a higher dose over the less toxic low dose.

1204

Lack of Efficacy of Oral Bovine Type II Collagen Added to Existing Therapy in Rheumatoid Arthritis

Kevin M. McKown, Laura D. Carbone, Stanley B. Kaplan, Jacob A. Aelion, Kristine M. Lohr, Michael A. Cremer, Juan Bustillo, Miguel Gonzalez, Gurjit Kaeley, Elaine L. Steere, Grant W. Somes, Linda K. Myers, Jerome M. Seyer, Andrew H. Kang, and Arnold E. Postlethwaite

In this study, the efficacy of oral bovine CII when added to existing therapy(ies) for RA was demonstrated. The use of agents such as CII to induce oral tolerance is of great interest to clinicians because of the potential specificity and safety of this form of therapy.

1209

An Assessment of the Annual and Long-Term Direct Costs of Rheumatoid Arthritis: The Impact of Poor Function and Functional Decline

Edward Yelin and Lee A. Wanke

This study establishes contemporary benchmarks for the costs of RA among persons in the care of rheumatologists, information that can help practicing physicians estimate the likely costs to be faced by their patients with this condition. In addition, it is shown that the principal determinant of the direct costs of RA is functional status.

1219

Does Rheumatoid Arthritis Remit During Pregnancy and Relapse Postpartum? Results from a Nationwide Study in the United Kingdom Performed Prospectively from Late Pregnancy

Jennifer H. Barrett, Paul Brennan, Magdalen Fiddler, and Alan J. Silman

This large, partly prospective, study of the influence of pregnancy on RA suggests that there is considerable variability in response. However, the tendency for the disease to improve during pregnancy and relapse postpartum was confirmed.

1228

Excessive Paternal Transmission in Psoriatic Arthritis

Proton Rahman, Dafna D. Gladman, Catherine T. Schentag, and Arturas Petronis

There is a growing list of autoimmune disorders that appear to have a differential expression according to the sex of the affected parent. The present study demonstrates excessive paternal transmission of PsA. The probands were significantly more likely to have an affected father, and a similar trend was noted among the offspring and second-degree relatives of the proband. Further clinical confirmation and elucidation of the genetic basis of this phenomenon is warranted since susceptibility to PsA may involve a gene(s) that is modified during gametogenesis.

1232

Arthritis of the Finger Joints: A Comprehensive Approach Comparing Conventional Radiography, Scintigraphy, Ultrasound, and Contrast-Enhanced Magnetic Resonance Imaging

M. Backhaus, T. Kamradt, D. Sandrock, D. Loreck, J. Fritz, K. J. Wolf, H. Raber, B. Hamm, G.-R. Burmester, and M. Bollow

Among imaging procedures currently used, conventional radiography is the standard of reference for the detection and quantification of joint destruction in arthritis patients. The disadvantage of this method is its lack of sensitivity in detecting early inflammatory changes in these patients. Newer methods may be more sensitive, but their specificity needs to be evaluated. This prospective study compared 4 imaging methods--conventional radiography, 3-phase bone scintigraphy, ultrasound, and magnetic resonance imaging (MRI) with precontrast and dynamic postcontrast examinations--in 60 patients with various forms of arthritis, including rheumatic arthritis, spondylarthropathy, and arthritis associated with connective tissue disease. The data indicate that MRI and ultrasound are valuable diagnostic methods in patients with arthritis who have normal findings on radiologic evaluation.

1246

Larger Increases in Bone Mineral Density During Alendronate Therapy are Associated with a Lower Risk of New Vertebral Fractures in Women with Postmenopausal Osteoporosis

Marc C. Hochberg, Philip D. Ross, Dennis Black, Steven R. Cummings, Harry K. Genant, Michael C. Nevitt, Elizabeth Barrett-Connor, Thomas Musliner, and Desmond Thompson, for the Fracture Intervention Trial Research Group

Participants in a Fracture Intervention Trial received 5 mg/day of the antiresorptive agent alendronate for 2 years, followed by 10 mg/day for the remainder of the study. BMD was measured at baseline, 12 months, and 24 months, and spine radiographs were obtained at baseline and at 36 or 48 months to identify new vertebral fractures. This study shows for the first time that women with the largest increases in BMD during 12 and 24 months of therapy with alendronate have the lowest incidence of new vertebral fractures over 36 or 48 months of followup.

1255

The Role of Parvovirus B19 in the Pathogenesis of Giant Cell Arteritis: A Preliminary Evaluation

Sherine E. Gabriel, Mark Espy, Dean D. Erdman, Johannes Bjornsson, Thomas F. Smith, and Gene G. Hunder

This study identified a statistically significant association between histologic evidence of GCA and the identification of parvovirus B19 in temporal artery biopsy tissue by use of polymerase chain reaction. More research is needed to confirm these intriguing findings.

1259

Musculoskeletal Manifestations in a Population-Based Cohort of Patients with Giant Cell Arteritis

Carlo Salvarani and Gene G. Hunder

In this report, the types, frequencies, response to treatment, and course of musculoskeletal manifestations occurring in giant cell arteritis are described. These include polymyalgia rheumatica, diffuse swelling of the distal extremities with or without pitting edema, tenosynovitis, carpal tunnel syndrome, and acute or chronic arthritis of 1 or more joints; the latter may suggest rheumatoid arthritis.

1267

Reduced Utilization and Cost of Primary Care Clinic Visits Resulting from Self-Care Education for Patients with Osteoarthritis of the Knee

Steven A. Mazzuca, Kenneth D. Brandt, Barry P. Katz, Mark P. Hanna, and Catherine A. Melfi

A controlled trial had previously confirmed the effectiveness of a self-care education intervention for patients with knee OA treated by primary care physicians. This study attempted to determine whether the cost of the intervention was offset by savings resulting from reduced utilization of ambulatory medical services. The findings suggest that, for most patients, the cost of instruction in effective self-care for knee OA may be offset within 12 months due to savings associated with fewer clinic visits.

1274

Ovarian Failure and Flares of Systemic Lupus Erythematosus

Chi Chiu Mok, Raymond Woon Sing Wong, and Chak Sing Lau

In animal models, there is strong evidence that estrogen exacerbates SLE. However, whether administration of exogenous estrogens is associated with disease flares in human SLE remains controversial. This study shows that patients who developed cyclophosphamide-induced ovarian failure did better in terms of disease flares when compared with patients who did not develop menopause after cyclophosphamide treatment. These findings provide clinical evidence to support the notion that a hypoestrogenemic state is protective against disease exacerbation in SLE.

1281

Chlamydia Trachomatis Nucleic Acids Can be Found in the Synovium of Some Asymptomatic Subjects

H. Ralph Schumacher, Jr., Thurayya Arayssi, Marianna Crane, Jennifer Lee, Herve Gerard, Alan P. Hudson, and John Klippel

This unique synovial biopsy survey of totally asymptomatic volunteer subjects with normal joint examination findings shows that Chlamydia trachomatis nucleic acids can occasionally be disseminated to such clinically normal joints. Mild histologic changes were noted, and one subject may now be developing objective evidence of disease. Thus, subtle joint abnormalities may occur without the affected subjects' awareness.

1285

Genetic Risk and Protective Factors for Idiopathic Inflammatory Myopathy in Koreans and American Whites: A Tale of Two Loci

Lisa G. Rider, Ejaz Shamim, Satoshi Okada, Janardan P. Pandey, Ira N. Targoff, Terrance P. O'Hanlon, Hyun-Ah Kim, Yong Seong Lim, Hoon Han, Yeong Wook Song, and Frederick W. Miller

Immune response genes predisposing to and protecting from disease in both US and Korean myositis patients differ at two chromosomal loci. The major genetic risk factors in US white patients are HLA alleles on chromosome 6 that share a common DRB1 first hypervariable region motif. Korean myositis patients have no HLA risk factors, but those without myositis-specific autoantibodies do have a unique protective factor, DRB1*14. The Gm 21 allotype is also a protective factor among Koreans. Multiple genetic loci need to be evaluated to identify genetic risk and protective factors for some autoimmune conditions in different ethnic groups.

1291

An Aggressive Form of Polyarticular Arthritis in a Man with CD154 Mutation (X-Linked Hyper-IgM Syndrome)

Elizabeth A. Webster, Aarif Y. Khakoo, Wendeline J. M. Mackus, Michael Karpusas, David W. Thomas, Anne Davidson, Charles L. Christian, and Seth Lederman

1296

Skin Necrosis in Giant Cell Arteritis

Oliver Distler, Ulf Muller-Ladner, and Thomas Gluck

1297

Plasma Adrenomedullin in Rheumatoid Arthritis Compared with other Rheumatic Diseases

Kazuo Yudoh, Hiroaki Matsuno, and Tomoatsu Kimura

1298

Association of Interleukin-4 Receptor and Interleukin-4 Promoter Gene Polymorphisms with Systemic Lupus Erythematosus

Satomi Kanemitsu, Akira Takabayashi, Yuka Sasaki, Ryuichi Kuromaru, Kenji Ihara, Yoshitugu Kaku, Kouko Sakai, and Toshiro Hara

1300

Anti-[(H2A/2B)-DNA] IgG Supports the Diagnosis of Procainamide-Induced Arthritis or Pleuritis

Chi Chi Lau and Terry Du Clos

1302

Recurrent Acute Calcium Pyrophosphate Dihydrate Arthritis Following Intraarticular Hyaluronate Injection

Eddys Disla, Ricardo Infante, Ahmed Fahmy, Irving Karten, and Girolamo G. Cuppari

1303

Error in Figure in Article by Guerassimov et al (Arthritis Rheum, March 1999)

1304

Detecting Peripheral Nerve Involvement in Rheumatoid Arthritis Patients: Comment on the Article by Lanzillo et al

Stephen Kishner

1304

Reply

B. Lanzillo, C. Crisci, N. Pappone, and C. di Girolamo

1305

Autoantibodies Against Bactericidal/Permeability-Increasing Protein in Cystic Fibrosis Patients: Comment on the Article by Hoffman and Specks

Giovanni Taccetti, Silvia Campana, Lore Marianelli, Elena Procopio, and Stefano Turchini

1307

Severe Exacerbation of Systemic Lupus Erythematosus After Hepatitis B Vaccination and Importance of Pneumococcal Vaccination in Patients with Autosplenectomy: Comment on the Article by Battafarano et al

Jean-Luc Senecal, Carole Bertrand, and Francois Coutlee

1308

Reply

Daniel F. Battafarano and Raymond J. Enzenauer

17A

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